Vaccines Directed To Langerhans Cells

Abstract

The present invention includes isolated anti-Langerin vaccines, methods for making and using an isolated anti-Langerin antibody or binding fragment thereof and one or more antigenic peptides at the carboxy-terminus of the isolated anti-Langerin antibody, wherein when two or more antigenic peptides are present, the peptides are separated by the one or more linker peptides that comprise at least one glycosylation site. The present invention also includes isolated vectors for the expression of the anti-Langerin antigen delivery vectors and their manufactures and use.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Ser. No. 61/242,283, filed Sep. 14, 2009, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates in general to the field of vaccines, and more particularly, to compositions and methods for targeting and delivering antigens to Langerhans cells for antigen presentation using high affinity anti-Langerin monoclonal antibodies and fusion proteins therewith.

INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC

[0004] None.

BACKGROUND OF THE INVENTION

[0005] Without limiting the scope of the invention, its background is described in connection with antigen presentation.

[0006] Dendritic Cells (DCs) are professional antigen-presenting cells (APCs) that induce and sustain immune responses and are fundamental in establishing both tolerance and immunity. DCs capture and present antigens to CD4.sup.+ T cells, which then determine the quantity and quality of antigen-specific CD8.sup.+ T cells. There are subsets of DCs.sup.1,2, including both myeloid and plasmacytoid DCs (mDCs and pDCs, respectively).

[0007] Prior Langerin related agents include those taught in U.S. Pat. No. 6,878,528, issued to Duvert-Frances, et al., which include polynucleotides encoding a mammalian Langerhans cell antigen, including purified mammalian DC cell surface protein, designated Langerin, nucleic acids encoding Langerin, and antibodies which specifically bind Langerin.

[0008] Other anti-DC related agents are taught in, e.g., United States Patent Application Publication No. 20060257412, filed by Bowdish, et al., which includes a method of treating autoimmune disease by inducing antigen presentation by tolerance inducing antigen presenting cells. Briefly, this application teaches that antibodies to antigen presenting cells may be utilized to interfere with the interaction of the antigen presenting cell and immune cells, including T cells. Peptides may be linked to the antibodies thereby generating an immune response to such peptides, e.g., those peptides associated with autoimmunity.

SUMMARY OF THE INVENTION

[0009] In one embodiment, the present invention includes compositions and methods for activating T and B cell responses by targeting antigens to antigen presenting cells along with the proper activation of the APC to activate T cell and B cells responses. One embodiment is a vaccine comprising an isolated anti-Langerin antibody or binding fragment thereof and one or more antigenic peptides at the carboxy-terminus of the anti-Langerin antibody, wherein when two or more antigens are present, they are separated by one or more linker peptides that comprise at least one glycosylation site. In one aspect, the antibody binding fragment is selected from an Fv, Fab, Fab', F(ab').sub.2, Fc, or a ScFv fragment. In another aspect, the antibody comprises one or more complementarity determining regions selected from: ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAYYC (SEQ ID NO.: 48); or a direct equivalent thereof. In another aspect, the antigenic peptide is a cancer antigen selected from: MWVPVVFLTLSVTWIGAAPLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHP QWV (SEQ ID NO.: 9); LTAAHCIRNKSVILLGRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSH D (SEQ ID NO.: 10); LMLLRLSEPAELTDAVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVI S (SEQ ID NO.: 11); NDVCAQVHPQKVTKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALP ERP (SEQ ID NO.: 12); SLYTKVVHYRKWIKDTIVANP (SEQ ID NO.: 13); IMDQVPFSV (SEQ ID NO.: 14); ITDQVPFSV (SEQ ID NO.: 15); YLEPGPVTV (SEQ ID NO.: 16); YLEPGPVTA (SEQ ID NO.: 17); KTWGQYWQV (SEQ ID NO.: 18); APLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHPQWVLTAAHCIRNKSVILL GRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSHDLMLLRLSEPAELTD AVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVISNDVCAQVHPQKV TKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALPERPSLYTKVVHYR KWIKDTIVANP (SEQ ID NO.: 19); DTTEPATPTTPVTTPTTTKVPRNQDWLGVSRQLRTKAWNRQLYPEWTEAQRLDCWRG GQVSLKVSNDGPTLIGANASFSIALNFPGSQKVLPDGQVIWVNNTIINGSQVWGGQPVY PQETDDACIFPDGGPCPSGSWSQKRSFVYVWKTWGQYWQVLGGPVSGLSIGTGRAML GTHTMEVTVYHRRGSQSYVPLAHSSSAFTITDQVPFSVSVSQLRALDGGNKHFLRNQ (SEQ ID NO.: 20); PLTFALQLHDPSGYLAEADLSYTWDFGDSSGTLISRAXVVTHTYLEPGPVTAQVVLQA AIPLTSCGSSPVPAS (SEQ ID NO.: 21); GTTDGHRPTAEAPNTTAGQVPTTEVVGTTPGQAPTAEPSGTTSVQVPTTEVISTAPVQM PTAESTGMTPEKVPVSEVMGTTLAEMSTPEATGMTPAEVSIVVLSGTTAA (SEQ ID NO. 22); QVTTTEWVETTARELPIPEPEGPDASSIMSTESITGSLGPLLDGTATLRLVKRQVPLDCVL YRYGSFSVTLDIVQ (SEQ ID NO.: 23); GIESAEILQAVPSGEGDAFELTVSCQGGLPKEACMEISSPGCQPPAQRLCQPVLPSPACQ LVLHQILKGGSGTYCLNVSLADTNSLAVVSTQLIVPGILLTGQEAGLGQ (SEQ ID NO.: 24); MEMKILRALNFGLGRPLPLHFLRRASKIGEVDVEQHTLAKYLMELTMLDY (SEQ ID NO.: 25); DWLVQVQMKFRLLQETMYMTVSIIDRFMQNNCVPKK (SEQ ID NO.: 26); MEHQLLCCEVETIRRAYPDANLLNDRVLRAMLKAEETCAPSVSYFKCV (SEQ ID NO.: 27); QKEVLPSMRKIVATWMLEVCEEQKCEEEVFPLAMNYLDRFLSLEPVKKSRLQLLGATC MFVASKMKETIPLTAEKLCIYTDNSIRPEELLQMELL (SEQ ID NO.: 28); LVNKLKWNLAAMTPHDFIEHFLSKMPEAEENKQIIRKHAQTFVALCATDVKFISNPPSM V (SEQ ID NO.: 29); or AAGSVVAAVQGLNLRSPNNFLSYYRLTRFLSRVIKCDPDCLRACQEQIEALLESSLRQA QQNMDPKAAEEEEEEEEEVDLACTPTDVRDVDI (SEQ ID NO.: 30), or binding fragments thereof. In another aspect, the antigenic peptide is a viral antigen selected from: VGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGL (SEQ ID NO.: 31); HTQGYFPDWQNYTPGPGVRYPLTFGWLYKL (SEQ ID NO.: 32); EKIRLRPGGKKKYKLKHIV (SEQ ID NO.: 33); NPPIPVGEIYKRWIILGLNKIVRMYSPTSILD (SEQ ID NO.: 34); AIFQSSMTKILEPFRKQNPDIVIYQYMDDLY (SEQ ID NO.: 35); DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDSHNGKLCRLKGIAPLQLGKCNIAG WLLGNPECDPLLPVRSWSYIVETPNSENGICYPGDFIDYEELREQLSSVSSFERFEIFPKES SWPNHNTNGVTAACSHEGKSSFYRNLLWLTEKEGSYPKLKNSYVNKKGKEVLVLWGI HHPPNSKEQQNLYQNENAYVSVVTSNYNRRFTPEIAERPKVRDQAGRMNYYWTLLKP GDTIIFEANGNLIAPMYAFALSRGFGSGIITSNASMHECNTKCQTPLGAINSSLPYQNIHP VTIGECPKYVRSAKLRMV (SEQ ID NO.: 36); DQICIGYHANNSTEQVDTIMEKNTVTHAQDILEKKHNGKLCDLDGVKPLILRDCSVA GWLLGNPMCDEFINVPEWSYIVEKANPVNDLCYPGDFNDYEELKHLLSRINHFEKIQIIP KSSWSSHEASLGVSSACPYQGKSSFFRNVVWLIKKNSTYPTIKRSYNNTNQEDLLVLW GIHHPNDAAEQTKLYQNPTTYISVGTSTLNQRLVPRIATRSKVNGQSGRMEFFWTILKP NDAINFESNGNFIAPEYAYKIVKKGDSTIMKSELEYGNCNTKCQTPMGAINSSMPFHNIH PLTIGECPKYVKSNRLVLA (SEQ ID NO.: 37); or PIVQNIQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTV GGHQAAMQMLKETINEEAAEWDRVHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIG WMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFRDYVDRFYKTLRAEQ ASQEVKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVL (SEQ ID NO.: 38). In another aspect, when two or more antigens are present, the antigens are separated by one or more peptide linkers are selected from: SSVSPTTSVHPTPTSVPPTPTKSSP (SEQ ID NO.: 39); PTSTPADSSTITPTATPTATPTIKG (SEQ ID NO.: 40); TVTPTATATPSAIVTTITPTATTKP (SEQ ID NO.: 41); or TNGSITVAATAPTVTPTVNATPSAA (SEQ ID NO.: 42). In another aspect, the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80 or binding fragments thereof. In another aspect, the anti-Langerin antibody is the expression product of the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79. In another aspect, the anti-Langerin antibody or binding fragment thereof is at least one of 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7 and humanized derivatives thereof. In another aspect, the anti-Langerin antibody or binding fragment thereof and the antigenic peptide are a fusion protein.

[0010] Another embodiment of the present invention includes an isolated nucleic acid vector that expresses an anti-Langerin antibody or binding fragment thereof and two or more antigenic peptides at the carboxy-terminus of the light chain, the heavy chain or both the light and heavy chains of the anti-Langerin antibody, wherein when two or more antigenic peptides are present, the antigenic peptides are separated by the one or more peptide linkers that comprise at least one glycosylation site. In one aspect, the antigenic peptides are cancer peptides selected from tumor associated antigens selected from CEA, prostate specific antigen (PSA), HER-2/neu, BAGE, GAGE, MAGE 1-4, 6 and 12, MUC (Mucin) (e.g., MUC-1, MUC-2, etc.), GM2 and GD2 gangliosides, ras, myc, tyrosinase, MART (melanoma antigen), MARCO-MART, cyclin B1, cyclin D, Pmel 17(gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate Ca psm, prostate serum antigen (PSA), PRAME (melanoma antigen), O-catenin, MUM-1-B (melanoma ubiquitous mutated gene product), GAGE (melanoma antigen) 1, BAGE (melanoma antigen) 2-10, c-ERB2 (Her2/neu), EBNA (Epstein-Barr Virus nuclear antigen) 1-6, gp75, human papilloma virus (HPV) E6 and E7, p53, lung resistance protein (LRP), Bcl-2, and Ki-67. In another aspect, the antigenic peptides are cancer peptides are selected from tumor associated antigens comprising antigens from leukemias and lymphomas, neurological tumors such as astrocytomas or glioblastomas, melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors, gastric cancer, colon cancer, liver cancer, pancreatic cancer, genitourinary tumors such cervix, uterus, ovarian cancer, vaginal cancer, testicular cancer, prostate cancer or penile cancer, bone tumors, vascular tumors, or cancers of the lip, nasopharynx, pharynx and oral cavity, esophagus, rectum, gall bladder, biliary tree, larynx, lung and bronchus, bladder, kidney, brain and other parts of the nervous system, thyroid, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and leukemia. In another aspect, the antigenic peptides are selected from Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain, HLA-A201-FluMP (58-66) peptide (GILGFVFTL) tetramer, Avian Flu (HA5-1), dockerin domain from C. thermocellum (doc), HIV gag p24 (gag), or a string of HIV peptides (Lipo5), PSA (KLQCVDLHV)-tetramer, or an HIVgag-derived p24-PLA. In another aspect, the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80 or binding fragments thereof. In another aspect, the anti-Langerin antibody is the expression product of the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79. In another aspect, the anti-Langerin antibody or binding fragment thereof is at least one of 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7 and humanized derivatives thereof. In another aspect, the anti-Langerin antibody or binding fragment thereof and the antigenic peptide are a fusion protein.

[0011] Yet another embodiment of the present invention includes a method of enhancing T and B cell responses comprising: immunizing a subject in need of vaccination with an effective amount of a vaccine comprising an isolated fusion protein comprising an anti-Langerin antibody or binding portion thereof and one or more antigenic peptides linked to the carboxy-terminus of the anti-Langerin antibody. In one aspect, the antigenic peptides are cancer peptides selected from tumor associated antigens selected from CEA, prostate specific antigen (PSA), HER-2/neu, BAGE, GAGE, MAGE 1-4, 6 and 12, MUC (Mucin) (e.g., MUC-1, MUC-2, etc.), GM2 and GD2 gangliosides, ras, myc, tyrosinase, MART (melanoma antigen), MARCO-MART, cyclin B1, cyclin D, Pmel 17(gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate Ca psm, prostate serum antigen (PSA), PRAME (melanoma antigen), .beta.-catenin, MUM-1-B (melanoma ubiquitous mutated gene product), GAGE (melanoma antigen)1, BAGE (melanoma antigen) 2-10, c-ERB2 (Her2/neu), EBNA (Epstein-Barr Virus nuclear antigen) 1-6, gp75, human papilloma virus (HPV) E6 and E7, p53, lung resistance protein (LRP), Bcl-2, and Ki-67. In another aspect, the antigenic peptides are cancer peptides selected from tumor associated antigens comprising antigens from leukemias, lymphomas, neurological tumors such as astrocytomas or glioblastomas, melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors, gastric cancer, colon cancer, liver cancer, pancreatic cancer, genitourinary tumors such cervix, uterus, ovarian cancer, vaginal cancer, testicular cancer, prostate cancer or penile cancer, bone tumors, vascular tumors, or cancers of the lip, nasopharynx, pharynx and oral cavity, esophagus, rectum, gall bladder, biliary tree, larynx, lung and bronchus, bladder, kidney, brain and other parts of the nervous system, thyroid, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and leukemia. In another aspect, the antigenic peptides are selected from Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain, HLA-A201-FluMP (58-66) peptide (GILGFVFTL) tetramer, Avian Flu (HA5-1), Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain (HA1-1), dockerin domain from C. thermocellum (doc), HIV gag p24 (gag), or a string of HIV peptides (Hipo5), PSA (KLQCVDLHV)-tetramer, or an HIVgag-derived p24-PLA.

[0012] Yet another embodiment is a method of making an anti-Langerin-antigen fusion protein comprising: expressing an isolated fusion protein comprising an anti-Langerin antibody or binding fragment thereof in a host cell, the fusion protein comprising one or more antigenic peptides at the carboxy-terminus of the anti-Langerin antibody or binding fragment thereof, wherein when two or more cancer peptides are present, the cancer peptides are separated by one or more linkers, at least one linker comprising a glycosylation site; and isolating the fusion protein. In one aspect, fusion protein expressed in the host is further isolated and purified. In another aspect, the host is a eukaryotic cell. In another aspect, the antigenic peptides are cancer peptides selected from tumor associated antigens selected from CEA, prostate specific antigen (PSA), HER-2/neu, BAGE, GAGE, MAGE 1-4, 6 and 12, MUC-related protein (Mucin) (MUC-1, MUC-2, etc.), GM2 and GD2 gangliosides, ras, myc, tyrosinase, MART (melanoma antigen), MARCO-MART, cyclin B1, cyclin D, Pmel 17(gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate Ca psm, prostate serum antigen (PSA), PRAME (melanoma antigen), .beta.-catenin, MUM-1-B (melanoma ubiquitous mutated gene product), GAGE (melanoma antigen).sub.1, BAGE (melanoma antigen) 2-10, c-ERB2 (Her2/neu), EBNA (Epstein-Barr Virus nuclear antigen) 1-6, gp75, human papilloma virus (HPV) E6 and E7, p53, lung resistance protein (LRP), Bcl-2, and Ki-67. In another aspect, the antigenic peptides are cancer peptides selected from tumor associated antigens comprising antigens from leukemias and lymphomas, neurological tumors such as astrocytomas or glioblastomas, melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors, gastric cancer, colon cancer, liver cancer, pancreatic cancer, genitourinary tumors such cervix, uterus, ovarian cancer, vaginal cancer, testicular cancer, prostate cancer or penile cancer, bone tumors, vascular tumors, or cancers of the lip, nasopharynx, pharynx and oral cavity, esophagus, rectum, gall bladder, biliary tree, larynx, lung and bronchus, bladder, kidney, brain and other parts of the nervous system, thyroid, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and leukemia. In another aspect, the cancer peptides are selected from at least one of: MWVPVVFLTLSVTWIGAAPLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHP QWV (SEQ ID NO.: 9); LTAAHCIRNKSVILLGRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSH D (SEQ ID NO.: 10); LMLLRLSEPAELTDAVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVI S (SEQ ID NO.: 11); NDVCAQVHPQKVTKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALP ERP (SEQ ID NO.: 12); SLYTKVVHYRKWIKDTIVANP (SEQ ID NO.: 13); IMDQVPFSV (SEQ ID NO.: 14); ITDQVPFSV (SEQ ID NO.: 15); YLEPGPVTV (SEQ ID NO.: 16); YLEPGPVTA (SEQ ID NO.: 17); KTWGQYWQV (SEQ ID NO.: 18); APLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHPQWVLTAAHCIRNKSVILL GRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSHDLMLLRLSEPAELTD AVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVISNDVCAQVHPQKV TKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALPERPSLYTKVVHYR KWIKDTIVANP (SEQ ID NO.: 19); DTTEPATPTTPVTTPTTTKVPRNQDWLGVSRQLRTKAWNRQLYPEWTEAQRLDCWRG GQVSLKVSNDGPTLIGANASFSIALNFPGSQKVLPDGQVIWVNNTIINGSQVWGGQPVY PQETDDACIFPDGGPCPSGSWSQKRSFVYVWKTWGQYWQVLGGPVSGLSIGTGRAML GTHTMEVTVYHRRGSQSYVPLAHSSSAFTITDQVPFSVSVSQLRALDGGNKHFLRNQ (SEQ ID NO.: 20); PLTFALQLHDPSGYLAEADLSYTWDFGDSSGTLISRAXVVTHTYLEPGPVTAQVVLQA AIPLTSCGSSPVPAS (SEQ ID NO.: 21); GTTDGHRPTAEAPNTTAGQVPTTEVVGTTPGQAPTAEPSGTTSVQVPTTEVISTAPVQM PTAESTGMTPEKVPVSEVMGTTLAEMSTPEATGMTPAEVSIVVLSGTTAA (SEQ ID NO.: 22); QVTTTEWVETTARELPIPEPEGPDASSIMSTESITGSLGPLLDGTATLRLVKRQVPLDCVL YRYGSFSVTLDIVQ (SEQ ID NO.: 23); GIESAEILQAVPSGEGDAFELTVSCQGGLPKEACMEISSPGCQPPAQRLCQPVLPSPACQ LVLHQILKGGSGTYCLNVSLADTNSLAVVSTQLIVPGILLTGQEAGLGQ (SEQ ID NO.: 24); MEMKILRALNFGLGRPLPLHFLRRASKIGEVDVEQHTLAKYLMELTMLDY (SEQ ID NO.: 25); DWLVQVQMKFRLLQETMYMTVSIIDRFMQNNCVPKK (SEQ ID NO.: 26); MEHQLLCCEVETIRRAYPDANLLNDRVLRAMLKAEETCAPSVSYFKCV (SEQ ID NO.: 27); QKEVLPSMRKIVATWMLEVCEEQKCEEEVFPLAMNYLDRFLSLEPVKKSRLQLLGATC MFVASKMKETIPLTAEKLCIYTDNSIRPEELLQMELL (SEQ ID NO.: 28); LVNKLKWNLAAMTPHDFIEHFLSKMPEAEENKQIIRKHAQTFVALCATDVKFISNPPSM V (SEQ ID NO.: 29); or AAGSVVAAVQGLNLRSPNNFLSYYRLTRFLSRVIKCDPDCLRACQEQIEALLESSLRQA QQNMDPKAAEEEEEEEEEVDLACTPTDVRDVDI (SEQ ID NO.: 30), or immunogenic fragments thereof.

[0013] In another embodiment, the invention includes a method of expanding antigen-specific T cells or B cells in vitro comprising: isolating peripheral blood mononuclear cells (PBMCs) from a cancer patient; incubating the isolated PBMCs with an immunogenic amount of an isolated anti-Langerin-(PL-Ag)x or anti-Langerin-(Ag-PL)x vaccine, wherein Ag is a tumor associated antigen and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of IL-2; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of anti-cancer specific T cells or B cells.

[0014] In yet another embodiment, the invention includes a tumor associated antigen-specific T cell or B cell made by the method comprising: isolating peripheral blood mononuclear cells (PBMCs) from a cancer patient; incubating the isolated PBMCs with an immunogenic amount of an anti-Langerin-(PL-Ag)x or anti-Langerin-(Ag-PL)x vaccine, wherein Ag is a tumor associated antigen and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of IL-2; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of tumor associated antigen-specific T cells or B cells.

[0015] Another embodiment of the invention includes a therapeutic vaccine comprising an isolated fusion protein comprising the formula: Ab-(PL-Ag)x; Ab-(Ag-PL)x; Ab-(PL-Ag-PL)x; Ab-(Ag-PL-Ag)x; Ab-(PL-Ag)x-PL; or Ab-(Ag-PL)x-Ag; wherein Ab is an anti-Langerin monoclonal antibody or binding fragment thereof; PL is at least one peptide linker comprising at least one glycosylation site; Ag is at least one infectious disease antigen; and x is an integer from 1 to 20.

[0016] Yet another embodiment includes a method of expanding antigen-specific T cells or B cells in vitro comprising: isolating peripheral blood mononuclear cells (PBMCs) from a patient suspected of having an infection; incubating the isolated PBMCs with an immunogenic amount of an isolated anti-Langerin-(PL-Ag)x or .alpha.Langerin-(Ag-PL)x vaccine, wherein Ag is an antigen of the infectious agent and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of one or more cytokines; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of anti-infections agent specific T cells or B cells. Another embodiment is a viral associated antigen-specific T cell or B cell made by the method comprising: isolating peripheral blood mononuclear cells (PBMCs) from a patient suspected of having a viral infection; incubating the isolated PBMCs with an immunogenic amount of an isolated anti-Langerin-(PL-Ag)x or anti-Langerin-(Ag-PL)x vaccine, wherein Ag is a viral associated antigen and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of one or more cytokines; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of viral associated antigen-specific T cells or B cells.

[0017] Another embodiment is a therapeutic vaccine comprising an isolated fusion protein comprising the formula: Ab-(PL-Ag)x; Ab-(Ag-PL)x; Ab-(PL-Ag-PL)x; Ab-(Ag-PL-Ag)x; Ab-(PL-Ag)x-PL; or Ab-(Ag-PL)x-Ag; wherein Ab is an anti-Langerin monoclonal antibody or binding fragment thereof; PL is at least one peptide linker comprising at least one glycosylation site; Ag is at least one viral antigen; and x is an integer from 1 to 20. In one example, the isolated antibody comprising one or more of complementarity determining regions selected from:

ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); or a direct equivalent thereof. In one aspect, the antibody is humanized. In another aspect, the antibody is 15B10 having ATCC Accession No. PTA-9852 and humanized derivatives thereof. In another aspect, the antibody is 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7, and humanized derivatives thereof.

[0018] Yet another embodiment is an isolated isolated nucleic acid that encodes a 15B10, 2G3, 91E7, 37C1, or 4C7 antibody, antibody binding fragment or a humanized derivative thereof. In one aspect, the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80; or binding fragments thereof respectively. In another aspect, the anti-Langerin antibody is the expression product from the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79; or binding fragments thereof, which are the 15B10, 2G3, 91E7, 37C1, or 4C7 antibodies, respectively.

[0019] Yet another embodiment of the present invention is a pharmaceutical composition comprising an isolated anti-Langerin antibody or binding fragment thereof and one or more antigenic peptides attached to the anti-Langerin antibody, wherein when two or more antigens are present, they are separated by one or more linker peptides that comprise at least one glycosylation site. In one aspect, the antibody binding fragment is selected from an Fv, Fab, Fab', F(ab').sub.2, Fc, or a ScFv fragment. In another aspect, the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80 or binding fragments thereof. In another aspect, the anti-Langerin antibody is the expression product of the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79. In another aspect, the anti-Langerin antibody or binding fragment thereof is at least one of 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7 and humanized derivatives thereof. In another aspect, the anti-Langerin antibody or binding fragment thereof and the antigenic peptide are a fusion protein. In another aspect, the composition further comprises an adjuvant. In another aspect, the composition further comprises one or more pharmaceutical excipients.

[0020] Yet another embodiment of the present invention is a therapeutic vaccine comprising a fusion protein comprising the formula: Ab-(PL-Ag)x; Ab-(Ag-PL)x; Ab-(PL-Ag-PL)x; Ab-(Ag-PL-Ag)x; Ab-(PL-Ag)x-PL; or Ab-(Ag-PL)x-Ag; wherein Ab is an anti-Langerin monoclonal antibody or binding fragment thereof; PL is at least one peptide linker comprising at least one glycosylation site; Ag is at least one viral antigen; and x is an integer from 1 to 20.

[0021] The invention provides a Langerin binding antibody (15B10) that comprises at least one immunoglobulin light chain variable domain (VL) which comprises the amino acid and nucleic acid sequence encoding:

ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); or and direct equivalent thereof.

[0022] Accordingly the invention provides a Langerin binding antibody (15B10) that comprises an antigen binding site comprising at least one immunoglobulin heavy chain variable domain (VH) which comprises the amino acid and nucleic acid sequence encoding: SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); and direct equivalents thereof.

[0023] The invention provides a Langerin binding antibody (2G3) that comprises at least one immunoglobulin light chain variable domain (VL) which comprises the amino acid and nucleic acid sequence encoding:

VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); or and direct equivalent thereof.

[0024] Accordingly the invention provides a Langerin binding antibody (2G3) that comprises an antigen binding site comprising at least one immunoglobulin heavy chain variable domain (VH) which comprises the amino acid and nucleic acid sequence encoding:

SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); and direct equivalents thereof.

[0025] In one aspect the invention provides a single domain Langerin antibody comprising an isolated immunoglobulin light chain comprising a heavy chain variable domain (VL) as defined above. In another aspect the invention provides a single domain Langrin binding molecule comprising an isolated immunoglobulin heavy chain comprising a heavy chain variable domain (VH) as defined above.

[0026] In another aspect the invention also provides a Langerin binding antibody comprising a light chain (VL) variable domains in which the Langerin binding antibody comprises at least one antigen binding site comprising: an antibody light chain variable domain (VL) which comprises in sequence hypervariable regions obtained from the amino acid and nucleic acid sequences encoding:

ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); or VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); and direct equivalents thereof.

[0027] In another aspect the invention also provides a Langerin binding antibody comprising, the amino acid and nucleic acid sequences of heavy chain variable domain (VH) which comprises in sequence hypervariable regions obtained from: SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); or SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); and direct equivalents thereof.

[0028] mAnti-Langerin15B10K--Nucleotide and mature protein amino acid sequence of the light chain of the mouse anti-Langerin 15B10 antibody cDNA, respectively. The variable region residues are underlined.

TABLE-US-00001 (SEQ ID NO. 49) ATGAAGTTGCCTGTTAGGCTGTTGGTGCTGATGTTCTGGATTCCTG CTTCCAGCAGTGATGTTGTGATGACCCAAACTCCACTCTCCCTGCC TGTCCGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAG AGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGC AGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAA CCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGG ACAAATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGG GACTTTATTTCTGCTCTCAAAGTACACATGTTCCGTACACGTTCGG AGGGGGGACCAAGCTGGAAATAAAACGGGCTGATGCTGCACCAACT GTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTG CCTCAGTCGTGTGCTTCTTGAACAACTTCTACCCCAAAGACATCAA TGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGCGTCCTG AACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGA ACAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAG CTATACCTGTGAGGCCACTCACAAGACATCAACTTCACCCATCGTC AAGAGCTTCAACAGGAATGAGTGTTAG (SEQ ID NO. 50) DVVMTQTPLSLPVRLGDQASISCRSSQSLVHSNGNTYLHWYLQKPG QSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTLKISRVEAEDLGLYF CSQSTHVPYTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVV CFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMNSTL TLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0029] mAnti-Langerin15B10H-LV-hIgG4H-C--Nucleotide and mature protein amino acid sequence of the heavy chain variable region of the mouse anti-Langerin 15B10 antibody fused to human IgG4, respectively. The variable region residues are underlined.

TABLE-US-00002 (SEQ ID NO. 51) ATGGAATGGAGGATCTTTCTCTTCATCCTGTCAGGAACTGCAGGTG TCCACTCCCAGGTTCAGCTGCGGCAGTCTGGACCTGAGCTGGTGAA GCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACA TTTACTGACTATGTTATAAGTTGGGTGAAGCAGAGAACTGGACAGG GCCTTGAGTGGATTGGAGATATTTATCCTGGAAGTGGTTATTCTTT CTACAATGAGAACTTCAAGGGCAAGGCCACACTGACTGCAGACAAA TCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGG ACTCTGCGGTCTATTTCTGTGCAACCTACTATAACTACCCTTTTGC TTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACA ACGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCT CCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGAC CTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAG CACCTGAGTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAA ACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGC GTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACT GGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCG GGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGG TCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAA AGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCA TCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGG TCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGA GCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTG GGTAAAGCTAGCTGA (SEQ ID NO. 52) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLE WIGDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSA VYFCATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPE FEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGKAS

[0030] mAnti-Langerin2G3L--Nucleotide and mature protein amino acid sequence of the light chain of the mouse anti-Langerin 2G3 antibody cDNA, respectively. The variable region residues are underlined.

TABLE-US-00003 (SEQ ID NO. 53) ATGGCCTGGATTTCACTTATACTCTCTCTCCTGGCTCTCAGCTCAGGG GCCATTTCCCAGGCTGTTGTGACTCAGGAATCTGCACTCACCACATCA CCTGGTGAAACAGTCACACTCACTTGTCGCTCAAGTACTGGGGCTGTT ACAACTAGTAACTATGCCAACTGGGTCCAAGAAAAACCAGATCATTTA TTCACTGGTCTAATAGGTGGTACCAACAACCGAGTTTCAGGTGTTCCT GCCAGATTCTCAGGCTCCCTGATTGGAGACAAGGCTGCCCTCACCATC ACAGGGGCACAGACTGAGGATGAGGCAATATATTTCTGTGCTCTATGG TACAGCAACCATTGGGTGTTCGGTGGAGGAACCAAACTGACTGTCCTA GGCCAGCCCAAGTCTTCGCCATCAGTCACCCTGTTTCCACCTTCCTCT GAAGAGCTCGAGACTAACAAGGCCACACTGGTGTGTACGATCACTGAT TTCTACCCAGGTGTGGTGACAGTGGACTGGAAGGTAGATGGTACCCCT GTCACTCAGGGTATGGAGACAACCCAGCCTTCCAAACAGAGCAACAAC AAGTACATGGCTAGCAGCTACCTGACCCTGACAGCAAGAGCATGGGAA AGGCATAGCAGTTACAGCTGCCAGGTCACTCATGAAGGTCACACTGTG GAGAAGAGTTTGTCCCGTGCTGACTGTTCCTAG (SEQ ID NO. 54) QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTG LIGGTNNRVSGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSN HWVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYP GVVTVDWKVDGT PVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHT VEKSLSRADCS

[0031] mAnti-Langerin2G3H--Nucleotide and mature protein amino acid sequence of the heavy chain of the mouse anti-Langerin 2G3 antibody cDNA, respectively. The variable region residues are underlined.

TABLE-US-00004 (SEQ ID NO. 55) ATGACATTGAACATGCTGTTGGGGCTGAAGTGGGTTTTCTTTGTTGTT TTTTATCAAGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGA GGATTGGTGCAGCCTAAAGGGTCATTGAAACTCTCATGTGCAGCCTCT GGATTAACCTTCAATATCTACGCCATGAACTGGGTCCGCCAGGCTCCA GGAAAGGGTTTGGAATGGGTTGCTCGCATAAGAAATAAAAGTAATAAT TATGCAACATATTATGCCGATTCAGTGAAAGACAGGTTCACCATCTCC AGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAACTTGAAA ACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGACA CCCCCATCTGTCTATCCACTGGCCCCTGGATCTGCTGCCCAAACTAAC TCCATGGTGACCCTGGGATGCCTGGTCAAGGGCTATTTCCCTGAGCCA GTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGCGGTGTGCACACC TTCCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTCAGTG ACTGTCCCCTCCAGCACCTGGCCCAGCGAGACCGTCACCTGCAACGTT GCCCACCCGGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGG GATTGTGGTTGTAAGCCTTGCATATGTACAGTCCCAGAAGTATCATCT GTCTTCATCTTCCCCCCAAAGCCCAAGGATGTGCTCACCATTACTCTG ACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGGATGATCCC GAGGTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCT CAGACGCAACCCCGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTC AGTGAACTTCCCATCATGCACCAGGACTGGCTCAATGGCAAGGAGTTC AAATGCAGGGTCAACAGTGCAGCTTTCCCTGCCCCCATCGAGAAAACC ATCTCCAAAACCAAAGGCAGACCGAAGGCTCCACAGGTGTACACCATT CCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTGACCTGC ATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGG AATGGGCAGCCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGAC ACAGATGGCTCTTACTTCGTCTACAGCAAGCTCAATGTGCAGAAGAGC AACTGGGAGGCAGGAAATACTTTCACCTGCTCTGTGTTACATGAGGGC CTGCACAACCACCATACTGAGAAGAGCCTCTCCCACTCTCCTGGTAAA GCTAGCTGA (SEQ ID NO. 56) EVQLVESGGGLVQPKGSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWV ARIRNKSNNYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMY YCVGRDWFDYWGQGTLVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGC LVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTW PSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPK PKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREE QFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGR PKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAEN YKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTE KSLSHSPGKAS

[0032] In another embodiment the invention includes an antibody comprising one or more of the complementarity determining regions selected from:

ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45);

SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46);

VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47);

[0033] SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); or a direct equivalent thereof. In one aspect, the antibody is humanized. In another aspect, the antibody is 15B10, 2G3 or humanized derivatives thereof. In another aspect, the invention includes nucleic acids that encode the 15B10, the 2G3 antibody or humanized derivatives thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which:

[0035] FIG. 1 shows that two main DC differentiation pathways exist. A myeloid pathway generates two subsets: Langerhans cells (LCs) found in stratified epithelia such as the skin, and interstitial DCs (intDCs) found in all other tissues.

[0036] FIG. 2 shows that recombinant anti-Langerin antibodies fused to antigens retain their ability to bind to cell surface Langerin.

[0037] FIG. 3 is a demonstration of the ability of recombinant anti-Langerin antibody fused to the human prostate specific cancer antigen to elicit the expansion of antigen-specific CD4+T cells from a health donor.

[0038] FIG. 4 is a demonstration of the ability of recombinant anti-Langerin antibody fused to the human prostate specific cancer antigen to elicit the expansion of antigen-specific CD8+T cells from a prostate cancer patient.

[0039] FIG. 5 shows that anti-Langerin preferentially targets epidermal LCs.

[0040] FIG. 6 shows the differential expression of Langerin by human skin DCs.

[0041] FIG. 7 shows that the anti-Langerin antibody (15B10) specifically stains human Langerhans cells.

[0042] FIG. 8 shows the binding results of the anti-Langerin antibodies against a non-human primate target.

[0043] FIG. 9 shows the ability of recombinant anti-Langerin 15B10 antibody fused to Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain to evoke potent antigen-specific antibody production in NHP.

[0044] FIG. 10 shows that recombinant fusion proteins of anti-human DC receptors and antigens induce antigen-specific immune responses in NHP.

[0045] FIG. 11 shows that the Anti-Langerin G3 antibody specifically stains NHP Langerhans cells.

[0046] FIG. 12 shows the antibody titers for anti-HIV-gag antibodies in NHP vaccination with a gag-microparticle, an anti-hIGG4-gag antibody, an anti-DCIR-gag vaccine and an anti-Langerin-gag-p24 vaccine, all with or without poly I:C as an adjuvant.

[0047] FIG. 13 shows FACS analysis on Langerin clones: 293F cells were transiently transfected with vectors directing the expression of full-length (cell surface) Langerin from human, Rhesus macaque, and mouse.

[0048] FIG. 14 show the results of ELISA binding analysis in two formats--direct (antigen bound to plate directly and bound antibody detected with an anti-mouse IgG-HRP conjugate) and capture (antibody bound to plate.

DETAILED DESCRIPTION OF THE INVENTION

[0049] While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.

[0050] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as "a", "an" and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

[0051] Subsets of Dendritic Cells (DCs). The present inventors have discovered that two main DC differentiation pathways exist. A myeloid pathway generates two subsets: Langerhans cells (LCs) found in stratified epithelia such as the skin, and interstitial DCs (intDCs) found in all other tissues. A plasmacytoid pathway generates plasmacytoid DCs (pDCs), which secrete large amounts of IFN.alpha..beta. after viral infection.sup.3 and efficiently present viral antigens in a novel mechanism.sup.4 (FIG. 1). DCs and their precursors show remarkable functional plasticity. For example, pDCs form a first barrier to the expansion of intruding viruses, thereby acting, through the release of interferon, as part of the innate immune response.sup.5,6. Monocytes can differentiate into either macrophages, which act as scavengers, or DCs that induce specific immune responses.sup.7,8. Different cytokines skew the in vitro differentiation of monocytes into DCs with different phenotypes and functions. Thus, when activated (e.g., by GM-CSF) monocytes encounter IL-4, they yield IL-4DCs.sup.9-11. By contrast, after encountering IFN.alpha., TNF.alpha., or IL-15, activated monocytes will differentiate into IFNDCs.sup.12-15, TNFDCs.sup.8, or IL-15DCs.sup.16. Each of these DC subsets has common as well as unique biological functions, determined by a unique combination of cell-surface molecules and cytokines For example, whereas IL-4DCs are a homologous population of immature cells devoid of LCs, large portions of IFNDCs express CD1a and Langerin.sup.8.

[0052] The invention includes also variants and other modification of an antibody (or "Ab") of fragments thereof, e.g., anti-Langerin fusion protein (antibody is used interchangeably with the term "immunoglobulin"). As used herein, the term "antibodies or binding fragments thereof," includes whole antibodies or binding fragments of an antibody, e.g., Fv, Fab, Fab', F(ab').sub.2, Fc, and single chain Fv fragments (ScFv) or any biologically effective fragments of an immunoglobulins that binds specifically to, e.g., Langerin. Antibodies from human origin or humanized antibodies have lowered or no immunogenicity in humans and have a lower number or no immunogenic epitopes compared to non-human antibodies. Antibodies and their fragments will generally be selected to have a reduced level or no antigenicity in humans.

[0053] As used herein, the terms "Ag" or "antigen" refer to a substance capable of either binding to an antigen binding region of an immunoglobulin molecule or of eliciting an immune response, e.g., a T cell-mediated immune response by the presentation of the antigen on Major Histocompatibility Antigen (MHC) cellular proteins. As used herein, "antigen" includes, but is not limited to, antigenic determinants, haptens, and immunogens, which may be peptides, small molecules, carbohydrates, lipids, nucleic acids or combinations thereof. The skilled immunologist will recognize that when discussing antigens that are processed for presentation to T cells, the term "antigen" refers to those portions of the antigen (e.g., a peptide fragment) that is a T cell epitope presented by MHC to the T cell receptor. When used in the context of a B cell mediated immune response in the form of an antibody that is specific for an "antigen", the portion of the antigen that binds to the complementarity determining regions of the variable domains of the antibody (light and heavy) the bound portion may be a linear or three-dimensional epitope. In the context of the present invention, the term antigen is used on both contexts, that is, the antibody is specific for a protein antigen (Langerin), but also carries one or more peptide epitopes for presentation by MHC to T cells. In certain cases, the antigens delivered by the vaccine or fusion protein of the present invention are internalized and processed by antigen presenting cells prior to presentation, e.g., by cleavage of one or more portions of the antibody or fusion protein.

[0054] As used herein, the term "antigenic peptide" refers to that portion of a polypeptide antigen that is specifically recognized by either B-cells or T-cells. B-cells respond to foreign antigenic determinants via antibody production, whereas T-lymphocytes are the mediate cellular immunity. Thus, antigenic peptides are those parts of an antigen that are recognized by antibodies, or in the context of an MHC, by T-cell receptors.

[0055] As used herein, the term "epitope" refers to any protein determinant capable of specific binding to an immunoglobulin or of being presented by a Major Histocompatibility Complex (MHC) protein (e.g., Class I or Class II) to a T-cell receptor. Epitopic determinants are generally short peptides 5-30 amino acids long that fit within the groove of the MHC molecule that presents certain amino acid side groups toward the T cell receptor and has certain other residues in the groove, e.g., due to specific charge characteristics of the groove, the peptide side groups and the T cell receptor. Generally, an antibody specifically binds to an antigen when the dissociation constant is 1 mM, 100 nM or even 10 nM.

[0056] As used herein, the term "vector" is used in two different contexts. When using the term "vector" with reference to a vaccine, a vector is used to describe a non-antigenic portion that is used to direct or deliver the antigenic portion of the vaccine. For example, an antibody or binding fragments thereof may be bound to or form a fusion protein with the antigen that elicits the immune response. For cellular vaccines, the vector for delivery and/or presentation of the antigen is the antigen presenting cell, which is delivered by the cell that is loaded with antigen. In certain cases, the cellular vector itself may also process and present the antigen(s) to T cells and activate an antigen-specific immune response. When used in the context of nucleic acids, a "vector" refers a construct that is capable of delivering, and preferably expressing, one or more genes or polynucleotide sequences of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

[0057] The compositions and methods of the present invention can be used with a wide variety of peptides and/or protein in which the antibody or binding fragment thereof and the peptide linker or "PL" create a protein that is stable and/or soluble.

[0058] As used herein, the compositions and methods use an anti-Langerin antigen delivery vector comprising the formula:

Ab-(PL-Ag)x or Ab-(Ag-PL)x;

wherein Ab is an anti-Langerin antibody or binding fragment thereof; PL is at least one Peptide Linker comprising at least one glycosylation site; Ag is at least one antigen; and x is an integer from 1 to 20.

[0059] As used herein, the terms "stable" and "unstable" when referring to proteins is used to describe a peptide or protein that maintains its three-dimensional structure and/or activity (stable) or that loses immediately or over time its three-dimensional structure and/or activity (unstable). As used herein, the term "insoluble" refers to those proteins that when produced in a cell (e.g., a recombinant protein expressed in a eukaryotic or prokaryotic cell or in vitro) are not soluble in solution absent the use of denaturing conditions or agents (e.g., heat or chemical denaturants, respectively). The antibody or binding fragment thereof and the linkers taught herein have been found to convert antibody fusion proteins with the peptides from insoluble and/or unstable into proteins that are stable and/or soluble. Another example of stability versus instability is when the domain of the protein with a stable conformation has a higher melting temperature (T.sub.m) than the unstable domain of the protein when measured in the same solution. A domain is stable compared to another domain when the difference in the T.sub.m is at least about 2.degree. C., more preferably about 4.degree. C., still more preferably about 7.degree. C., yet more preferably about 10.degree. C., even more preferably about 15.degree. C., still more preferably about 20.degree. C., even still more preferably about 25.degree. C., and most preferably about 30.degree. C., when measured in the same solution.

[0060] As used herein, "polynucleotide" or "nucleic acid" refers to a strand of deoxyribonucleotides or ribonucleotides in either a single- or a double-stranded form (including known analogs of natural nucleotides). A double-stranded nucleic acid sequence will include the complementary sequence. The polynucleotide sequence may encode variable and/or constant region domains of immunoglobulin that are formed into a fusion protein with one or more linkers. For use with the present invention, multiple cloning sites (MCS) may be engineered into the locations at the carboxy-terminal end of the heavy and/or light chains of the antibodies to allow for in-frame insertion of peptide for expression between the linkers. As used herein, the term "isolated polynucleotide" refers to a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof. By virtue of its origin the "isolated polynucleotide" (1) is not associated with all or a portion of a polynucleotide in which the "isolated polynucleotides" are found in nature, (2) is operably linked to a polynucleotide which it is not linked to in nature, or (3) does not occur in nature as part of a larger sequence. The skilled artisan will recognize that to design and implement a vector having the formula Ab-(PL-Ag)x or Ab-(Ag-PL)x, can be manipulated at the nucleic acid level by using techniques known in the art, such as those taught in Current Protocols in Molecular Biology, 2007 by John Wiley and Sons, relevant portions incorporated herein by reference. Briefly, the Ab, Ag and PL encoding nucleic acid sequences can be inserted using polymerase chain reaction, enzymatic insertion of oligonucleotides or polymerase chain reaction fragments in a vector, which may be an expression vector. To facilitate the insertion of (PL-Ag)x or (Ag-PL)x at the carboxy terminus of the antibody light chain, the heavy chain, or both, a multiple cloning site (MCS) may be engineered in sequence with the antibody sequences.

[0061] As used herein, the term "polypeptide" refers to a polymer of amino acids and does not refer to a specific length of the product; thus, peptides, oligopeptides, and proteins are included within the definition of polypeptide. This term also does not refer to or exclude post expression modifications of the polypeptide, for example, glycosylations, acetylations, phosphorylations and the like. Included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), polypeptides with substituted linkages, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. The term "domain," or "polypeptide domain" refers to that sequence of a polypeptide that folds into a single globular region in its native conformation, and that may exhibit discrete binding or functional properties. As used herein, the term "fusion protein" refers to a hybrid protein expressed by a nucleic acid molecule comprising nucleotide sequences of at least two genes into a protein. For example, a fusion protein can comprise at least part of anti-Langerin antibody or binding fragment thereof fused with one or more antigen and/or one or more linkers if more than one antigen is fused with the antibody or fragment thereof.

[0062] A polypeptide or amino acid sequence "derived from" a designated nucleic acid sequence refers to a polypeptide having an amino acid sequence identical to that of a polypeptide encoded in the sequence, or a portion thereof wherein the portion consists of at least 3-5 amino acids, preferably at least 4-7 amino acids, more preferably at least 8-10 amino acids, and even more preferably at least 11-15 amino acids, or which is immunologically identifiable with a polypeptide encoded in the sequence. This terminology also includes a polypeptide expressed from a designated nucleic acid sequence.

[0063] As used herein, "pharmaceutically acceptable carrier" refers to any material that when combined with an immunoglobulin (Ig) fusion protein of the present invention allows the Ig to retain biological activity and is generally non-reactive with the subject's immune system. Examples include, but are not limited to, standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as an oil/water emulsion, and various types of wetting agents. Certain diluents may be used with the present invention, e.g., for aerosol or parenteral administration, that may be phosphate buffered saline or normal (0.85%) saline.

[0064] The invention provides a Langerin binding antibody (15B10) that comprises at least one immunoglobulin light chain variable domain (VL) which comprises the amino acid and nucleic acid sequence encoding:

ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); or and direct equivalent thereof.

[0065] Accordingly the invention provides a Langerin binding antibody (15B10) that comprises an antigen binding site comprising at least one immunoglobulin heavy chain variable domain (VH) which comprises the amino acid and nucleic acid sequence encoding:

SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); and direct equivalents thereof.

[0066] The invention provides a Langerin binding antibody (2G3) that comprises at least one immunoglobulin light chain variable domain (VL) which comprises the amino acid and nucleic acid sequence encoding:

VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); or and direct equivalent thereof.

[0067] Accordingly the invention provides a Langerin binding antibody (2G3) that comprises an antigen binding site comprising at least one immunoglobulin heavy chain variable domain (VH) which comprises the amino acid and nucleic acid sequence encoding:

SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); and direct equivalents thereof.

[0068] In one aspect the invention provides a single domain Langerin antibody comprising an isolated immunoglobulin light chain comprising a heavy chain variable domain (VL) as defined above. In another aspect the invention provides a single domain Langerin binding molecule comprising an isolated immunoglobulin heavy chain comprising a heavy chain variable domain (VH) as defined above.

[0069] In another aspect the invention also provides a Langerin binding antibody comprising a light chain (VL) variable domains in which the Langerin binding antibody comprises at least one antigen binding site comprising: an antibody light chain variable domain (VL) which comprises in sequence hypervariable regions obtained from the amino acid and nucleic acid sequences encoding:

ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); or VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); and direct equivalents thereof.

[0070] In another aspect the invention also provides a Langerin binding antibody comprising, the amino acid and nucleic acid sequences of heavy chain variable domain (VH) which comprises in sequence hypervariable regions obtained from: SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); or SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); and direct equivalents thereof.

[0071] Unless otherwise indicated, any polypeptide chain is herein described as having an amino acid sequence starting at the N-terminal end and ending at the C-terminal end. When the antigen binding site comprises both the VH and VL domains, these may be located on the same polypeptide molecule or, preferably, each domain may be on a different chain, the VH domain being part of an immunoglobulin heavy chain or binding fragment thereof and the VL being part of an immunoglobulin light chain or binding fragment thereof.

[0072] As used herein, the term "Langerin binding molecule" or "Langerin binding antibody" refer to any molecule capable of binding to the Langerin antigen either alone or associated with other molecules having one or more the VL and VH CDRs taught herein, in some cases 2, 3, 4, 5, or all 6 CDRs. The binding reaction may be shown by standard methods (qualitative assays) including, for example, a bioassay for determining by blocking the binding of other molecules to Langerin or any kind of binding or activity assays (e.g., activation, reduction or modulation of an immune response), with reference to a negative control test in which an antibody of unrelated specificity but of the same isotype, e.g., an anti-CD25 or anti-CD80 antibody, is used.

[0073] The present invention may also be made into a single chain antibody having the variable domains of the heavy and light chains of an antibody covalently bound by a peptide linker usually including from 10 to 30 amino acids, preferably from 15 to 25 amino acids. Therefore, such a structure does not include the constant part of the heavy and light chains and it is believed that the small peptide spacer should be less antigenic than a whole constant part.

[0074] As used herein, the term "chimeric antibody" refers to an antibody in which the constant regions of heavy or light chains or both are of human origin while the variable domains of both heavy and light chains are of non-human (e.g., mouse, hamster or rat) origin or of human origin but derived from a different human antibody.

[0075] As used herein, the term "CDR-grafted antibody" refers to an antibody in which the hypervariable complementarity determining regions (CDRs) are derived from a donor antibody, such as a non-human (e.g., mouse) antibody or a different human antibody, while all or substantially all the other parts of the immunoglobulin (e.g., the conserved regions of the variable domains, i.e., framework regions), are derived from an acceptor antibody (in the case of a humanized antibody--an antibody of human origin). A CDR-grafted antibody may include a few amino acids of the donor sequence in the framework regions, for instance in the parts of the framework regions adjacent to the hypervariable regions.

[0076] As used herein, the term "human antibody" refers to an antibody in which the constant and variable regions of both the heavy and light chains are all of human origin, or substantially identical to sequences of human origin, not necessarily from the same antibody and includes antibodies produced by mice in which the mouse, hamster or rat immunoglobulin variable and constant part genes have been replaced by their human counterparts, e.g. as described in general terms in EP 0546073 B1, U.S. Pat. No. 5,545,806, U.S. Pat. No. 5,569,825, U.S. Pat. No. 5,625,126, U.S. Pat. No. 5,633,425, U.S. Pat. No. 5,661,016, U.S. Pat. No. 5,770,429, EP Patent No. 0 438-474 B1 and EP Patent No. 0 463151 B1, relevant portions incorporated herein by reference.

[0077] The Langerin binding antibodies of the invention include humanized antibodies that comprise the CDRs obtained from the anti-Langerin 15B10 or 2G3 antibody. One example of a chimeric antibody includes the variable domains of both heavy and light chains are of human origin, for instance those of the anti-Langerin 15B10 or 2G3 antibody. The constant region domains preferably also comprise suitable human constant region domains, for instance as described in "Sequences of Proteins of Immunological Interest", Kabat E. A. et al, US Department of Health and Human Services, Public Health Service, National Institute of Health.

[0078] Hypervariable regions may be associated with any kind of framework regions, e.g., of human origin. Suitable framework regions were described Kabat E. A. One heavy chain framework is a heavy chain framework, for instance those of the anti-Langerin 15B10 or 2G3 antibody, includes sequences for the light chain framework regions: FR1L, FR2L, FR3L and

[0079] FR4L regions. In a similar manner, the anti-Langerin 15B10 or 2G3 heavy chain framework that includes the sequence of FR1H, FR2H, FR3H and FR4H regions. The CDRs may be added to a human antibody framework, such as those described in 7,456,260, issued to Rybak, et al., which teach new human variable chain framework regions and humanized antibodies comprising the framework regions, relevant portions and framework sequences incorporated herein by reference. To accomplish the engraftment at a genetic level, the present invention also includes the underlying nucleic acid sequences for the VL AND VH regions as well as the complete antibodies and the humanized versions thereof. The nucleic acid sequences of the present invention include the anti-Langerin antibody light and the heavy chains, respectively, as well as those nucleic acid sequences that include variable codon usage for the same amino acid sequences and conservative variations thereof having 85, 90, 95 or 100% sequence identity at the nucleic or amino acid level. Likewise, the CDRs may have 85, 90, 95 or 100% sequence identity at the nucleic or amino acid level, individually, in groups or 2, 3, 4 or 5 or all together.

[0080] Monoclonal antibodies raised against a protein naturally found in all humans are typically developed in a non-human system e.g. in mice, and as such are typically non-human proteins. As a direct consequence of this, a xenogenic antibody as produced by a hybridoma, when administered to humans, elicits an undesirable immune response that is predominantly mediated by the constant part of the xenogenic immunoglobulin. Xenogeneic antibodies tend to elicit a host immune response, thereby limiting the use of such antibodies as they cannot be administered over a prolonged period of time. Therefore, it is particularly useful to use single chain, single domain, chimeric, CDR-grafted, or especially human antibodies that are not likely to elicit a substantial allogenic response when administered to humans. The present invention includes antibodies with minor changes in an amino acid sequence such as deletion, addition or substitution of one, a few or even several amino acids which are merely allelic forms of the original protein having substantially identical properties.

[0081] The inhibition of the binding of Langerin to its receptor may be conveniently tested in various assays including such assays are described hereinafter in the text. By the term "to the same extent" is meant that the reference and the equivalent molecules exhibit, on a statistical basis, essentially identical Langerin binding inhibition curves in one of the assays referred to above. For example, the assay used may be an assay of competitive inhibition of binding of Langerin by the binding molecules of the invention.

[0082] Generally, the human anti-Langerin antibody comprises at least: (a) one light chain which comprises a variable domain having an amino acid sequence substantially identical to the 15B10 or 2G3 antibody starting with the amino acid at position 1 and ending with the amino acid at position 107 and the constant part of a human light chain; and (b) one heavy chain which comprises a variable domain having an amino acid sequence substantially identical to the 15B10 or 2G3 antibody and the constant part of a human heavy chain. The constant part of a human heavy chain may be of the .gamma.1, .gamma.2, .gamma.3, .gamma.4, .mu., .beta.2, or .delta. or .epsilon. type, preferably of the .gamma.-type, whereas the constant part of a human light chain may be of the .kappa. or .lamda. type (which includes the .lamda.1, .lamda.2 and .lamda.3 subtypes) but is preferably of the .kappa. type. The amino acid sequences of the general locations of the variable and constant domains are well known in the art and generally follow the Kabat nomenclature.

[0083] A Langerin binding molecule of the invention may be produced by recombinant DNA techniques. In view of this, one or more DNA molecules encoding the binding molecule must be constructed, placed under appropriate control sequences and transferred into a suitable host organism for expression.

[0084] In a very general manner, there are accordingly provided: (i) DNA molecules encoding a single domain Langerin binding molecule of the invention, a single chain Langerin binding molecule of the invention, a heavy or light chain or binding fragments thereof of a Langerin binding molecule of the invention; and (ii) the use of the DNA molecules of the invention for the production of a Langerin binding molecule of the invention by recombinant methods.

[0085] The present state of the art is such that the skilled worker in the art can synthesize the DNA molecules of the invention given the information provided herein, i.e., the amino acid sequences of the hypervariable regions and the DNA sequences coding for them. A method for constructing a variable domain gene is for example described in EPA 239 400, relevant portions incorporated herein by reference. Briefly, a gene encoding a variable domain of a MAb is cloned. The DNA segments encoding the framework and hypervariable regions are determined and the DNA segments encoding the hypervariable regions are removed so that the DNA segments encoding the framework regions are fused together with suitable restriction sites at the junctions. The restriction sites may be generated at the appropriate positions by mutagenesis of the DNA molecule by standard procedures. Double stranded synthetic CDR cassettes are prepared by DNA synthesis according to the sequences given in for 15B10 or 2G3 (amino acid and nucleic acid sequences, respectively). These cassettes are often provided with sticky ends so that they can be ligated at the junctions of the framework.

[0086] It is not necessary to have access to the mRNA from a producing hybridoma cell line in order to obtain a DNA construct coding for the Langerin binding molecules of the invention. For example, PCT application WO 90/07861 gives full instructions for the production of an antibody by recombinant DNA techniques given only written information as to the nucleotide sequence of the gene, relevant portions incorporated herein by reference. Briefly, the method comprises the synthesis of a number of oligonucleotides, their amplification by the PCR method, and their splicing to give the desired DNA sequence.

[0087] Expression vectors comprising a suitable promoter or genes encoding heavy and light chain constant parts are publicly available. Thus, once a DNA molecule of the invention is prepared it may be conveniently transferred in an appropriate expression vector. DNA molecules encoding single chain antibodies may also be prepared by standard methods, for example, as described in WO 88/1649. In view of the foregoing, no hybridoma or cell line deposit is necessary to comply with the criteria of sufficiency of description.

[0088] For example, first and second DNA constructs are made that bind specifically to Langerin. Briefly, a first DNA construct encodes a light chain of an antibody, CDRs or binding fragments thereof and comprises a) a first part which encodes a variable domain comprising alternatively framework and hypervariable regions, the hypervariable regions being in sequence CDR1L, CDR2L and CDR3L the amino acid sequences of which are found in SEQ ID NOs. 45-48; this first part starting with a codon encoding the first amino acid of the variable domain and ending with a codon encoding the last amino acid of the variable domain, and b) a second part encoding a light chain constant part or binding fragment thereof which starts with a codon encoding the first amino acid of the constant part of the heavy chain and ends with a codon encoding the last amino acid of the constant part or binding fragment thereof, followed by a stop codon.

[0089] The first part encodes a variable domain having an amino acid sequence substantially identical to the amino acid sequences of 15B10 or 2G3. A second part encodes the constant part of a human heavy chain, more preferably the constant part of the human yl chain. This second part may be a DNA fragment of genomic origin (comprising introns) or a cDNA fragment (without introns).

[0090] The second DNA construct encodes a heavy chain or binding fragment thereof and comprises a) a first part which encodes a variable domain comprising alternatively framework and hypervariable regions; the hypervariable regions being CDR1H and optionally CDR2H and CDR3H, the amino acid sequences of 15B10 or 2G3; this first part starting with a codon encoding the first amino acid of the variable domain and ending with a codon encoding the last amino acid of the variable domain, and b) a second part encoding a heavy chain constant part or binding fragment thereof which starts with a codon encoding the first amino acid of the constant part of the light chain and ends with a codon encoding the last amino acid of the constant part or binding fragment thereof followed by a stop codon.

[0091] The first part encodes a variable domain having an amino acid sequence substantially identical to the amino acid sequence of 15B10 or 2G3. The first part has the nucleotide sequence of the 15B10 or 2G3 antibodies starting with the nucleotide at position 1 and ending with the nucleotide at position 321. Also preferably the second part encodes the constant part of a human light chain, more preferably the constant part of the human .kappa. chain.

[0092] The invention also includes Langerin binding molecules in which one or more of the residues of CDR1L, CDR2L, CDR3L, CDR1H, CDR2H or CDR3H or the frameworks, typically only a few (e.g. FR1-4L or H), are changed from the residues of the 15B10 or 2G3 antibodies; by, e.g., site directed mutagenesis of the corresponding DNA sequences. The invention includes the DNA sequences coding for such changed Langerin binding molecules. In particular the invention includes a Langerin binding molecules in which one or more residues of CDR1L, CDR2L and/or CDR3L have been changed from the residues of the 15B10 or 2G3 antibodies and one or more residues of CDR1H, CDR2H and/or CDR3H have been changed from the residues of the 15B10 or 2G3 antibodies.

[0093] Each of the DNA constructs are placed under the control of suitable control sequences, in particular under the control of a suitable promoter. Any kind of promoter may be used, provided that it is adapted to the host organism in which the DNA constructs will be transferred for expression. However, if expression is to take place in a mammalian cell, an immunoglobulin gene promoter may be used in B cells. The first and second parts may be separated by an intron, and, an enhancer may be conveniently located in the intron between the first and second parts. The presence of such an enhancer that is transcribed but not translated, may assist in efficient transcription. In particular embodiments the first and second DNA constructs comprise the enhancer of, e.g., a heavy chain human gene.

[0094] The antibody or binding fragments thereof can be isolated, purified, and stored using any method known in the art. The binding fragments retain the specific binding activity of the intact antibody, and can be used for any application that employs the intact antibody (e.g., therapeutics, diagnostic assays, competitive binding assays, etc.).

[0095] In another aspect, the invention provides an antibody or binding fragment generated by the above-described method, and may further include a half-life extending vehicle, such as those known to those skilled in the art. Such vehicles include, but are not limited to, linear polymers (e.g., polyethylene glycol (PEG), polylysine, dextran, etc.); branched-chain polymers (See, e.g., U.S. Pat. No. 4,289,872; U.S. Pat. No. 5,229,490; WO 93/21259); a lipid; a cholesterol group (such as a steroid); a carbohydrate or polysaccharide; or any natural or synthetic protein, polypeptide or peptide. Additionally, it will be appreciated that one or more Fc regions, can also be employed with the invention to increase half-life. It will be appreciated that the vehicle can be linked to the antibody or binding fragment by way of various techniques known in the art including, for example, covalent linkage.

[0096] The desired antibody may be produced in an animal as an ascites, in cell culture or in a transgenic animal. A suitable transgenic animal may be obtained according to standard methods that include micro injecting into eggs the first and second DNA constructs placed under suitable control sequences transferring the so prepared eggs into appropriate pseudo-pregnant females and selecting a descendant expressing the desired antibody.

[0097] The invention also provides an expression vector able to replicate in a prokaryotic or eukaryotic cell line, which comprises at least one of the DNA constructs above described. Each expression vector containing a DNA construct is then transferred into a suitable host organism. When the DNA constructs are separately inserted on two expression vectors, they may be transferred separately, i.e. one type of vector per cell, or co-transferred, this latter possibility being preferred. A suitable host organism may be a bacterium, a yeast or a mammalian cell line, this latter being preferred. More preferably, the mammalian cell line is of lymphoid origin, e.g., a myeloma, hybridoma or a normal immortalized B-cell, which conveniently does not express any endogenous antibody heavy or light chain.

[0098] When the antibody chains are produced in a cell culture, the DNA constructs must first be inserted into either a single expression vector or into two separate but compatible expression vectors, the latter possibility being preferred. For expression in mammalian cells it is preferred that the coding sequence of the Langerin binding molecule is integrated into the host cell DNA within a locus which permits or favors high level expression of the Langerin binding molecule.

[0099] In a further aspect of the invention there is provided a process for the product of a Langerin binding molecule that comprises: (i) culturing an organism which is transformed with an expression vector as defined above; and (ii) recovering the Langerin binding molecule from the culture.

[0100] In accordance with the present invention it has been found that the anti-Langerin antibodies 15B10, 2G3, 91E7, 37C1, or 4C7 and humanized derivatives thereof, appear to have binding specificity for the antigenic epitope of human Langerin. It is therefore most surprising that antibodies to this epitope, e.g. the anti-Langerin 15B10, 2G3, 91E7, 37C1, or 4C7 and humanized derivatives thereof, are capable of delivering antigen efficiently into dendritic cells (DCs). Antibodies, in particular chimeric and CDR-grafted antibodies and especially human antibodies, which have binding specificity for the antigenic epitope of mature human Langerin; and use of such antibodies for DC antigen loading are novel and are included within the scope of the present invention.

[0101] To use the anti-Langerin antibody of the present invention for treatment indications, the appropriate dosage will, of course, vary depending upon, for example, the antibody disclosed herein to be employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in prophylactic use, satisfactory results are generally found at dosages from about 0.05 mg to about 10 mg per kilogram body weight more usually from about 0.1 mg to about 5 mg per kilogram body weight. The frequency of dosing for prophylactic uses will normally be in the range from about once per week up to about once every 3 months, more usually in the range from about once every 2 weeks up to about once every 10 weeks, e.g., once every 4 to 8 weeks. The anti-Langerin antibody of the present can be administered parenterally, intravenously, e.g., into the antecubital or other peripheral vein, intramuscularly, or subcutaneously.

[0102] Pharmaceutical compositions of the invention may be manufactured in conventional manner, e.g., in a lyophilized form. For immediate administration it is dissolved in a suitable aqueous carrier, for example sterile water for injection or sterile buffered physiological saline. If it is considered desirable to make up a solution of larger volume for administration by infusion rather as a bolus injection, it is advantageous to incorporate human serum albumin or the patient's own heparinized blood into the saline at the time of formulation. The presence of an excess of such physiologically inert protein prevents loss of antibody by adsorption onto the walls of the container and tubing used with the infusion solution. If albumin is used, a suitable concentration is from 0.5 to 4.5% by weight of the saline solution.

[0103] One embodiment of the present invention provides an immunoconjugate comprising a humanized antibody of the invention, e.g., a humanized anti-Langerin antibody, linked to one or more effector molecules, antigen(s) and/or a detectable label(s). Preferably, the effector molecule is a therapeutic molecule such as, for example, one or more peptides that comprise one or more T cell epitopes, a toxin, a small molecule, a cytokine or a chemokine, an enzyme, or a radiolabel.

[0104] Exemplary toxins include, but are not limited to, Pseudomonas exotoxin or diphtheria toxin. Examples of small molecules include, but are not limited to, chemotherapeutic compounds such as taxol, doxorubicin, etoposide, and bleiomycin. Exemplary cytokines include, but are not limited to, IL-1, IL-2, IL-4, IL-5, IL-6, and IL-12, IL-17, and IL-25. Exemplary enzymes include, but are not limited to, RNAses, DNAses, proteases, kinases, and caspases. Exemplary radioisotopes include, but are not limited to, 32P and 125I.

[0105] As used herein, the term "epitope" refers to a molecule or substance capable of stimulating an immune response. In one example, epitopes include but are not limited to a polypeptide and a nucleic acid encoding a polypeptide, wherein expression of the nucleic acid into a polypeptide is capable of stimulating an immune response when the polypeptide is processed and presented on a Major Histocompatibility Complex (MHC) molecule. Generally, epitopes include peptides presented on the surface of cells non-covalently bound to the binding groove of Class I or Class II MHC, such that they can interact with T cell receptors and the respective T cell accessory molecules.

[0106] Proteolytic Processing of Antigens. Epitopes that are displayed by MHC on antigen presenting cells are cleavage peptides or products of larger peptide or protein antigen precursors. For MHC I epitopes, protein antigens are often digested by proteasomes resident in the cell. Intracellular proteasomal digestion produces peptide fragments of about 3 to 23 amino acids in length that are then loaded onto the MHC protein. Additional proteolytic activities within the cell, or in the extracellular milieu, can trim and process these fragments further. Processing of MHC Class II epitopes generally occurs via intracellular proteases from the lysosomal/endosomal compartment. The present invention includes, in one embodiment, pre-processed peptides that are attached to the anti-Langerin antibody (or binding fragment thereof) that directs the peptides against which an enhanced immune response is sought directly to antigen presenting cells.

[0107] To identify epitopes potentially effective as immunogenic compounds, predictions of MHC binding alone are useful but often insufficient. The present invention includes methods for specifically identifying the epitopes within antigens most likely to lead to the immune response sought for the specific sources of antigen presenting cells and responder T cells.

[0108] The present invention allows for a rapid and easy assay for the identification of those epitopes that are most likely to produce the desired immune response using the patient's own antigen presenting cells and T cell repertoire. The compositions and methods of the present invention are applicable to any protein sequence, allowing the user to identify the epitopes that are capable of binding to MHC and are properly presented to T cells that will respond to the antigen. Accordingly, the invention is not limited to any particular target or medical condition, but instead encompasses and MHC epitope(s) from any useful source.

[0109] As used herein, the term "veneered" refers to a humanized antibody framework onto which antigen-binding sites or CDRs obtained from non-human antibodies (e.g., mouse, rat or hamster), are placed into human heavy and light chain conserved structural framework regions (FRs), for example, in a light chain or heavy chain polynucleotide to "graft" the specificity of the non-human antibody into a human framework from, e.g., SEQ ID NOS: 45-48 or the nucleic acids that encode those sequences, as will be readily apparent to the skilled artisan. The polynucleotide expression vector or vectors that express the veneered antibodies can be transfected mammalian cells for the expression of recombinant human antibodies which exhibit the antigen specificity of the non-human antibody and will undergo posttranslational modifications that will enhance their expression, stability, solubility, or combinations thereof.

[0110] Antigens.

[0111] Examples of viral antigens for use with the present invention include, but are not limited to, e.g., HIV, HCV, CMV, adenoviruses, retroviruses, picornaviruses, etc. Non-limiting example of retroviral antigens such as retroviral antigens from the human immunodeficiency virus (HIV) antigens such as gene products of the gag, pol, and env genes, the Nef protein, reverse transcriptase, and other HIV components; hepatitis viral antigens such as the S, M, and L proteins of hepatitis B virus, the pre-S antigen of hepatitis B virus, and other hepatitis, e.g., hepatitis A, B, and C, viral components such as hepatitis C viral RNA; influenza viral antigens such as hemagglutinin and neuraminidase and other influenza viral components; measles viral antigens such as the measles virus fusion protein and other measles virus components; rubella viral antigens such as proteins E1 and E2 and other rubella virus components; rotaviral antigens such as VP7sc and other rotaviral components; cytomegaloviral antigens such as envelope glycoprotein B and other cytomegaloviral antigen components; respiratory syncytial viral antigens such as the RSV fusion protein, the M2 protein and other respiratory syncytial viral antigen components; herpes simplex viral antigens such as immediate early proteins, glycoprotein D, and other herpes simplex viral antigen components; varicella zoster viral antigens such as gpI, gpII, and other varicella zoster viral antigen components; Japanese encephalitis viral antigens such as proteins E, M-E, M-E-NS1, NS1, NS1-NS2A, 80% E, and other Japanese encephalitis viral antigen components; rabies viral antigens such as rabies glycoprotein, rabies nucleoprotein and other rabies viral antigen components. See Fundamental Virology, Second Edition, eds. Fields, B. N. and Knipe, D. M. (Raven Press, New York, 1991) for additional examples of viral antigens. The at least one viral antigen may be peptides from an adenovirus, retrovirus, picornavirus, herpesvirus, rotaviruses, hantaviruses, coronavirus, togavirus, flavirvirus, rhabdovirus, paramyxovirus, orthomyxovirus, bunyavirus, arenavirus, reovirus, papilomavirus, parvovirus, poxvirus, hepadnavirus, or spongiform virus. In certain specific, non-limiting examples, the at least one viral antigen are peptides obtained from at least one of HIV, CMV, hepatitis A, B, and C, influenza, measles, polio, smallpox, rubella; respiratory syncytial, herpes simplex, varicella zoster, Epstein-Barr, Japanese encephalitis, rabies, flu, and/or cold viruses.

[0112] In one aspect, the one or more of the antigenic peptides are selected from at least one of: Nef (66-97): VGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGL (SEQ ID NO.: 31); Nef (116-145): HTQGYFPDWQNYTPGPGVRYPLTFGWLYKL (SEQ ID NO.: 32); Gag p17 (17-35): EKIRLRPGGKKKYKLKHIV (SEQ ID NO.: 33); Gag p17-p24 (253-284): NPPIPVGEIYKRWIILGLNKIVRMYSPTSILD (SEQ ID NO.: 34); or Pol 325-355 (R.sub.T 158-188) is: AIFQSSMTKILEPFRKQNPDIVIYQYMDDLY (SEQ ID NO.: 35). In one aspect, the fusion protein peptides are separated by one or more linkers selected from:

TABLE-US-00005 SSVSPTTSVHPTPTSVPPTPTKSSP; (SEQ ID NO.: 39) PTSTPADSSTITPTATPTATPTIKG; (SEQ ID NO.: 40) TVTPTATATPSAIVTTITPTATTKP; (SEQ ID NO.: 41) or TNGSITVAATAPTVTPTVNATPSAA. (SEQ ID NO.: 42)

[0113] Antigenic targets that may be delivered using the anti-Langerin-antigen vaccines of the present invention include genes encoding antigens such as viral antigens, bacterial antigens, fungal antigens or parasitic antigens. Pathogens include trypanosomes, tapeworms, roundworms, helminthes, malaria. Tumor markers, such as fetal antigen or prostate specific antigen, may be targeted in this manner. Other examples include: HIV env proteins and hepatitis B surface antigen. Administration of a vector according to the present invention for vaccination purposes would require that the vector-associated antigens be sufficiently non-immunogenic to enable long-term expression of the transgene, for which a strong immune response would be desired. In some cases, vaccination of an individual may only be required infrequently, such as yearly or biennially, and provide long-term immunologic protection against the infectious agent. Specific examples of organisms, allergens and nucleic and amino sequences for use in vectors and ultimately as antigens with the present invention may be found in U.S. Pat. No. 6,541,011, relevant portions incorporated herein by reference, in particular, the tables that match organisms and specific sequences that may be used with the present invention.

[0114] Bacterial antigens for use with the anti-Langerin-antigen vaccines disclosed herein include, but are not limited to, e.g., bacterial antigens such as pertussis toxin, filamentous hemagglutinin, pertactin, FIM2, FIM3, adenylate cyclase and other pertussis bacterial antigen components; diptheria bacterial antigens such as diptheria toxin or toxoid and other diptheria bacterial antigen components; tetanus bacterial antigens such as tetanus toxin or toxoid and other tetanus bacterial antigen components; streptococcal bacterial antigens such as M proteins and other streptococcal bacterial antigen components; gram-negative bacilli bacterial antigens such as lipopolysaccharides and other gram-negative bacterial antigen components, Mycobacterium tuberculosis bacterial antigens such as mycolic acid, heat shock protein 65 (HSP65), the 30 kDa major secreted protein, antigen 85A and other mycobacterial antigen components; Helicobacter pylori bacterial antigen components; pneumococcal bacterial antigens such as pneumolysin, pneumococcal capsular polysaccharides and other pneumococcal bacterial antigen components; haemophilus influenza bacterial antigens such as capsular polysaccharides and other haemophilus influenza bacterial antigen components; anthrax bacterial antigens such as anthrax protective antigen and other anthrax bacterial antigen components; rickettsiae bacterial antigens such as rompA and other rickettsiae bacterial antigen component. Also included with the bacterial antigens described herein are any other bacterial, mycobacterial, mycoplasmal, rickettsial, or chlamydial antigens. Partial or whole pathogens may also be: haemophilus influenza; Plasmodium falciparum; neisseria meningitidis; streptococcus pneumoniae; neisseria gonorrhoeae; salmonella serotype typhi; shigella; vibrio cholerae; Dengue Fever; Encephalitides; Japanese Encephalitis; lyme disease; Yersinia pestis; west nile virus; yellow fever; tularemia; hepatitis (viral; bacterial); RSV (respiratory syncytial virus); HPIV 1 and HPIV 3; adenovirus; small pox; allergies and cancers.

[0115] Fungal antigens for use with compositions and methods of the invention include, but are not limited to, e.g., candida fungal antigen components; histoplasma fungal antigens such as heat shock protein 60 (HSP60) and other histoplasma fungal antigen components; cryptococcal fungal antigens such as capsular polysaccharides and other cryptococcal fungal antigen components; coccidiodes fungal antigens such as spherule antigens and other coccidiodes fungal antigen components; and tinea fungal antigens such as trichophytin and other coccidiodes fungal antigen components.

[0116] Examples of protozoal and other parasitic antigens include, but are not limited to, e.g., plasmodium falciparum antigens such as merozoite surface antigens, sporozoite surface antigens, circumsporozoite antigens, gametocyte/gamete surface antigens, blood-stage antigen pf 155/RESA and other plasmodial antigen components; toxoplasma antigens such as SAG-1, p30 and other toxoplasmal antigen components; schistosomae antigens such as glutathione-S-transferase, paramyosin, and other schistosomal antigen components; leishmania major and other leishmaniae antigens such as gp63, lipophosphoglycan and its associated protein and other leishmanial antigen components; and trypanosoma cruzi antigens such as the 75-77 kDa antigen, the 56 kDa antigen and other trypanosomal antigen components.

[0117] Antigen that can be targeted using the anti-Langerin-antigen vaccines of the present invention will generally be selected based on a number of factors, including: likelihood of internalization, level of immune cell specificity, type of immune cell targeted, level of immune cell maturity and/or activation and the like. In this embodiment, the antibodies may be mono- or bi-specific antibodies that include one anti-Langerin binding domain and one binding domain against a second antigen, e.g., cell surface markers for dendritic cells such as, MHC class I, MHC Class II, B7-2, CD18, CD29, CD31, CD43, CD44, CD45, CD54, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR and/or Dectin-1 and the like; while in some cases also having the absence of CD2, CD3, CD4, CD8, CD14, CD15, CD16, CD 19, CD20, CD56, and/or CD57. Examples of cell surface markers for antigen presenting cells include, but are not limited to, MHC class I, MHC Class II, CD45, B7-1, B7-2, IFN-.gamma. receptor and IL-2 receptor, ICAM-1 and/or Fc.gamma. receptor. Examples of cell surface markers for T cells include, but are not limited to, CD3, CD4, CD8, CD 14, CD20, CD11b, CD16, CD45 and HLA-DR.

[0118] Target antigens on cell surfaces for delivery include those characteristic of tumor antigens typically will be derived from the cell surface, cytoplasm, nucleus, organelles and the like of cells of tumor tissue. Examples of tumor targets for the antibody portion of the present invention include, without limitation, hematological cancers such as leukemias and lymphomas, neurological tumors such as astrocytomas or glioblastomas, melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors such as gastric or colon cancer, liver cancer, pancreatic cancer, genitourinary tumors such cervix, uterus, ovarian cancer, vaginal cancer, testicular cancer, prostate cancer or penile cancer, bone tumors, vascular tumors, or cancers of the lip, nasopharynx, pharynx and oral cavity, esophagus, rectum, gall bladder, biliary tree, larynx, lung and bronchus, bladder, kidney, brain and other parts of the nervous system, thyroid, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and leukemia.

[0119] Examples of antigens that may be delivered alone or in combination to immune cells for antigen presentation using the present invention includes tumor proteins, e.g., mutated oncogenes; viral proteins associated with tumors; and tumor mucins and glycolipids. The antigens may be viral proteins associated with tumors would be those from the classes of viruses noted above. Certain antigens may be characteristic of tumors (one subset being proteins not usually expressed by a tumor precursor cell), or may be a protein that is normally expressed in a tumor precursor cell, but having a mutation characteristic of a tumor. Other antigens include mutant variant(s) of the normal protein having an altered activity or subcellular distribution, e.g., mutations of genes giving rise to tumor antigens.

[0120] Specific non-limiting examples of tumor antigens for use in an anti-Langerin-fusion protein vaccine include, e.g., CEA, prostate specific antigen (PSA), HER-2/neu, BAGE, GAGE, MAGE 1-4, 6 and 12, MUC (Mucin) (e.g., MUC-1, MUC-2, etc.), GM2 and GD2 gangliosides, ras, myc, tyrosinase, MART (melanoma antigen), Pmel 17(gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate Ca psm, PRAME (melanoma antigen), .beta.-catenin, MUM-1-B (melanoma ubiquitous mutated gene product), GAGE (melanoma antigen)1, MAGE, BAGE (melanoma antigen) 2-10, c-ERB2 (Her2/neu), DAGE, EBNA (Epstein-Barr Virus nuclear antigen) 1-6, gp75, human papilloma virus (HPV) E6 and E7, p53, lung resistance protein (LRP), Bcl-2, Ki-67, Cyclin B1, gp100, Survivin, and NYESO-1.

[0121] In addition, the immunogenic molecule can be an autoantigen involved in the initiation and/or propagation of an autoimmune disease, the pathology of which is largely due to the activity of antibodies specific for a molecule expressed by the relevant target organ, tissue, or cells, e.g., SLE or MG. In such diseases, it can be desirable to direct an ongoing antibody-mediated (i.e., a Th2-type) immune response to the relevant autoantigen towards a cellular (i.e., a Th1-type) immune response. Alternatively, it can be desirable to prevent onset of or decrease the level of a Th2 response to the autoantigen in a subject not having, but who is suspected of being susceptible to, the relevant autoimmune disease by prophylactically inducing a Th1 response to the appropriate autoantigen. Autoantigens of interest include, without limitation: (a) with respect to SLE, the Smith protein, RNP ribonucleoprotein, and the SS-A and SS-B proteins; and (b) with respect to MG, the acetylcholine receptor. Examples of other miscellaneous antigens involved in one or more types of autoimmune response include, e.g., endogenous hormones such as luteinizing hormone, follicular stimulating hormone, testosterone, growth hormone, prolactin, and other hormones.

[0122] Antigens involved in autoimmune diseases, allergy, and graft rejection can be used in the compositions and methods of the invention. For example, an antigen involved in any one or more of the following autoimmune diseases or disorders can be used in the present invention: diabetes, diabetes mellitus, arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis), multiple sclerosis, myasthenia gravis, systemic lupus erythematosis, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia greata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Crohn's disease, Graves ophthalmopathy, sarcoidosis, primary biliary cirrhosis, uveitis posterior, and interstitial lung fibrosis. Examples of antigens involved in autoimmune disease include glutamic acid decarboxylase 65 (GAD 65), native DNA, myelin basic protein, myelin proteolipid protein, acetylcholine receptor components, thyroglobulin, and the thyroid stimulating hormone (TSH) receptor.

[0123] Examples of antigens involved in allergy include pollen antigens such as Japanese cedar pollen antigens, ragweed pollen antigens, rye grass pollen antigens, animal derived antigens such as dust mite antigens and feline antigens, histocompatiblity antigens, and penicillin and other therapeutic drugs. Examples of antigens involved in graft rejection include antigenic components of the graft to be transplanted into the graft recipient such as heart, lung, liver, pancreas, kidney, and neural graft components. The antigen may be an altered peptide ligand useful in treating an autoimmune disease.

[0124] It will be appreciated by those of skill in the art that the sequence of any protein effector molecule may be altered in a manner that does not substantially affect the functional advantages of the effector protein. For example, glycine and alanine are typically considered to be interchangeable as are aspartic acid and glutamic acid and asparagine and glutamine. One of skill in the art will recognize that many different variations of effector sequences will encode effectors with roughly the same activity as the native effector. The effector molecule and the antibody may be conjugated by chemical or by recombinant means as described above. Chemical modifications include, for example, derivitization for the purpose of linking the effector molecule and the antibody to each other, either directly or through a linking compound, by methods that are well known in the art of protein chemistry. Both covalent and noncovalent attachment methods may be used with the humanized antibodies of the present invention.

[0125] The procedure for attaching an effector molecule to an antibody will vary according to the chemical structure of the moiety to be attached to the antibody. Polypeptides typically contain a variety of functional groups; e.g., carboxylic acid (COOH), free amine (--NH.sub.2) or sulfhydryl (--SH) groups, which are available for reaction with a suitable functional group on an antibody to result in the binding of the effector molecule. Alternatively, the antibody can be derivatized to expose or to attach additional reactive functional groups, e.g., by attachment of any of a number of linker molecules such as those available from Pierce Chemical Company, Rockford Ill.

[0126] The linker is capable of forming covalent bonds to both the antibody and to the effector molecule. Suitable linkers are well known to those of skill in the art and include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers. Where the antibody and the effector molecule are polypeptides, the linkers may be joined to the constituent amino acids through their side groups (e.g., through a disulfide linkage to cysteine). However, in a preferred embodiment, the linkers will be joined to the alpha carbon amino and carboxyl groups of the terminal amino acids.

[0127] In some circumstances, it is desirable to free the effector molecule from the antibody when the immunoconjugate has reached its target site. Therefore, in these circumstances, immunoconjugates will comprise linkages that are cleavable in the vicinity of the target site. Cleavage of the linker to release the effector molecule from the antibody may be prompted by enzymatic activity or conditions to which the immunoconjugate is subjected either inside the target cell or in the vicinity of the target site. When the target site is a tumor, a linker that is cleavable under conditions present at the tumor site (e.g. when exposed to tumor-associated enzymes or acidic pH) may be used.

[0128] Exemplary chemical modifications of the effector molecule and the antibody of the present invention also include derivitization with polyethylene glycol (PEG) to extend time of residence in the circulatory system and reduce immunogenicity, according to well known methods (See for example, Lisi, et al., Applied Biochem. 4:19 (1982); Beauchamp, et al., Anal Biochem. 131:25 (1982); and Goodson, et al., Bio/Technology 8:343 (1990)).

[0129] The present invention contemplates vaccines for use in both active and passive immunization embodiments. Immunogenic compositions, proposed to be suitable for use as a vaccine, may be prepared most readily directly from immunogenic T-cell stimulating peptides prepared in a manner disclosed herein. The final vaccination material is dialyzed extensively to remove undesired small molecular weight molecules and/or lyophilized for more ready formulation into a desired vehicle. In certain embodiment of the present invention, the compositions and methods of the present invention are used to manufacture a cellular vaccine, e.g., the antigen-delivering anti-Langerin binding portion of the antibody is used to direct the antigen(s) to an antigen presenting cell, which then "loads" the antigen onto MHC proteins for presentation. The cellular vaccine is, therefore, the antigen presenting cell that has been loaded using the compositions of the present invention to generate antigen-loaded antigen presenting cells.

[0130] When the vaccine is the anti-Langerin binding protein itself, e.g., a complete antibody or binding fragments thereof, then these "active ingredients" can be made into vaccines using methods understood in the art, e.g., U.S. Pat. Nos. 4,608,251; 4,601,903; 4,599,231; 4,599,230; and 4,578,770, relevant portions incorporated herein by reference. Typically, such vaccines are prepared as injectables, e.g., as liquid solutions or suspensions or solid forms suitable for re-suspension in liquid prior to injection. The preparation may also be emulsified. The active immunogenic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the vaccine may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants that enhance the effectiveness of the vaccines.

[0131] The vaccines are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective and immunogenic. The quantity to be administered depends on the subject to be treated, including, e.g., the capacity of the individual's immune system to generate an immune response. Precise amounts of cells or active ingredient required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are of the order of a few thousand cells (to millions of cells) for cellular vaccines. For standard epitope or epitope delivery vaccines then the vaccine may be several hundred micrograms active ingredient per vaccination. Suitable regimes for initial administration and booster shots are also variable, but are typified by an initial administration followed by subsequent inoculations or other administrations.

[0132] The manner of application may vary widely, however, certain embodiments herein will most likely be delivered intravenously or at the site of a tumor or infection directly. Regardless, any of the conventional methods for administration of a vaccine are applicable. The dosage of the vaccine will depend on the route of administration and will vary according to the size of the host.

[0133] In many instances, it will be desirable to have multiple administrations of the vaccine, e.g., four to six vaccinations provided weekly or every other week. A normal vaccination regimen will often occur in two to twelve week intervals or from three to six week intervals. Periodic boosters at intervals of 1-5 years, usually three years, may be desirable to maintain protective levels of the immune response or upon a likelihood of a remission or re-infection. The course of the immunization may be followed by assays for, e.g., T cell activation, cytokine secretion or even antibody production, most commonly conducted in vitro. These immune response assays are well known and may be found in a wide variety of patents and as taught herein.

[0134] The vaccine of the present invention may be provided in one or more "unit doses" depending on whether the nucleic acid vectors are used, the final purified proteins, or the final vaccine form is used. Unit dose is defined as containing a predetermined-quantity of the therapeutic composition calculated to produce the desired responses in association with its administration, i.e., the appropriate route and treatment regimen. The quantity to be administered, and the particular route and formulation, are within the skill of those in the clinical arts. The subject to be treated may also be evaluated, in particular, the state of the subject's immune system and the protection desired. A unit dose need not be administered as a single injection but may include continuous infusion over a set period of time. Unit dose of the present invention may conveniently be described in terms of DNA/kg (or protein/Kg) body weight, with ranges between about 0.05, 0.10, 0.15, 0.20, 0.25, 0.5, 1, 10, 50, 100, 1,000 or more mg/DNA or protein/kg body weight are administered.

[0135] Likewise, the amount of anti-Langerin-antigen vaccine delivered can vary from about 0.2 to about 8.0 mg/kg body weight. Thus, in particular embodiments, 0.4 mg, 0.5 mg, 0.8 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg and 7.5 mg of the vaccine may be delivered to an individual in vivo. The dosage of vaccine to be administered depends to a great extent on the weight and physical condition of the subject being treated as well as the route of administration and the frequency of treatment. A pharmaceutical composition that includes a naked polynucleotide prebound to a liposomal or viral delivery vector may be administered in amounts ranging from 1 .mu.g to 1 mg polynucleotide to 1 .mu.g to 100 mg protein. Thus, particular compositions may include between about 1 .mu.g, 5 .mu.g, 10 .mu.g, 20 .mu.g, 30 .mu.g, 40 .mu.g, 50 .mu.g, 60 .mu.g, 70 .mu.g, 80 .mu.g, 100 .mu.g, 150 .mu.g, 200 .mu.g, 250 .mu.g, 500 .mu.g, 600 .mu.g, 700 .mu.g, 800 .mu.g, 900 .mu.g or 1,000 .mu.g polynucleotide or protein that is bound independently to 1 .mu.g, 5 .mu.g, 10 .mu.g, 20 .mu.g, 3.0 .mu.g, 40 .mu.g 50 .mu.g, 60 .mu.g, 70 .mu.g, 80 .mu.g, 100 .mu.g, 150 .mu.g, 200 .mu.g, 250 .mu.g, 500 .mu.g, 600 .mu.g, 700 .mu.g, 800 .mu.g, 900 .mu.g, 1 mg, 1.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg vector.

[0136] Antibodies of the present invention may optionally be covalently or non-covalently linked to a detectable label. Detectable labels suitable for such use include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical methods. Useful labels in the present invention include magnetic beads (e.g. DYNABEADS.TM.), fluorescent dyes (e.g., fluorescein isothiocyanate, Texas red, rhodamine, green fluorescent protein, and the like), radiolabels (e.g., .sup.3H, .sup.125I, .sup.35S, .sup.14C, or .sup.32P), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and colorimetric labels such as colloidal gold or colored glass or plastic (e.g. polystyrene, polypropylene, latex, etc.) beads.

[0137] Methods of detecting such labels are well known to those of skill in the art. Thus, for example, radiolabels may be detected using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted illumination. Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label.

[0138] The antibody and/or immunoconjugate compositions of this invention are particularly useful for parenteral administration, such as intravenous administration or administration into a body cavity. The compositions for administration will commonly comprise a solution of the antibody and/or immunoconjugate dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, well-known sterilization techniques. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of fusion protein in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the patient's needs.

[0139] Thus, a typical pharmaceutical immunoconjugate composition of the present invention for intravenous administration would be about 0.1 to 10 mg per patient per day. Dosages from 0.1 up to about 100 mg per patient per day may be used. Actual methods for preparing administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as REMINGTON'S PHARMACEUTICAL SCIENCE, 19TH ED., Mack Publishing Company, Easton, Pa. (1995).

[0140] The compositions of the present invention can be administered for therapeutic treatments. In therapeutic applications, compositions are administered to a patient suffering from a disease, in an amount sufficient to cure or at least partially arrest the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective dose." Amounts effective for this use will depend upon the severity of the disease and the general state of the patient's health. An effective amount of the compound is that which provides either subjective relief of a symptom(s) or an objectively identifiable improvement as noted by the clinician or other qualified observer.

[0141] Single or multiple administrations of the compositions are administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition should provide a sufficient quantity of the proteins of this invention to effectively treat the patient. Preferably, the dosage is administered once but may be applied periodically until either a therapeutic result is achieved or until side effects warrant discontinuation of therapy. Generally, the dose is sufficient to treat or ameliorate symptoms or signs of disease without producing unacceptable toxicity to the patient.

[0142] Controlled release parenteral formulations of the immunoconjugate compositions of the present invention can be made as implants, oily injections, or as particulate systems. For a broad overview of protein delivery systems see, Banga, A. J., THERAPEUTIC PEPTIDES AND PROTEINS: FORMULATION, PROCESSING, AND DELIVERY SYSTEMS, Technomic Publishing Company, Inc., Lancaster, Pa., (1995) incorporated herein by reference. Particulate systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles. Microcapsules contain the therapeutic protein as a central core. In microspheres the therapeutic is dispersed throughout the particle. Particles, microspheres, and microcapsules smaller than about 1 .mu.m are generally referred to as nanoparticles, nanospheres, and nanocapsules, respectively. Capillaries have a diameter of approximately 5 .mu.m so that only nanoparticles are administered intravenously. Microparticles are typically around 100 .mu.m in diameter and are administered subcutaneously or intramuscularly.

[0143] Polymers can be used for ion-controlled release of immunoconjugate compositions of the present invention. Various degradable and non-degradable polymeric matrices for use in controlled drug delivery are known in the art (Langer, R., Accounts Chem. Res. 26:537-542 (1993)). For example, the block copolymer, poloxamer 407.RTM. exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature, hydroxyapatite has been used as a microcarrier for controlled release of proteins, and/or liposomes may be used for controlled release as well as drug targeting of the lipid-capsulated drug. Numerous additional systems for controlled delivery of therapeutic proteins are known. See, e.g., U.S. Pat. Nos. 5,055,303, 5,188,837, 4,235,871, 4,501,728, 4,837,028 4,957,735 and 5,019,369, 5,055,303; 5,514,670; 5,413,797; 5,268,164; 5,004,697; 4,902,505; 5,506,206, 5,271,961; 5,254,342 and 5,534,496, relevant portions of each of which are incorporated herein by reference.

[0144] Among various uses of the immunoconjugates of the invention are included a variety of disease conditions caused by specific human cells that may be eliminated by the toxic action of the fusion protein. For example, for the humanized Anti-Langerin antibodies, e.g., 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7 and binding fragments thereof, disclosed herein. For example, one application for immunoconjugates is the treatment of malignant cells expressing Langerin. Exemplary malignant cells include those of chronic lymphocytic leukemia and hairy cell leukemia.

[0145] In another embodiment, this invention provides kits for the delivery of antigens, e.g., Langerin or an immunoreactive fragment thereof, conjugated or in the form of a fusion protein with one or more T cell or B cell epitopes. A "biological sample" as used herein is a sample of biological tissue or fluid that contains the antigen. Such samples include, but are not limited to, tissue from biopsy, blood, and blood cells (e.g., white cells). Preferably, the cells are lymphocytes, e.g., dendritic cells. Biological samples also include sections of tissues, such as frozen sections taken for histological purposes. A biological sample is typically obtained from a multicellular eukaryote, preferably a mammal such as rat, mouse, cow, dog, guinea pig, or rabbit, and more preferably a primate, such as a macaque, chimpanzee, or human. Most preferably, the sample is from a human. The antibodies of the invention may also be used in vivo, for example, as a diagnostic tool for in vivo imaging.

[0146] Kits will typically comprise a nucleic acid sequence that encodes an antibody of the present invention (or binding fragment thereof) with one or more framework portions or multiple cloning sites at the carboxy-terminal end into which the coding sequences for one or more antigens may be inserted. In some embodiments, the antibody will be a humanized anti-Langerin Fv fragment, such as an scFv or dsFv fragment. In addition the kits will typically include instructional materials disclosing methods of use of an antibody of the present invention (e.g. for loading into dendritic cells prior to immunization with the dendritic cells, which can be autologous dendritic cells). The kits may also include additional components to facilitate the particular application for which the kit is designed. Thus, for example, the kit may additionally contain methods of detecting the label (e.g. enzyme substrates for enzymatic labels, filter sets to detect fluorescent labels, appropriate secondary labels such as a sheep anti-mouse-HRP, or the like). The kits may additionally include buffers and other reagents routinely used for the practice of a particular method. Such kits and appropriate contents are well known to those of skill in the art.

[0147] In another set of uses for the invention, immunoconjugates targeted by antibodies of the invention can be used to purge targeted cells from a population of cells in a culture. For example, if a specific population of T cells is preferred, the immunoconjugates of the present invention may be used to enrich a population of T cells having the opposite effect of the on-going immune response. Thus, for example, cells cultured from a patient having a cancer can be purged of cancer cells by providing the patient with dendritic cells that were antigen loaded using the antibodies of the invention as a targeting moiety for the antigens that will trigger an immune response against the cancer, virus or other pathogen. Likewise, the immunoconjugates can be used to increase the population of regulatory T cells or drive the immune response toward or away from a cytotoxic T cell response or even drive a B cell response.

[0148] Differential functions of DC subsets: The present inventors have demonstrated that LCs and intDCs derived from CD34+ hematopoietic progenitor cells differ in their capacity to activate lymphocytes (FIG. 1). IntDCs induce the differentiation of naive B cells into immunoglobulin-secreting plasma cells and differentiation of CD4+T cells into follicular helper T cells (TFH).sup.17,18, while LCs are particularly efficient activators of cytotoxic CD8+ lymphocytes (CTLs). In addition, only interstitial DCs produce IL-10 and their enzymatic activity, which might be fundamental for the selection of peptides that will be presented to T cells, is not the same. Indeed, different enzymes are likely to degrade a antigen into different peptide repertoires, as shown for HIV nef protein.sup.19. This will lead to different sets of MHC/peptide complexes being presented and to a distinct antigen-specific T-cell repertoire. Dudziak, et al..sup.20 have shown that antigens delivered to DCs through the subset-specific lectin Dectin-1 were presented differentially on MHC class II, while those presented through DEC-205 were mostly on MHC Class I and this difference was intrinsic to the DC subsets.

[0149] DC subsets play an important role in determining CD4+T cell responses. Either polarized DCs or distinct DC subsets provide T cells with different signals that determine the types of immune response (Type 1 versus Type 2).sup.21. Thus, in mice, splenic CD8+DCs prime naive CD4+T cells to make Th1 cytokines in a process involving IL-12, whereas splenic CD8+DCs prime naive CD4+T cells to make Th2 cytokines.sup.22,23. Furthermore, different signals from the same DCs can induce different T-cell polarization, as shown by the induction of IL-12 production and Th1-cell polarization when DCs are activated with Escherichia coli lipopolysaccharide (LPS), but no IL-12 production and Th2-cell polarization when DCs are exposed to LPS from Porphyromonas gingivalis.sup.24. CD40-ligand (CD40L)-activated DCs prime Th1 responses through an IL-12-dependent mechanism, whereas pDCs activated with IL-3 and CD40L have been shown to secrete negligible amounts of IL-12 and prime Th2 responses.sup.25. Soares, et al. also reported that two DC subsets that express different lectins have innate propensities to differentially affect the Th1/Th2 balance in vivo by distinct mechanisms. More interestingly, we have found that delivering the same antigens to the same type of DCs, but through different DC-receptors, induces a different quality of CD4+T cell responses (see preliminary data). Thus, both DC subsets and activation signals to which DCs are exposed are important factors determining the nature of immune outcome.

[0150] FIG. 2--Recombinant anti-Langerin antibodies fused to antigens retain their ability to bind to cell surface Langerin. CHO--S cells were stably transfected with a plasmid directing the expression of full-length human Langerin. Pure recombinant anti-Langerin 2G3 or 15B10 mouse V region-human IgG4 chimeric antibodies or the same antibodies with C-terminal fusions to Influenza A Hemagglutinin HA-1 domain from Avian Flu (HA5-1), Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain (HA1-1), dockerin domain from C. thermocellum (doc), HIV gag p24 (gag), or a string of HIV peptides (Hipo5), were titrated against the Langerin-CHO cells. After incubation on ice, the cells were washed and treated with an anti-human Fc-PE reagent. After further incubation on ice, the cells were washed and analyzed on a FACS Array instrument to determine the amount of cell-bound florescence (expressed as % MFI compared to untransfected CHO--S cells).

[0151] This data shows that addition of antigen to the H-chain C-termini does not affect the binding of the antibody to cell surface Langerin and also demonstrates that these anti-Langerin antibodies serve as effective vehicles to bring antigen to the surface of cells bearing human Langerin.

[0152] FIG. 3--demonstration of the ability of recombinant anti-Langerin antibody fused to the human prostate specific cancer antigen to elicit the expansion of antigen-specific CD4+T cells from a health donor. FIG. 3a compares delivering PSA to DCs through CD40 and Langerin induces IFN.gamma.-producing PSA-specific CD4+T cells. CD4+T cells from healthy donors were co-cultured with IFNDCs targeted with anti-CD40-PSA or anti-Langerin-PSA for 8 days. Cells were stimulated with individual peptides (59 peptides of 15-mers) of PSA (5 .mu.M). After 2 days, culture supernatants were analyzed for measuring IFN.gamma.. Dotted lines represent upper limits of average.+-.SD for no peptides and responses above this line are considered significant. FIG. 3b shows that CD4+T cells were stained for measuring the frequency of peptide-specific intracellular IFN.gamma.+ cells.

[0153] These data show that an anti-Langerin vaccine bearing a cancer antigen can prime a potent antigen-specific anti-CD4+T cell response in vitro using immune cells from a normal individual. In this in vitro culture system this agent is as potent as an anti-CD40 based vaccine--these DCs express both receptors. In vivo, an anti-Langerin-based vaccine would target antigen only to Langerhans cells (LCs), and based on recent research [Immunity, Volume 29, Issue 3, 497-510, 19 Sep. 2008] LCs preferentially induce the differentiation of CD4+T cells secreting T helper 2 (Th2) cell cytokines and are particularly efficient at priming and cross priming naive CD8+T cells--the latter characteristic is particularly desirable for evoking anti-cancer CTL responses. In contrast, anti-CD40 targeting agents would deliver antigen to a much broader array of APC in vivo.

[0154] FIG. 4--demonstration of the ability of recombinant anti-Langerin antibody fused to the human prostate specific cancer antigen to elicit the expansion of antigen-specific CD8+T cells from a prostate cancer patient. DCs targeted with anti-CD40-PSA and anti-Langerin-PSA targeted to DCs induces PSA-specific CD8+T cell responses. (a) IFNDCs were targeted with 1 mg mAb fusion proteins with PSA. Purified autologous CD8+T cells were co-cultured for 10 days. Cells were stained with anti-CD8 and PSA (KLQCVDLHV)-tetramer. Cells are from HLA-A*0201 positive prostate cancer patients. The PSA tetramer reagent identified T cells bearing T cell receptors specifically reactive with HLA-A*0201 complexes bearing the PSA KLQCVDLHV peptide.

[0155] These data show that an anti-Langerin vaccine bearing a cancer antigen can prime a potent antigen-specific anti-CD8+T cell response in vitro using immune cells from a prostate cancer. In this in vitro culture system this agent is as potent as a anti-CD40 based vaccine--these DCs express both receptors. In vivo, an anti-Langerin-based vaccine would target antigen only to Langerhans cells (LCs), and based on recent research [Immunity, Volume 29, Issue 3, 497-510, 19 Sep. 2008] LCs preferentially induce the differentiation of CD4+T cells secreting T helper 2 (Th2) cell cytokines and are particularly efficient at priming and cross priming naive CD8+T cells--the latter characteristic is particularly desirable for evoking anti-cancer CTL responses. In contrast, anti-CD40 targeting agents would deliver antigen to a much broader array of APC in vivo.

[0156] FIG. 5--Anti-Langerin preferentially targets epidermal LCs. Purified skin DC subsets (Epidermal LCs, dermal CD1a+DCs and CD14+DCs) from HLA-A201 donor were cultured with 8 nM anti-Langerin, IgG4 conjugates mAbs, free FluMP or without antigen for 3 h. Syngeneic purified CD8+T cells were cultured with the antigen-pulsed DCs at a DC/T ratio 1:20. CD40L (100 ng/ml; R&D) was added to the culture after 24 h. CD40-ligation enhances crosspresentation by DCs. The cocultures were incubated at 37.degree. C. for 8-10 days. IL-2 (10 U/ml) was added at day 3. The response of FluMP-specific CD8+T cells was evaluated using HLA-A201-FluMP (58-66) peptide (GILGFVFTL) tetramer.

[0157] The data in panel FIG. 5A: 2D FACs-plots showing FluMP-specific CD8+T cell expansion as evaluated by specific HLA-A201-FluMP (58-66) tetramer staining demonstrating that targeting antigen via anti-Langerin elicits antigen-specific CD8+T cell expansion only through LCs, which is more robust than other methods of antigen delivery such as free FluMP. Some response is induced by the dermal CD1a+DCs, in concordance with the ability of these cells to upregulate Langerin in culture. FIG. 5B summarizes the data in a graph shows mean.+-.sd, N=3. FIG. 5C. IFN-.gamma. levels in the culture supernatants of human LCs that were culture for 8 days with either Langerin-FluMP, control IgG4-FluMP, free FluMP or no antigen after 8 days.

[0158] FIG. 6 shows the differential expression of Langerin by human skin DCs. FIG. 6A shows the expression of Langerin on isolated human skin DC subsets. Data show restricted expression of Langerin on human LCs, but not on dermal CD1a+ or CD14+DCs. FIG. 6B show a gene expression analysis of Langerin by skin DCs isolated from 3 different specimens. RNA was prepared from sorted migrated skin mDC subsets: epidermal LCs, dermal CD1a+DCs and CD14+DCs. FIG. 6C shows the immunofluorescent staining of normal human skin using Langerin and HLA-DR mAbs.

[0159] FIG. 7--Anti-Langerin 15B10 antibody (produced by hybridoma ATCC Accession No. PTA-9852) specifically stains human Langerhans cells. Human epithelial sheet was prepared and stained with Alexa568 [red]-labeled anti-Langerin 15B10 and a commercial anti-HLA antibody labeled green. The top image shows the red and green image superimposed highlighting the co-localization of these two markers.

[0160] Constructs.

[0161] mAnti-Langerin15B10K--Nucleotide and mature protein amino acid sequence of the light chain of the mouse anti-Langerin 15B10 antibody cDNA, respectively. The variable region residues are underlined.

TABLE-US-00006 (SEQ ID NO. 1) ATGAAGTTGCCTGTTAGGCTGTTGGTGCTGATGTTCTGGATTCCTGCT TCCAGCAGTGATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTC CGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTT GTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCA GGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCT GGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAAATTTCACA CTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGACTTTATTTCTGC TCTCAAAGTACACATGTTCCGTACACGTTCGGAGGGGGGACCAAGCTG GAAATAAAACGGGCTGATGCTGCACCAACTGTATCCATCTTCCCACCA TCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTG AACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGC AGTGAACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGC AAAGACAGCACCTACAGCATGAACAGCACCCTCACGTTGACCAAGGAC GAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACA TCAACTTCACCCATCGTCAAGAGCTTCAACAGGAATGAGTGTTAG (SEQ ID NO. 2) DVVMTQTPLSLPVRLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQS PKLLIYKVSNRFSGVPDRFSGSGSGTNFTLKISRVEAEDLGLYFCSQS THVPYTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNF YPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMNSTLTLTKDEYE RHNSYTCEATHKTSTSPIVKSFNRNEC

[0162] mAnti-Langerin15B10H-LV-hIgG4H-C--Nucleotide and mature protein amino acid sequence of the heavy chain variable region of the mouse anti-Langerin 15B10 antibody fused to human IgG4, respectively. The variable region residues are underlined.

TABLE-US-00007 (SEQ ID NO. 3) ATGGAATGGAGGATCTTTCTCTTCATCCTGTCAGGAACTGCAGGTGTC CACTCCCAGGTTCAGCTGCGGCAGTCTGGACCTGAGCTGGTGAAGCCT GGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTTACT GACTATGTTATAAGTTGGGTGAAGCAGAGAACTGGACAGGGCCTTGAG TGGATTGGAGATATTTATCCTGGAAGTGGTTATTCTTTCTACAATGAG AACTTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCACCACA GCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTAT TTCTGTGCAACCTACTATAACTACCCTTTTGCTTACTGGGGCCAAGGG ACTCTGGTCACTGTCTCTGCAGCCAAAACAACGGGCCCATCCGTCTTC CCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC AGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCC AGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCA TGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACCATCAGTCTTC CTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCT GAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTC CAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGC AAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCA TCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTC AAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGG CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGC TGA (SEQ ID NO. 4) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWI GDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFC ATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKAS

[0163] mAnti-Langerin2G3L (produced by hybridoma ATCC Accession No. PTA-9853)--Nucleotide and mature protein amino acid sequence of the light chain of the mouse anti-Langerin 2G3 antibody cDNA, respectively. The variable region residues are underlined.

TABLE-US-00008 (SEQ ID NO. 5) ATGGCCTGGATTTCACTTATACTCTCTCTCCTGGCTCTCAGCTCAGGG GCCATTTCCCAGGCTGTTGTGACTCAGGAATCTGCACTCACCACATCA CCTGGTGAAACAGTCACACTCACTTGTCGCTCAAGTACTGGGGCTGTT ACAACTAGTAACTATGCCAACTGGGTCCAAGAAAAACCAGATCATTTA TTCACTGGTCTAATAGGTGGTACCAACAACCGAGTTTCAGGTGTTCCT GCCAGATTCTCAGGCTCCCTGATTGGAGACAAGGCTGCCCTCACCATC ACAGGGGCACAGACTGAGGATGAGGCAATATATTTCTGTGCTCTATGG TACAGCAACCATTGGGTGTTCGGTGGAGGAACCAAACTGACTGTCCTA GGCCAGCCCAAGTCTTCGCCATCAGTCACCCTGTTTCCACCTTCCTCT GAAGAGCTCGAGACTAACAAGGCCACACTGGTGTGTACGATCACTGAT TTCTACCCAGGTGTGGTGACAGTGGACTGGAAGGTAGATGGTACCCCT GTCACTCAGGGTATGGAGACAACCCAGCCTTCCAAACAGAGCAACAAC AAGTACATGGCTAGCAGCTACCTGACCCTGACAGCAAGAGCATGGGAA AGGCATAGCAGTTACAGCTGCCAGGTCACTCATGAAGGTCACACTGTG GAGAAGAGTTTGTCCCGTGCTGACTGTTCCTAG (SEQ ID NO. 6) QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTG LIGGTNNRVSGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSN HWVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYP GVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHS SYSCQVTHEGHTVEKSLSRADCS

[0164] mAnti-Langerin2G3H--Nucleotide and mature protein amino acid sequence of the heavy chain of the mouse anti-Langerin 2G3 antibody cDNA, respectively. The variable region residues are underlined.

TABLE-US-00009 (SEQ ID NO. 7) ATGACATTGAACATGCTGTTGGGGCTGAAGTGGGTTTTCTTTGTTGTT TTTTATCAAGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGA GGATTGGTGCAGCCTAAAGGGTCATTGAAACTCTCATGTGCAGCCTCT GGATTAACCTTCAATATCTACGCCATGAACTGGGTCCGCCAGGCTCCA GGAAAGGGTTTGGAATGGGTTGCTCGCATAAGAAATAAAAGTAATAAT TATGCAACATATTATGCCGATTCAGTGAAAGACAGGTTCACCATCTCC AGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAACTTGAAA ACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGACA CCCCCATCTGTCTATCCACTGGCCCCTGGATCTGCTGCCCAAACTAAC TCCATGGTGACCCTGGGATGCCTGGTCAAGGGCTATTTCCCTGAGCCA GTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGCGGTGTGCACACC TTCCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTCAGTG ACTGTCCCCTCCAGCACCTGGCCCAGCGAGACCGTCACCTGCAACGTT GCCCACCCGGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGG GATTGTGGTTGTAAGCCTTGCATATGTACAGTCCCAGAAGTATCATCT GTCTTCATCTTCCCCCCAAAGCCCAAGGATGTGCTCACCATTACTCTG ACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGGATGATCCC GAGGTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCT CAGACGCAACCCCGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTC AGTGAACTTCCCATCATGCACCAGGACTGGCTCAATGGCAAGGAGTTC AAATGCAGGGTCAACAGTGCAGCTTTCCCTGCCCCCATCGAGAAAACC ATCTCCAAAACCAAAGGCAGACCGAAGGCTCCACAGGTGTACACCATT CCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTGACCTGC ATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGG AATGGGCAGCCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGAC ACAGATGGCTCTTACTTCGTCTACAGCAAGCTCAATGTGCAGAAGAGC AACTGGGAGGCAGGAAATACTTTCACCTGCTCTGTGTTACATGAGGGC CTGCACAACCACCATACTGAGAAGAGCCTCTCCCACTCTCCTGGTAAA GCTAGCTGA (SEQ ID NO. 8) EVQLVESGGGLVQPKGSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWV ARIRNKSNNYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMY YCVGRDWFDYWGQGTLVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGC LVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTW PSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPK PKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREE QFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGR PKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAEN YKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTE KSLSHSPGKAS

[0165] C84 rAB-pIRES2 [mAnti-Langerin2G3H-LV-hIgG4H-C-Dockerin] The coding region for this H chain-dockerin fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00010 (SEQ ID NO. 57) ATGACATTGAACATGCTGTTGGGGCTGAGGTGGGTTTTCTTTGTTGTT TTTTATCAAGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGA GGATTGGTGCAGCCTAAAGGGTCATTGAAACTCTCATGTGCAGCCTCT GGATTAACCTTCAATATCTACGCCATGAACTGGGTCCGCCAGGCTCCA GGAAAGGGTTTGGAATGGGTTGCTCGCATAAGAAATAAAAGTAATAAT TATGCAACATATTATGCCGATTCAGTGAAAGACAGGTTCACCATCTCC AGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAACTTGAAA ACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGAAG GGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG GTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAAC GTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCC AAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGG GGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATG ATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAG GAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTG CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTAC CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGC AAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTG TACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCC GTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTG GACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCT CTGGGTAAAGCTAGCAATTCTCCTCAAAATGAAGTACTGTACGGAGAT GTGAATGATGACGGAAAAGTAAACTCCACTGACTTGACTTTGTTAAAA AGATATGTTCTTAAAGCCGTCTCAACTCTCCCTTCTTCCAAAGCTGAA AAGAACGCAGATGTAAATCGTGACGGAAGAGTTAATTCCAGTGATGTC ACAATACTTTCAAGATATTTGATAAGGGTAATCGAGAAATTACCAATA TAA

[0166] The mature H chain sequence for C84 heavy chain is shown below. Joining sequence AS is bold and dockerin is underlined.

TABLE-US-00011 (SEQ ID NO. 58) EVQLVESGGGLVQPKGSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWV ARIRNKSNNYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMY YCVGRDWFDYWGQGTLVTVSAAKTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASNSPQNEVLYGDVNDDGKVNSTDLTLLKRYVLKAV STLPSSKAEKNADVNRDGRVNSSDVTILSRYLIRVIEKLPI

[0167] C85 rAB-pIRES2 [mAnti-Langerin2G3H-LV-hIgG4H-C-Flex-FluHA1-1-6xHis] The coding region for this H chain-Flu HA1-1 fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00012 (SEQ ID NO. 59) ATGACATTGAACATGCTGTTGGGGCTGAGGTGGGTTTTCTTTGTTGTT TTTTATCAAGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGA GGATTGGTGCAGCCTAAAGGGTCATTGAAACTCTCATGTGCAGCCTCT GGATTAACCTTCAATATCTACGCCATGAACTGGGTCCGCCAGGCTCCA GGAAAGGGTTTGGAATGGGTTGCTCGCATAAGAAATAAAAGTAATAAT TATGCAACATATTATGCCGATTCAGTGAAAGACAGGTTCACCATCTCC AGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAACTTGAAA ACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGAAG GGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG GTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAAC GTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCC AAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGG GGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATG ATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAG GAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTG CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTAC CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGC AAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTG TACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCC GTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTG GACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCT CTGGGTAAAGCTAGCGATACAACAGAACCTGCAACACCTACAACACCT GTAACAACAGACACAATATGTATAGGCTACCATGCGAACAATTCAACC GACACTGTTGACACAGTACTCGAGAAGAATGTGACAGTGACACACTCT GTTAACCTGCTCGAAGACAGCCACAACGGAAAACTATGTAGATTAAAA GGAATAGCCCCACTACAATTGGGGAAATGTAACATCGCCGGATGGCTC TTGGGAAACCCAGAATGCGACCCACTGCTTCCAGTGAGATCATGGTCC TACATTGTAGAAACACCAAACTCTGAGAATGGAATATGTTATCCAGGA GATTTCATCGACTATGAGGAGCTGAGGGAGCAATTGAGCTCAGTGTCA TCATTCGAAAGATTCGAAATATTTCCCAAAGAAAGCTCATGGCCCAAC CACAACACAAACGGAGTAACGGCAGCATGCTCCCATGAGGGGAAAAGC AGTTTTTACAGAAATTTGCTATGGCTGACGGAGAAGGAGGGCTCATAC CCAAAGCTGAAAAATTCTTATGTGAACAAAAAAGGGAAAGAAGTCCTT GTACTGTGGGGTATTCATCACCCGCCTAACAGTAAGGAACAACAGAAT CTCTATCAGAATGAAAATGCTTATGTCTCTGTAGTGACTTCAAATTAT AACAGGAGATTTACCCCGGAAATAGCAGAAAGACCCAAAGTAAGAGAT CAAGCTGGGAGGATGAACTATTACTGGACCTTGCTAAAACCCGGAGAC ACAATAATATTTGAGGCAAATGGAAATCTAATAGCACCAATGTATGCT TTCGCACTGAGTAGAGGCTTTGGGTCCGGCATCATCACCTCAAACGCA TCAATGCATGAGTGTAACACGAAGTGTCAAACACCCCTGGGAGCTATA AACAGCAGTCTCCCTTACCAGAATATACACCCAGTCACAATAGGAGAG TGCCCAAAATACGTCAGGAGTGCCAAATTGAGGATGGTTCACCATCA CCATCACCATTGA

[0168] The mature H chain sequence for C85 heavy chain is shown below. Joining sequence AS is bold and Flu HA1-1 is underlined. A flexible linker joining sequence is italicized.

TABLE-US-00013 (SEQ ID NO. 60) EVQLVESGGGLVQPKGSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWV ARIRNKSNNYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMY YCVGRDWFDYWGQGTLVTVSAAKTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASDTTEPATPTTPVTTDTICIGYHANNSTDTVDTVL EKNVTVTHSVNLLEDSHNGKLCRLKGIAPLQLGKCNIAGWLLGNPECD PLLPVRSWSYIVETPNSENGICYPGDFIDYEELREQLSSVSSFERFEI FPKESSWPNHNTNGVTAACSHEGKSSFYRNLLWLTEKEGSYPKLKNSY VNKKGKEVLVLWGIHHPPNSKEQQNLYQNENAYVSVVTSNYNRRFTPE IAERPKVRDQAGRMNYYWTLLKPGDTIIFEANGNLIAPMYAFALSRGF GSGIITSNASMHECNTKCQTPLGAINSSLPYQNIHPVTIGECPKYVRS AKLRMVHHHHHH

[0169] C86 rAB-pIRES2 [mAnti-Langerin2G3H-LV-hIgG4H-C-Flex-FluHA5-1-6xHis] The coding region for this H chain-Flu HA5-1 fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00014 (SEQ ID NO. 61) ATGACATTGAACATGCTGTTGGGGCTGAGGTGGGTTTTCTTTGTTGTT TTTTATCAAGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGA GGATTGGTGCAGCCTAAAGGGTCATTGAAACTCTCATGTGCAGCCTCT GGATTAACCTTCAATATCTACGCCATGAACTGGGTCCGCCAGGCTCCA GGAAAGGGTTTGGAATGGGTTGCTCGCATAAGAAATAAAAGTAATAAT TATGCAACATATTATGCCGATTCAGTGAAAGACAGGTTCACCATCTCC AGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAACTTGAAA ACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGAAG GGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG GTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAAC GTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCC AAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGG GGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATG ATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAG GAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTG CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTAC CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGC AAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTG TACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCC GTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTG GACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCT CTGGGTAAAGCTAGCGATACAACAGAACCTGCAACACCTACAACACCT GTAACAACAGATCAGATTTGCATTGGTTACCATGCAAACAACTCGACA GAGCAGGTTGACACAATAATGGAAAAGAACGTTACTGTTACACATGCC CAAGACATACTGGAAAAGAAACACAACGGGAAGCTCTGCGATCTAGAT GGAGTGAAGCCTCTAATTTTGAGAGATTGTAGCGTAGCTGGATGGCTC CTCGGAAACCCAATGTGTGACGAATTCATCAATGTGCCGGAATGGTCT TACATAGTGGAGAAGGCCAATCCAGTCAATGACCTCTGTTACCCAGGG GATTTCAATGACTATGAAGAATTGAAACACCTATTGAGCAGAATAAAC CATTTTGAGAAAATTCAGATCATCCCCAAAAGTTCTTGGTCCAGTCAT GAAGCCTCATTAGGGGTGAGCTCAGCATGTCCATACCAGGGAAAGTCC TCCTTTTTCAGAAATGTGGTATGGCTTATCAAAAAGAACAGTACATAC CCAACAATAAAGAGGAGCTACAATAATACCAACCAAGAAGATCTTTTG GTACTGTGGGGGATTCACCATCCTAATGATGCGGCAGAGCAGACAAAG CTCTATCAAAACCCAACCACCTATATTTCCGTTGGGACATCAACACTA AACCAGAGATTGGTACCAAGAATAGCTACTAGATCCAAAGTAAACGGG CAAAGTGGAAGGATGGAGTTCTTCTGGACAATTTTAAAGCCGAATGAT GCAATCAACTTCGAGAGTAATGGAAATTTCATTGCTCCAGAATATGCA TACAAAATTGTCAAGAAAGGGGACTCAACAATTATGAAAAGTGAATTG GAATATGGTAACTGCAACACCAAGTGTCAAACTCCAATGGGGGCGATA AACTCTAGCATGCCATTCCACAATATACACCCTCTCACCATTGGGGAA TGCCCCAAATATGTGAAATCAAACAGATTAGTCCTTGCGCACCATCAC CATCACCATTGA

[0170] The mature H chain sequence for C86 heavy chain is shown below. Joining sequence AS is bold and Flu HA5-1 is underlined. A flexible linker joining sequence is italicized.

TABLE-US-00015 (SEQ ID NO. 62) EVQLVESGGGLVQPKGSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWV ARIRNKSNNYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMY YCVGRDWFDYWGQGTLVTVSAAKTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASDTTEPATPTTPVTTDQICIGYHANNSTEQVDTIM EKNVTVTHAQDILEKKHNGKLCDLDGVKPLILRDCSVAGWLLGNPMCD EFINVPEWSYIVEKANPVNDLCYPGDFNDYEELKHLLSRINHFEKIQI IPKSSWSSHEASLGVSSACPYQGKSSFFRNVVWLIKKNSTYPTIKRSY NNTNQEDLLVLWGIHHPNDAAEQTKLYQNPTTYISVGTSTLNQRLVPR IATRSKVNGQSGRMEFFWTILKPNDAINFESNGNFIAPEYAYKIVKKG DSTIMKSELEYGNCNTKCQTPMGAINSSMPFHNIHPLTIGECPKYVKS NRLVLAHHHHHH

[0171] C804 rAB-cetHS-puro [mAnti-L angerin2 G3H-LV-hIgGK-C-Flex-hPSA] The coding region for this H chain-PSA fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00016 (SEQ ID NO. 63) ATGACATTGAACATGCTGTTGGGGCTGAAGTGGGTTTTCTTTGTTGTT TTTTATCAAGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGA GGATTGGTGCAGCCTAAAGGGTCATTGAAACTCTCATGTGCAGCCTCT GGATTAACCTTCAATATCTACGCCATGAACTGGGTCCGCCAGGCTCCA GGAAAGGGTTTGGAATGGGTTGCTCGCATAAGAAATAAAAGTAATAAT TATGCAACATATTATGCCGATTCAGTGAAAGACAGGTTCACCATCTCC AGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAACTTGAAA ACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGAAG GGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGA GAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGT GGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAA CGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTC CAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGG GGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCAT GATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCA GGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTA CCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGG CAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCAT CGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGT GTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC CGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGT GGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGAT GCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTC TCTGGGTAAAGCTAGCGATACAACAGAACCTGCAACACCTACAACACC TGTAACAACACCGACAACAACACTTCTAGCGCCCCTCATCCTGTCTCG GATTGTGGGAGGCTGGGAGTGCGAGAAGCATTCCCAACCCTGGCAGGT GCTTGTGGCCTCTCGTGGCAGGGCAGTCTGCGGCGGTGTTCTGGTGCA CCCCCAGTGGGTCCTCACAGCTGCCCACTGCATCAGGAACAAAAGCGT GATCTTGCTGGGTCGGCACAGCCTGTTTCATCCTGAAGACACAGGCCA GGTATTTCAGGTCAGCCACAGCTTCCCACACCCGCTCTACGATATGAG CCTCCTGAAGAATCGATTCCTCAGGCCAGGTGATGACTCCAGCCACGA CCTCATGCTGCTCCGCCTGTCAGAGCCTGCCGAGCTCACGGATGCTGT GAAGGTCATGGACCTGCCCACCCAGGAGCCAGCACTGGGGACCACCTG CTACGCCTCAGGCTGGGGCAGCATTGAACCAGAGGAGTTCTTGACCCC AAAGAAACTTCAGTGTGTGGACCTCCATGTTATTTCCAATGACGTGTG TGCGCAAGTTCACCCTCAGAAGGTGACCAAGTTCATGCTGTGTGCTGG ACGCTGGACAGGGGGCAAAAGCACCTGCTCGGGTGATTCTGGGGGCCC ACTTGTCTGTAATGGTGTGCTTCAAGGTATCACGTCATGGGGCAGTGA ACCATGTGCCCTGCCCGAAAGGCCTTCCCTGTACACCAAGGTGGTGCA TTACCGGAAGTGGATCAAGGACACCATCGTGGCCAACCCCTGA

[0172] The mature H chain sequence for C804 heavy chain is shown below. Joining sequence AS is bold and PSA is underlined. A flexible linker joining sequence is italicized.

TABLE-US-00017 (SEQ ID NO. 64) EVQLVESGGGLVQPKGSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVA RIRNKSNNYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMYYC VGRDWFDYWGQGTLVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGKASDTTEPATPTTPVTTPTTTLLAPLILSRIVGGWECEKHSQPWQVL VASRGRAVCGGVLVHPQWVLTAAHCIRNKSVILLGRHSLFHPEDTGQVF QVSHSFPHPLYDMSLLKNRFLRPGDDSSHDLMLLRLSEPAELTDAVKVM DLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVISNDVCAQVH PQKVTKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALP ERPSLYTKVVHYRKWIKDTIVANP

[0173] C87 rAB-pIRES2 [mAnti-Langerin15B10H-SLAML-V-hIgG4H-Flex-FluHA5-1-6xHis] The coding region for this H chain-Flu HA5-1 fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00018 (SEQ ID NO. 65) ATGGACCCCAAAGGCTCCCTTTCCTGGAGAATACTTCTGTTTCTCTCC CTGGCTTTTGAGTTGTCGTACGGACAGGTTCAGCTGCGGCAGTCTGGA CCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCT TCTGGATACACATTTACTGACTATGTTATAAGTTGGGTGAAGCAGAGA ACTGGACAGGGCCTTGAGTGGATTGGAGATATTTATCCTGGAAGTGGT TATTCTTTCTACAATGAGAACTTCAAGGGCAAGGCCACACTGACTGCA GACAAATCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCT GAGGACTCTGCGGTCTATTTCTGTGCAACCTACTATAACTACCCTTTT GCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACA ACGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG TCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAA GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACG TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAC GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAG GTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACC GTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAAGCTAGCGATACAACAGAACCTGCAACACCTACAACA CCTGTAACAACAGATCAGATTTGCATTGGTTACCATGCAAACAACTCG ACAGAGCAGGTTGACACAATAATGGAAAAGAACGTTACTGTTACACAT GCCCAAGACATACTGGAAAAGAAACACAACGGGAAGCTCTGCGATCTA GATGGAGTGAAGCCTCTAATTTTGAGAGATTGTAGCGTAGCTGGATGG CTCCTCGGAAACCCAATGTGTGACGAATTCATCAATGTGCCGGAATGG TCTTACATAGTGGAGAAGGCCAATCCAGTCAATGACCTCTGTTACCCA GGGGATTTCAATGACTATGAAGAATTGAAACACCTATTGAGCAGAATA AACCATTTTGAGAAAATTCAGATCATCCCCAAAAGTTCTTGGTCCAGT CATGAAGCCTCATTAGGGGTGAGCTCAGCATGTCCATACCAGGGAAAG TCCTCCTTTTTCAGAAATGTGGTATGGCTTATCAAAAAGAACAGTACA TACCCAACAATAAAGAGGAGCTACAATAATACCAACCAAGAAGATCTT TTGGTACTGTGGGGGATTCACCATCCTAATGATGCGGCAGAGCAGACA AAGCTCTATCAAAACCCAACCACCTATATTTCCGTTGGGACATCAACA CTAAACCAGAGATTGGTACCAAGAATAGCTACTAGATCCAAAGTAAAC GGGCAAAGTGGAAGGATGGAGTTCTTCTGGACAATTTTAAAGCCGAAT GATGCAATCAACTTCGAGAGTAATGGAAATTTCATTGCTCCAGAATAT GCATACAAAATTGTCAAGAAAGGGGACTCAACAATTATGAAAAGTGAA TTGGAATATGGTAACTGCAACACCAAGTGTCAAACTCCAATGGGGGCG ATAAACTCTAGCATGCCATTCCACAATATACACCCTCTCACCATTGGG GAATGCCCCAAATATGTGAAATCAAACAGATTAGTCCTTGCGCACCAT CACCATCACCATTGA

[0174] The mature H chain sequence for C87 heavy chain is shown below. Joining sequence AS is bold and Flu HA5-1 is underlined.

TABLE-US-00019 (SEQ ID NO. 66) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWI GDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFC ATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASDTTEPATPTTPVTTDQICIGYHANNSTEQVDTIM EKNVTVTHAQDILEKKHNGKLCDLDGVKPLILRDCSVAGWLLGNPMCD EFINVPEWSYIVEKANPVNDLCYPGDFNDYEELKHLLSRINHFEKIQI IPKSSWSSHEASLGVSSACPYQGKSSFFRNVVWLIKKNSTYPTIKRSY NNTNQEDLLVLWGIHHPNDAAEQTKLYQNPTTYISVGTSTLNQRLVPR IATRSKVNGQSGRMEFFWTILKPNDAINFESNGNFIAPEYAYKIVKKG DSTIMKSELEYGNCNTKCQTPMGAINSSMPFHNIHPLTIGECPKYVKS NRLVLAHHHHHH

[0175] C88 rAB-pIRES2 [mAnti-Langerin15B10H-SLAML-V-hIgG4H-C-Dockerin] The coding region for this H chain-dockerin fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00020 (SEQ ID NO. 67) ATGGACCCCAAAGGCTCCCTTTCCTGGAGAATACTTCTGTTTCTCTCC CTGGCTTTTGAGTTGTCGTACGGACAGGTTCAGCTGCGGCAGTCTGGA CCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCT TCTGGATACACATTTACTGACTATGTTATAAGTTGGGTGAAGCAGAGA ACTGGACAGGGCCTTGAGTGGATTGGAGATATTTATCCTGGAAGTGGT TATTCTTTCTACAATGAGAACTTCAAGGGCAAGGCCACACTGACTGCA GACAAATCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCT GAGGACTCTGCGGTCTATTTCTGTGCAACCTACTATAACTACCCTTTT GCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACA ACGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG TCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAA GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACG TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAC GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAG GTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACC GTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAAGCTAGCAATTCTCCTCAAAATGAAGTACTGTACGGA GATGTGAATGATGACGGAAAAGTAAACTCCACTGACTTGACTTTGTTA AAAAGATATGTTCTTAAAGCCGTCTCAACTCTCCCTTCTTCCAAAGCT GAAAAGAACGCAGATGTAAATCGTGACGGAAGAGTTAATTCCAGTGAT GTCACAATACTTTCAAGATATTTGATAAGGGTAATCGAGAAATTACCA ATATAA

[0176] The mature H chain sequence for C88 heavy chain is shown below. Joining sequence AS is bold and dockerin is shaded grey. A flexible linker joining sequence is underlined.

TABLE-US-00021 (SEQ ID NO. 68) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWI GDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFC ATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSVHTFPAVLQSSGLYSLSSVVTVPSSSL GTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLGKASNSPQNEVLYGDVNDDGKVNSTDLTLLKRYVLKAVS TLPSSKAEKNADVNRDGRVNSSDVTILSRYLIRVIEKLPI

[0177] C89 rAB-pIRES2[mAnti-Langerin15B10H-SLAML-V-hIgG4H-Flex-FluHA1-1-6x- His] The coding region for this H chain-Flu HA1-1 fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00022 (SEQ ID NO. 69) ATGGACCCCAAAGGCTCCCTTTCCTGGAGAATACTTCTGTTTCTCTCC CTGGCTTTTGAGTTGTCGTACGGACAGGTTCAGCTGCGGCAGTCTGGA CCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCT TCTGGATACACATTTACTGACTATGTTATAAGTTGGGTGAAGCAGAGA ACTGGACAGGGCCTTGAGTGGATTGGAGATATTTATCCTGGAAGTGGT TATTCTTTCTACAATGAGAACTTCAAGGGCAAGGCCACACTGACTGCA GACAAATCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCT GAGGACTCTGCGGTCTATTTCTGTGCAACCTACTATAACTACCCTTTT GCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACA ACGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG TCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAA GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACG TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAC GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAG GTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACC GTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAAGCTAGCGATACAACAGAACCTGCAACACCTACAACA CCTGTAACAACAGACACAATATGTATAGGCTACCATGCGAACAATTCA ACCGACACTGTTGACACAGTACTCGAGAAGAATGTGACAGTGACACAC TCTGTTAACCTGCTCGAAGACAGCCACAACGGAAAACTATGTAGATTA AAAGGAATAGCCCCACTACAATTGGGGAAATGTAACATCGCCGGATGG CTCTTGGGAAACCCAGAATGCGACCCACTGCTTCCAGTGAGATCATGG TCCTACATTGTAGAAACACCAAACTCTGAGAATGGAATATGTTATCCA GGAGATTTCATCGACTATGAGGAGCTGAGGGAGCAATTGAGCTCAGTG TCATCATTCGAAAGATTCGAAATATTTCCCAAAGAAAGCTCATGGCCC AACCACAACACAAACGGAGTAACGGCAGCATGCTCCCATGAGGGGAAA AGCAGTTTTTACAGAAATTTGCTATGGCTGACGGAGAAGGAGGGCTCA TACCCAAAGCTGAAAAATTCTTATGTGAACAAAAAAGGGAAAGAAGTC CTTGTACTGTGGGGTATTCATCACCCGCCTAACAGTAAGGAACAACAG AATCTCTATCAGAATGAAAATGCTTATGTCTCTGTAGTGACTTCAAAT TATAACAGGAGATTTACCCCGGAAATAGCAGAAAGACCCAAAGTAAGA GATCAAGCTGGGAGGATGAACTATTACTGGACCTTGCTAAAACCCGGA GACACAATAATATTTGAGGCAAATGGAAATCTAATAGCACCAATGTAT GCTTTCGCACTGAGTAGAGGCTTTGGGTCCGGCATCATCACCTCAAAC GCATCAATGCATGAGTGTAACACGAAGTGTCAAACACCCCTGGGAGCT ATAAACAGCAGTCTCCCTTACCAGAATATACACCCAGTCACAATAGGA GAGTGCCCAAAATACGTCAGGAGTGCCAAATTGAGGATGGTTCACCAT CACCATCACCATTGA

[0178] The mature H chain sequence for C89 heavy chain is shown below. Joining sequence AS is bold and Flu HA1-1 is underlined. A flexible linker joining sequence is italicized.

TABLE-US-00023 (SEQ ID NO. 70) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWI GDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFC ATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASDTTEPATPTTPVTTDTICIGYHANNSTDTVDTVL EKNVTVTHSVNLLEDSHNGKLCRLKGIAPLQLGKCNIAGWLLGNPECD PLLPVRSWSYIVETPNSENGICYPGDFIDYEELREQLSSVSSFERFEI FPKESSWPNHNTNGVTAACSHEGKSSFYRNLLWLTEKEGSYPKLKNSY VNKKGKEVLVLWGIHHPPNSKEQQNLYQNENAYVSVVTSNYNRRFTPE IAERPKVRDQAGRMNYYWTLLKPGDTIIFEANGNLIAPMYAFALSRGF GSGIITSNASMHECNTKCQTPLGAINSSLPYQNIHPVTIGECPKYVRS AKLRMVHHHHHH

[0179] C246 rAB-pIRES2[mAnti-Langerin15B10H-SLAML-V-hIgG4H-Viralgag] The coding region for this H chain-gag fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00024 (SEQ ID NO. 71) ATGGACCCCAAAGGCTCCCTTTCCTGGAGAATACTTCTGTTTCTCTCC CTGGCTTTTGAGTTGTCGTACGGACAGGTTCAGCTGCGGCAGTCTGGA CCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCT TCTGGATACACATTTACTGACTATGTTATAAGTTGGGTGAAGCAGAGA ACTGGACAGGGCCTTGAGTGGATTGGAGATATTTATCCTGGAAGTGGT TATTCTTTCTACAATGAGAACTTCAAGGGCAAGGCCACACTGACTGCA GACAAATCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCT GAGGACTCTGCGGTCTATTTCTGTGCAACCTACTATAACTACCCTTTT GCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACA ACGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG TCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAA GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACG TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAC GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAG GTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACC GTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAAGCTAGCGACATGGCCAAGAAGGAGACAGTCTGGAGG CTCGAGGAGTTCGGTAGGCCTATAGTGCAGAACATCCAGGGGCAAATG GTACATCAGGCCATATCACCTAGAACTTTAAATGCATGGGTAAAAGTA GTAGAAGAGAAGGCTTTCAGCCCAGAAGTAATACCCATGTTTTCAGCA TTATCAGAAGGAGCCACCCCACAAGATTTAAACACCATGCTAAACACA GTGGGGGGACATCAAGCAGCCATGCAAATGTTAAAAGAGACCATCAAT GAGGAAGCTGCAGAATGGGATAGAGTACATCCAGTGCATGCAGGGCCT ATTGCACCAGGCCAGATGAGAGAACCAAGGGGAAGTGACATAGCAGGA ACTACTAGTACCCTTCAGGAACAAATAGGATGGATGACAAATAATCCA CCTATCCCAGTAGGAGAAATTTATAAAAGATGGATAATCCTGGGATTA AATAAAATAGTAAGAATGTATAGCCCTACCAGCATTCTGGACATAAGA CAAGGACCAAAAGAACCTTTTAGAGACTATGTAGACCGGTTCTATAAA ACTCTAAGAGCCGAGCAAGCTTCACAGGAGGTAAAAAATTGGATGACA GAAACCTTGTTGGTCCAAAATGCGAACCCAGATTGTAAGACTATTTTA AAAGCATTGGGACCAGCGGCTACACTAGAAGAAATGATGACAGCATGT CAGGGAGTAGGAGGACCCGGCCATAAGGCAAGAGTTTTGTGA

[0180] The mature H chain sequence for C89 heavy chain is shown below. Joining sequence AS is bold and Gag p24 is underlined. A flexible linker joining sequence is italicized.

TABLE-US-00025 (SEQ ID NO. 72) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWI GDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFC ATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASDMAKKETVWRLEEFGRPIVQNIQGQMVHQAISPR TLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVGGHQAAM QMLKETINEEAAEWDRVHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQ IGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFR DYVDRFYKTLRAEQASQEVKNWMTETLLVQNANPDCKTILKALGPAAT LEEMMTACQGVGGPGHKARVL

[0181] C742 rAB-cetHS-puro [mAnti-Langerin-15B10H-LV-hIgG4H-C-Flex-hPSA] The coding region for this H chain-PSA fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGC restriction site.

TABLE-US-00026 (SEQ ID NO. 73) ATGGAATGGAGGATCTTTCTCTTCATCCTGTCAGGAACTGCAGGTGTC CACTCCCAGGTTCAGCTGCGGCAGTCTGGACCTGAGCTGGTGAAGCCT GGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTTACT GACTATGTTATAAGTTGGGTGAAGCAGAGAACTGGACAGGGCCTTGAG TGGATTGGAGATATTTATCCTGGAAGTGGTTATTCTTTCTACAATGAG AACTTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCACCACA GCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTAT TTCTGTGCAACCTACTATAACTACCCTTTTGCTTACTGGGGCCAAGGG ACTCTGGTCACTGTCTCTGCAGCCAAAACAACGGGCCCATCCGTCTTC CCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC AGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCC AGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCA TGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACCATCAGTCTTC CTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCT GAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTC CAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGC AGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCAT CCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCA AAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACG GCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACA ACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCG ATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAA CAACACTTCTAGCGCCCCTCATCCTGTCTCGGATTGTGGGAGGCTGGG AGTGCGAGAAGCATTCCCAACCCTGGCAGGTGCTTGTGGCCTCTCGTG GCAGGGCAGTCTGCGGCGGTGTTCTGGTGCACCCCCAGTGGGTCCTCA CAGCTGCCCACTGCATCAGGAACAAAAGCGTGATCTTGCTGGGTCGGC ACAGCCTGTTTCATCCTGAAGACACAGGCCAGGTATTTCAGGTCAGCC ACAGCTTCCCACACCCGCTCTACGATATGAGCCTCCTGAAGAATCGAT TCCTCAGGCCAGGTGATGACTCCAGCCACGACCTCATGCTGCTCCGCC TGTCAGAGCCTGCCGAGCTCACGGATGCTGTGAAGGTCATGGACCTGC CCACCCAGGAGCCAGCACTGGGGACCACCTGCTACGCCTCAGGCTGGG GCAGCATTGAACCAGAGGAGTTCTTGACCCCAAAGAAACTTCAGTGTG TGGACCTCCATGTTATTTCCAATGACGTGTGTGCGCAAGTTCACCCTC AGAAGGTGACCAAGTTCATGCTGTGTGCTGGACGCTGGACAGGGGGCA AAAGCACCTGCTCGGGTGATTCTGGGGGCCCACTTGTCTGTAATGGTG TGCTTCAAGGTATCACGTCATGGGGCAGTGAACCATGTGCCCTGCCCG AAAGGCCTTCCCTGTACACCAAGGTGGTGCATTACCGGAAGTGGATCA AGGACACCATCGTGGCCAACCCCTGA

[0182] The mature H chain sequence for C742 heavy chain is shown below. Joining sequence AS is bold and PSA is underlined. A flexible linker joining sequence is italicized.

TABLE-US-00027 (SEQ ID NO. 74) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWI GDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFC ATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASDTTEPATPTTPVTTPTTTLLAPLILSRIVGGWEC EKHSQPWQVLVASRGRAVCGGVLVHPQWVLTAAHCIRNKSVILLGRHS LFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSHDLMLLRLS EPAELTDAVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVD LHVISNDVCAQVHPQKVTKFMLCAGRWTGGKSTCSGDSGGPLVCNGVL QGITSWGSEPCALPERPSLYTKVVHYRKWIKDTIVANP

[0183] C1011 rAB-cetHS-puro [mAnti-Langerin15B10H-LV-hIgG4H-C-Flex-v1-Pep-gag17-f1-gag253-f2-nef116-f- 3-nef66-f4-pol 158] a.k.a. Anti-Langerin15B10H-HIPO5. The coding region for this H chain-HIV peptides fusion protein is shown below. Start and stop codons are in bold, as is the joining GCTAGT restriction site.

TABLE-US-00028 (SEQ ID NO. 75) ATGGAATGGAGGATCTTTCTCTTCATCCTGTCAGGAACTGCAGGTGTC CACTCCCAGGTTCAGCTGCGGCAGTCTGGACCTGAGCTGGTGAAGCCT GGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTTACT GACTATGTTATAAGTTGGGTGAAGCAGAGAACTGGACAGGGCCTTGAG TGGATTGGAGATATTTATCCTGGAAGTGGTTATTCTTTCTACAATGAG AACTTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCACCACA GCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTAT TTCTGTGCAACCTACTATAACTACCCTTTTGCTTACTGGGGCCAAGGG ACTCTGGTCACTGTCTCTGCAGCCAAAACAACGGGCCCATCCGTCTTC CCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC AGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCC AGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCA TGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACCATCAGTCTTC CTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCT GAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTC CAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGC AAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCA TCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTC AAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGG CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGT CAGACCCCCACCAACACCATCAGCGTGACCCCCACCAACAACAGCACC CCCACCAACAACAGCAACCCCAAGCCCAACCCCGCTAGTGAGAAGATC CGGCTGCGGCCCGGCGGCAAGAAGAAGTACAAGCTGAAGCACATCGTG GCTAGTAGCAGCGTGAGCCCCACCACCAGCGTGCACCCCACCCCCACC AGCGTGCCCCCCACCCCCACCAAGAGCAGCCCCGCTAGTAACCCCCCC ATCCCCGTGGGCGAGATCTACAAGCGGTGGATCATCCTGGGCCTGAAC AAGATCGTGCGGATGTACAGCCCCACCAGCATCCTGGACGCTAGTCCC ACCAGCACCCCCGCCGACAGCAGCACCATCACCCCCACCGCCACCCCC ACCGCCACCCCCACCATCAAGGGCGCTAGTCACACCCAGGGCTACTTC CCCGACTGGCAGAACTACACCCCCGGCCCCGGCGTGCGGTACCCCCTG ACCTTCGGCTGGCTGTACAAGCTGGCTAGTACCGTGACCCCCACCGCC ACCGCCACCCCCAGCGCCATCGTGACCACCATCACCCCCACCGCCACC ACCAAGCCCGCTAGTGTGGGCTTCCCCGTGACCCCCCAGGTGCCCCTG CGGCCCATGACCTACAAGGCCGCCGTGGACCTGAGCCACTTCCTGAAG GAGAAGGGCGGCCTGGCTAGTACCAACGGCAGCATCACCGTGGCCGCC ACCGCCCCCACCGTGACCCCCACCGTGAACGCCACCCCCAGCGCCGCC GCTAGTGCCATCTTCCAGAGCAGCATGACCAAGATCCTGGAGCCCTTC CGGAAGCAGAACCCCGACATCGTGATCTACCAGTACATGGACGACCTG TACGCTAGCTGA

[0184] The mature H chain sequence for C1011 heavy chain is shown below. Joining sequences AS are bold and HIV peptides are underlined. A flexible linker joining sequence is italicized.

TABLE-US-00029 (SEQ ID NO. 76) QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWI GDIYPGSGYSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFC ATYYNYPFAYWGQGTLVTVSAAKTTGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGKASQTPTNTISVTPTNNSTPTNNSNPKPNPASEKIRL RPGGKKKYKLKHIVASSSVSPTTSVHPTPTSVPPTPTKSSPASNPPIP VGEIYKRWIILGLNKIVRMYSPTSILDASPTSTPADSSTITPTATPTA TPTIKGASHTQGYFPDWQNYTPGPGVRYPLTFGWLYKLASTVTPTATA TPSAIVTTITPTATTKPASVGFPVTPQVPLRPMTYKAAVDLSHFLKEK GGLASTNGSITVAATAPTVTPTVNATPSAAASAIFQSSMTKILEPFRK QNPDIVIYQYMDDLYAS

[0185] FIG. 8 shows the binding of recombinant anti-Langerin antibodies fused to antigens retain their ability to bind to beads decorated with human and non-human primate (NHP) Langerin ectodomain proteins. Luminex beads of different colors were covalently linked to cellulose binding protein fused to dockerin. The beads were then mixed with either human Langerin ectodomain fused to cohesin, or with NHP (Rhesus macaque) Langerin ectodomain fused to cohesin. The beads were washed and mixed, then incubated with serial dilutions of various pure recombinant anti-Langerin 2G3 or 15B10 mouse V region-human IgG4 chimeric antibodies or the same antibodies with C-terminal fusions to human prostate specific antigen (PSA), or control pure recombinant anti-CD40 12E12 mouse V region-human IgG4 chimeric antibody. After washing, the beads were incubated with an anti-human Fc-PE reagent, washed again, and then read on a BioPlex instrument to detect florescence bound to the different colored beads (expressed as % MFI relative to the maximal signal seen on each bead type.

[0186] FIG. 9 shows the ability of recombinant anti-Langerin 15B10 antibody fused to Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain to evoke potent antigen-specific antibody production in NHP. NHP were injected intramuscularly (im) with 10E6 pr8 Flu virus and subcutaneously (sc) HIV gag p24 protein (First boost); .about.2 months later the NHP were again injected with HIV gag p24 protein (Second boost); about 6 weeks and 4 months later, the NHP were injected intradermal (id) with 100 .mu.g anti-Langerin 15B10 HA1-1 fusion protein with poly IC as adjuvant, or with anti-DCIR HA1-1 fusion protein with poly IC, or with a standard dose of commercial Vaccigrip Flu vaccine and 10E6 pr8 Flu virus. At the indicated dates, serum samples were taken and pooled (4 NHP per group) and serial dilutions were tested for HA1-1 specific IgG antibodies by a baed-based assay. The data shows that the anti-Langerin-HA1-1 vaccine raises potent high titer anti-HA1-1 antibody responses in NHP--the titers observed were 1-2 logs higher than observed with the Vaccigrip control group.

[0187] These data show that both anti-Langerin 15B10 and 2G3 recombinant antibodies or such antibodies linked to a cancer antigen retain significant binding to NHP Langerin--a very desirable property for commercial development of these antibodies as antigen-targeting vaccines [this enables mechanism-based preclinical testing of safety and efficacy in NHP models].

[0188] FIG. 10 shows that recombinant fusion proteins of anti-human DC receptors and antigens induce antigen-specific immune responses in NHP: Rhesus macaques (4 animals in each group) immunized i.m. with live influenza virus (A/PR8, H1N1) and HIVgag-derived p24-PLA on day 0. On day 28, animals were boosted with p24-PLA alone. On day 77 and day 119, each group of animals was immunized as described in FIG. 18 (below). Anti-Langerin-HA1 response in Rhesus macaque--IFN-.gamma. response measured by ELISPOT after ex vivo stimulation with HA peptides. Red arrows indicate priming injections with live influenza virus (A/PR8, H1N1). Blue arrows indicate boost injections. Control group (4 animals) were immunized i.m. with live influenza virus and commercial flu vaccine, VACCIGRIP, with 100 ug poly I:C per animal. Experimental group (4 animals) were boosted i.d. with anti-DCIR-HA1 (100 .mu.g/animals) with 100 .mu.g of poly I:C per animal. The data above show that anti-Langerin-HA1 elicited potent HA1-specific T cells responses as measured by IFN.gamma. ELISPOT.

[0189] FIG. 11 shows that the Anti-Langerin G3 antibody specifically stains NHP Langerhans cells. Rhesus macaque skin sections were prepared and stained with anti-Langerin 2G3 and then Texas Red-labeled goat ant-mouse reagent. Cell nuclei were stained with DAPI [blue]. This shows specific staining of NHP LC demonstrating the specific cross-reactivity of this anti-human Langerin antibody with NHP Langerin.

[0190] The 15B10.3 hydridoma has been deposited under the Budapest Treaty with the U.S. American Type Culture Collection and received Deposit No. PTA-9852; and the 2G3.6 hybridoma received Deposit No. PTA-9853.

[0191] FIG. 12 shows the antibody titers for anti-HIV-gag antibodies in NHP vaccination with a gag-microparticle, an anti-hIGG4-gag antibody, an anti-DCIR-gag vaccine and an anti-Langerin-gag-p24 vaccine, all with or without poly I:C as an adjuvant. Briefly, non-human primates (NHP) were immunized and anti-Langerin-gag24 antibody responses were determined. It was found that more potent were possible with the anti-Langerin-gagp24 constructs than with gag p24 on a microcarrier or control antibody-p24. Unlike anti-DCIR targeting, it was found that anti-Langerin-Ag vaccination is relatively independent of poly I:C adjuvant. Each curve is an individual monkey, the assay is serum dilutions tested for antibodies against p24. Cynomolgus macaques were injected i.d. with 250 ug of each antibody-HIV gag p24 vaccine or gag p24 attached to a microcarrier (p24 amount was normalized to correspond to the actual amount of p24 mass injected). The animals were then injected twice more at 6 week intervals. The FIG. 12 graph shows represents ELISA assay for antigen-specific anti-gag p24 titers of serum samples taken 2 weeks after the third injection. FIG. 12 shows serial dilutions of the sera graphed for each individual monkey [graph lines shown in blue]. A parallel group of monkeys were co-injected with the p24 proteins and poly I:C adjuvant [graph lines shown in red].

[0192] FIG. 13--FACS analysis on Langerin clones: 293F cells were transiently transfected with vectors directing the expression of full-length (cell surface) langerin from human, Rhesus macaque, and mouse. Cells were stained with a dilution series of the pure monoclonal antibodies, washed, then counterstained with an anti-mouse IgG-PE conjugate, then washed again. Cells were analyzed by flow cytometry. The data are expressed as % cells giving a positive cell surface staining signal relative to the control untransfected cells.

[0193] FIG. 14--ELISA analysis in two formats--direct (antigen bound to plate directly and bound antibody detected with an anti-mouse IgG-HRP conjugate) and capture (antibody bound to plate, capturing a fixed concentration of biotinylated Langerin ectodomain protein, detected with a neutravidin-HRP reagent). ELISA data for human, Rhesus macaque, and mouse Langerin ectodomain proteins are shown.

TABLE-US-00030 TABLE 1 Immunogenicity in cynomolgus macaques of anti-Langerin- Gag and anti-DCIR-Gag fusion protein, for FIG. 12. Group 1 (n = 6) 0.25 mg anti-Langerin-Gag Group 2 (n = 6) 0.25 mg anti-Langerin-Gag + 0.25 mg PolyIC Group 3 (n = 6) 0.25 mg anti-DCIR-Gag Group 4 (n = 6) 0.25 mg anti-DCIR-Gag + 0.25 mg PolyIC Group 5 (n = 3) 0.25 mg IgG4-Gag Group 6 (n = 3) 0.25 mg IgG4-Gag + 0.25 mg PolyIC Group 7 (n = 3) 0.0635 mg Gag Group 8 (n = 3) 0.0635 mg Gag + 0.25 mg PolyIC Timepoints Blood (weeks) Micor- Rectal post priming PBMC array Plasma Wash -3 X X X -2 X X X -1 X X Vaccination 0 X X 2 X X X Vaccination 6 X X X 8 X X X X 10 X X Vaccination 12 X X 13 X X X 14 X X X 15 X X X 16 X X X 18 X X X 22 X X X X

TABLE-US-00031 mAnti-Langerin 91E7K light chain sequence (SEQ ID NO.: 51) ATGGATTTTCAGATGCAGATTATCAGCTTGCTGCTAATCAGTGTCACA GTCATAGTGTCTAATGGAGAAATTGTGCTCACCCAGTCTCCAACCACC ATGGCTGCATCTCCCGGGGAGAAGATCACTATCACCTGCAGTGCCAGC TCAAGTATAAGTTCCCATTACTTACATTGGTATCAGCAGAAGCCAGGA TTCTCCCCTAAACTCTTGATTTATAGGACATCCAATCTGGCTTCTGGA GTCCCAGCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTC ACAATTGACACCATGGAGGCTGAAGATGTTGCCACTTACTACTGCCAG CAGGGTAGTAGTATACCATTCACGTTCGGCTCGGGGACAAAGTTGGAA ATAAAACGGGCTGATGCTGCACCAACTGTATCCATCTTCCCACCATCC AGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAAC AACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGT GAACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAA GACAGCACCTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAG TATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCA ACTTCACCCATCGTCAAGAGCTTCAACAGGAATGAGTGTTAG mAnti-Langerin 91E7K light chain sequence (SEQ ID NO.: 52) EIVLTQSPTTMAASPGEKITITCSASSSISSHYLHWYQQKPGFSPKWY RTSNLASGVPARFSGSGSGTSYSLTIDTMEAEDVATYYCQQGSSIPFT FGSGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDIN VKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYT CEATHKTSTSPIVKSFNRNEC mAnti-Langerin 91E7H [mouse IgG2a] heavy chain (SEQ ID NO.: 53) ATGAGATCACTGTTCTCTTTACAGTTACTGAGCACACAGGACCTCGCC ATGGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCTACAGGT GTCCACTCTCAGGTCCAACTGCAGCAGCCTGGGGCTGAACTTGTGAAG CCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTTC ACCAGTTACTGGATGCAGTGGGTAAAGCAGAGGCCTGGACAGGGCCTT GAGTGGATCGGAGAGATTGATCCTTCTGATAGCTATACTAACTACAAT CAAAGGTTCAAGGGCAAGGCCACATTGACTGTGGACACATCCTCCAGC ACAGCCTACATACAGCTCAGCAGCCTGACGTCTGAGGACTCTGCGGTC TGTTTCTGTGCAAGACGCTACTATGGTAACTACGATGGGTTTGCTTAC TGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACAACAGCC CCATCGGTCTATCCACTGGCCCCTGTGTGTGGAGGTACAACTGGCTCC TCGGTGACTCTAGGATGCCTGGTCAAGGGTTATTTCCCTGAGCCAGTG ACCTTGACCTGGAACTCTGGATCCCTGTCCAGTGGTGTGCACACCTTC CCAGCTCTCCTGCAGTCTGGCCTCTACACCCTCAGCAGCTCAGTGACT GTAACCTCGAACACCTGGCCCAGCCAGACCATCACCTGCAATGTGGCC CACCCGGCAAGCAGCACCAAAGTGGACAAGAAAATTGAGCCCAGAGTG CCCATAACACAGAACCCCTGTCCTCCACTCAAAGAGTGTCCCCCATGC GCAGCTCCAGACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCA AAGATCAAGGATGTACTCATGATCTCCCCGAGCCCCATGGTCACATGT GTGGTGGTGGATGTGAGCGAGGATGACCCAGACGTCCAGATCAGCTGG TTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGA GAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAG CACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAAC AGAGCCCTCCCATCCCCCATCGAGAAAACCATCTCAAAACCCAGAGGG CCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGCAGAAGAG ATGACTAAGAAAGAGTTCAGTCTGACCTGCATGATCACAGGCTTCTTA CCTGCCGAAATTGCTGTGGACTGGACCAGCAATGGGCGTACAGAGCAA AACTACAAGAACACCGCAACAGTCCTGGACTCTGATGGTTCTTACTTC ATGTACAGCAAGCTCAGAGTACAAAAGAGCACTTGGGAAAGAGGAAGT CTTTTCGCCTGCTCAGTGGTCCACGAGGGTCTGCACAATCACCTTACG ACTAAGACCATCTCCCGGTCTCTGGGTAAAGCTAGCTGA [GCTAGC in bold is for the in-frame fusion of antigens at the H-chain C-terminus] mAnti-Langerin 91E7H [mouse IgG2a] Mature H heavy chain sequence (SEQ ID NO.: 54) QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMQWVKQRPGQGLEWI GEIDPSDSYTNYNQRFKGKATLTVDTSSSTAYIQLSSLTSEDSAVCFC ARRYYGNYDGFAYWGQGTLVTVSAAKTTAPSVYPLAPVCGGTTGSSVT LGCLVKGYFPEPVTLTWNSGSLSSGVHTFPALLQSGLYTLSSSVTVTS NTWPSQTITCNVAHPASSTKVDKKIEPRVPITQNPCPPLKECPPCAAP DLLGGPSVFIFPPKIKDVLMISPSPMVTCVVVDVSEDDPDVQISWFVN NVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNRAL PSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKKEFSLTCMITGFLPAE IAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLRVQKSTWERGSLFA CSVVHEGLHNHLTTKTISRSLGKAS mAnti-Langerin 37C1K light chain (SEQ ID NO.: 55) ATGAGGGCCCCTGCTCAGTTTTTTGGGATCTTGTTGCTCTGGTTTCCA GGTATCAGATGTGACATCAAGATGACCCAGTCTCCATCCTCCATGTAT GCATCGCTGGGAGAGAGAGTCACTATTACTTGCAAGGCGAGTCAGGAC ATTAAAAGCTATTTAACTTGGTACCAGCAGAAACCATGGAAATCTCCT AAGACCCTGATCAATTATGCAACAAGCTTGGCAGATGGGGTCCCATCA AGATTCAGTGGCAGTGGATCTGGACAAGATTATTCTCTAACCATCAGC AGCCTGGAGTCTGACGATACAGCAACTTATTACTGTCTACAGCATGGT CAGAGTCCGTTCACGTTCGGAGGGGGGACCAGGCTGGAGATAAAACGG GCTGATGCTGCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAG TTAACATCTGGAGGTGCCTCGGTCGTGTGCTTCTTGAACAACTTCTAC CCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAA AATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACC TACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGA CATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAACTTCACCC ATCGTCAAGAGCTTCAACAGGAATGAGTGTTAG mAnti-Langerin 37C1K light chain (SEQ ID NO.: 56) DIKMTQSPSSMYASLGERVTITCKASQDIKSYLTWYQQKPWKSPKTLI NYATSLADGVPSRFSGSGSGQDYSLTISSLESDDTATYYCLQHGQSPF TFGGGTRLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDI NVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSY TCEATHKTSTSPIVKSFNRNEC mAnti-Langerin 37C1H [mouse IgG2a] heavy chain (SEQ ID NO.: 57) ATGAGATCACTGTTCTCTTTACAGTTACTGAGCACACAGGACCTCGCC ATGGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCTACAGGT GTCCACTCTCAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTTGTGAAG CCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTTC ACCAGTTACTGGATGCAGTGGGTAAAGCAGAGGCCTGGACAGGGCCTT GAGTGGACCGGAGAGATTGATCCTTCTGATAGCTATACTAACTACAAT CAAAGGTTCAAGGGCAAGGCCACATTGACTGTGGACACATCCTCCAGC ACAGCCTACACACAGCTCAGCAGCCTGACGTCTGAGGACTCTGCGGTC CATTTCTGTGCAAGACGCTACTATGGTAACTACGATGGGTTTGCTTAC TGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACAACAGCC CCATCGGTCTATCCACTGGCCCCTGTGTGTGGAGGTACAACTGGCTCC TCGGTGACTCTAGGATGCCTGGTCAAGGGTTATTTCCCTGAGCCAGTG ACCTTGACCTGGAACTCTGGATCCCTGTCCAGTGGTGTGCACACCTTC CCAGCTCTCCTGCAGTCTGGCCTCTACACCCTCAGCAGCTCAGTGACT GTAACCTCGAACACCTGGCCCAGCCAGACCATCACCTGCAATGTGGCC CACCCGGCAAGCAGCACCAAAGTGGACAAGAAAATTGAGCCCAGAGTG CCCATAACACAGAACCCCTGTCCTCCACTCAAAGAGTGTCCCCCATGC GCAGCTCCAGACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCA AAGGTCAAGGATGTACTCATGATCTCCCTGAGCCCCATGGTCACATGT GTGGTGGTGGATGTGAGCGAGGATGACCCAGACGTCCAGATCAGCTGG TTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGA GAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAG CACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAAC AGAGCCCTCCCATCCCCCATCGAGAAAACCATCTCAAAACCCAGAGGG CCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGCAGAAGAG ATGACTAAGAAAGAGTTCAGTCTGACCTGCATGATCACAGGCTTCTTA CCTGCCGAAATTGCTGTGGACTGGACCAGCAATGGGCGTACAGAGCAA AACTACAAGAACACCGCAACAGTCCTGGACTCTGATGGTTCTTACTTC ATGTACAGCAAGCTCAGAGTACAAAAGAGCACTTGGGAAAGAGGAAGT CTTTTCGCCTGCTCAGTGGTCCACGAGGGTCTGCACAATCACCTTACG ACTAAGACCATCTCCCGGTCTCTGGGTAAAGCTAGCTGA mAnti-Langerin 37C1H [mouse IgG2a] heavy chain (SEQ ID NO.: 58) QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMQWVKQRPGQGLEWT GEIDPSDSYTNYNQRFKGKATLTVDTSSSTAYTQLSSLTSEDSAVHFC ARRYYGNYDGFAYWGQGTLVTVSAAKTTAPSVYPLAPVCGGTTGSSVT LGCLVKGYFPEPVTLTWNSGSLSSGVHTFPALLQSGLYTLSSSVTVTS

NTWPSQTITCNVAHPASSTKVDKKIEPRVPITQNPCPPLKECPPCAAP DLLGGPSVFIFPPKVKDVLMISLSPMVTCVVVDVSEDDPDVQISWFVN NVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNRAL PSPIEKTISKPRGPVRAPQVYVLPPPAEEMTKKEFSLTCMITGFLPAE IAVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLRVQKSTWERGSLFA CSVVHEGLHNHLTTKTISRSLGKAS mAnti-Langerin 4C7K (light chain) (SEQ ID NO.: 77) ATGGATTTTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCTTCA GTCATAATGTCCAGAGGACAAATTGTTCTCTCCCAGTCTCCAGCAATC CTGTCTGCATCTCCAGGGGAGAAGGTCACAATGACTTGCAGGGCCAGC TCAAGTGTAAGTTACATGCACTGGTACCAGCGGAAGCCAGGATCCTCC CCCAAACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCT GCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTATTCTCTCACAATC AGCAGAGTGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCAGTGG AGTAGTAACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA CGGGCTGATGCTGCACCAACTGTATCCATCTTCCCACCATCCAGTGAG CAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAACAACTTC TACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGA CAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGC ACCTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAA CGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAACTTCA CCCATCGTCAAGAGCTTCAACAGGAATGAGTGTTAG (SEQ ID NO.: 78) QIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWYQRKPGSSPKPWIY ATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSSNPLT FGAGTKLELKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDIN VKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYT CEATHKTSTSPIVKSFNRNEC mAnti-Langerin 4C7H [mouse IgG2a] Heavy Chain (SEQ ID NO.: 79) ATGGAATGGAGCTGGGTCTTTCTCTTCCTCCTGTCAGTAATTGCAGGT GTCCAATCCCAGGTTCAGCTGCAGCAGTCTGGGGCTGAGCTGGTGAGG CCTGGGGCTTCAGTGACGCTGTCCTGCAAGGCTTCGGGCTACACATTT ATTGACCATGATATGCACTGGGTGCAGCAGACACCTGTGTATGGCCTG GAATGGATCGGAGCTATTGATCCTGAAACTGGTGATACTGGCTACAAT CAGAAGTTCAAGGGCAAGGCCATACTGACTGCAGACAAATCCTCCAGG ACAGCCTACATGGAACTCCGCAGCCTGACATCTGAGGACTCTGCCGTC TATTACTGTACAATCCCCTTCTACTATAGTAACTACAGCCCGTTTGCT TACTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAACA GCCCCATCGGTCTATCCACTGGCCCCTGTGTGTGGAGGTACAACTGGC TCCTCGGTGACTCTAGGATGCCTGGTCAAGGGTTATTTCCCTGAGCCA GTGACCTTGACCTGGAACTCTGGATCCCTGTCCAGTGGTGTGCACACC TTCCCAGCTCTCCTGCAGTCTGGCCTCTACACCCTCAGCAGCTCAGTG ACTGTAACCTCGAACACCTGGCCCAGCCAGACCATCACCTGCAATGTG GCCCACCCGGCAAGCAGCACCAAAGTGGACAAGAAAATTGAGCCCAGA GTGCCCATAACACAGAACCCCTGTCCTCCACTCAAAGAGTGTCCCCCA TGCGCAGACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAG ATCAAGGATGTACTCATGATCTCCCTGAGCCCCATGGTCACATGTGTG GTGGTGGATGTGAGCGAGGATGACCCAGACGCCCAGATCAGCTGGTTT GTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAG GATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCAC CAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAGA GCCCTCCCATCCCCCATCGAGAAAACCATCTCAAAACCCAGAGGGCCA GTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGCAGAAGAGATG ACTAAGAAAGAGTTCAGTCTGACCTGCATGATCACAGGCTTCTTACCT GCCGAAATTGCTGTGGACTGGACCAGCAATGGGCGTACAGAGCAAAAC TACAAGAACACCGCAACAGTCCTGGACTCTGATGGTTCTTACTTCATG TACAGCAAGCTCAGAGTACAAAAGAGCACTTGGGAAAGAGGAAGTCTT TTCGCCTGCTCAGTGGTCCACGAGGGTCTGCACAATCACCTTACGACT AAGACCATCTCCCGGTCTCTGGGTAAAGCTAGCTGA mAnti-Langerin 4C7H [mouse IgG2a] Heavy Chain (SEQ ID NO.: 80) QVQLQQSGAELVRPGASVTLSCKASGYTFIDHDMHWVQQTPVYGLEWI GAIDPETGDTGYNQKFKGKAILTADKSSRTAYMELRSLTSEDSAVYYC TIPFYYSNYSPFAYWGQGALVTVSAAKTTAPSVYPLAPVCGGTTGSSV TLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPALLQSGLYTLSSSVTVT SNTWPSQTITCNVAHPASSTKVDKKIEPRVPITQNPCPPLKECPPCAD LLGGPSVFIFPPKIKDVLMISLSPMVTCVVVDVSEDDPDAQISWFVNN VEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNRALP SPIEKTISKPRGPVRAPQVYVLPPPAEEMTKKEFSLTCMITGFLPAEI AVDWTSNGRTEQNYKNTATVLDSDGSYFMYSKLRVQKSTWERGSLFAC SVVHEGLHNHLTTKTISRSLGKAS

[0194] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.

[0195] It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.

[0196] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0197] The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[0198] As used in this specification and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. As used herein, the phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. As used herein, the phrase "consisting of" excludes any element, step, or ingredient not specified in the claim except for, e.g., impurities ordinarily associated with the element or limitation.

[0199] The term "or combinations thereof" as used herein refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0200] As used herein, words of approximation such as, without limitation, "about", "substantial" or "substantially" refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present. The extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature. In general, but subject to the preceding discussion, a numerical value herein that is modified by a word of approximation such as "about" may vary from the stated value by at least.+-.1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.

[0201] All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. 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.

REFERENCES

[0202] 1. Banchereau J, Steinman R M. Dendritic cells and the control of immunity. Nature. 1998; 392:245-252. [0203] 2. Pascual V, Banchereau J, Palucka A. The Central Role of Dendritic Cells and Interferon-alpha in SLE. Curr Opin Rheumatol. 2003;in press. [0204] 3. Palucka K, Banchereau J. Dendritic cells: a link between innate and adaptive immunity. J Clin Immunol. 1999; 19:12-25. [0205] 4. Di Pucchio T, Chatterjee B, Smed-Sorensen A, et al. Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I. Nat. Immunol. 2008; 9:551-557. [0206] 5. Kadowaki N, Antonenko S, Lau J Y, Liu Y J. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J Exp Med. 2000; 192:219-226. [0207] 6. Fonteneau J F, Gilliet M, Larsson M, et al. Activation of influenza virus-specific CD4+ and CD8+T cells: a new role for plasmacytoid dendritic cells in adaptive immunity. Blood. 2003; 101:3520-3526. [0208] 7. Randolph G J, Beaulieu S, Lebecque S, Steinman R M, Muller W A. Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking Science. 1998; 282:480-483. [0209] 8. Chomarat P, Dantin C, Bennett L, Banchereau J, Palucka A K. TNF skews monocyte differentiation from macrophages to dendritic cells. J. Immunol. 2003; 171:2262-2269. [0210] 9. Romani N, Gruner S, Brang D, et al. Proliferating dendritic cell progenitors in human blood. J Exp Med. 1994; 180:83-93. [0211] 10. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor a. JExpMed. 1994; 179:1109-1118. [0212] 11. Peters J H, Xu H, Ruppert J, Ostermeier D, Friedrichs D, Gieseler R K. Signals required for differentiating dendritic cells from human monocytes in vitro. Adv Exp Med. Biol. 1993; 329:275-280. [0213] 12. Paquette R L, Hsu N C, Kiertscher S M, et al. Interferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol. 1998; 64:358-367. [0214] 13. Luft T, Jefford M, Luetjens P, et al. Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets. Blood. 2002; 100:1362-1372. [0215] 14. He B, Xu W, Santini P A, et al. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity. 2007; 26:812-826. [0216] 15. Blanco P, Palucka A K, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 2001; 294:1540-1543. [0217] 16. Mohamadzadeh M, Berard F, Essert G, et al. Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells. J Exp Med. 2001; 194:1013-1020. [0218] 17. Caux C, Massacrier C, Vanbervliet B, et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor alpha: II. Functional analysis. Blood. 1997; 90:1458-1470. [0219] 18. Caux C, Vanbervliet B, Massacrier C, et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. J Exp Med. 1996; 184:695-706. [0220] 19. Seifert U, Maranon C, Shmueli A, et al. An essential role for tripeptidyl peptidase in the generation of an MHC class I epitope. Nat. Immunol. 2003; 4:375-379. [0221] 20. Dudziak D, Kamphorst A O, Heidkamp G F, et al. Differential antigen processing by dendritic cell subsets in vivo. Science. 2007; 315:107-111. [0222] 21. Shortman K, Liu Y J. Mouse and human dendritic cell subtypes. Nature Rev Immunol. 2002; 2:151-161. [0223] 22. Maldonado-Lopez R, De Smedt T, Michel P, et al. CD8alpha+ and CD8alpha-subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med. 1999; 189:587-592. [0224] 23. Pulendran B, Smith J L, Caspary G, et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci. 1999; 96:1036-1041. [0225] 24. Pulendran B, Kumar P, Cutler C W, Mohamadzadeh M, Van Dyke T, Banchereau J. Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J. Immunol. 2001; 167:5067-5076. [0226] 25. Rissoan M C, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science. 1999; 283:1183-1186.

Sequence CWU 1

1

8011395DNAArtificial SequenceSynthetic oligonucleotide. 1atggaatgga ggatctttct cttcatcctg tcaggaactg caggtgtcca ctcccaggtt 60cagctgcggc agtctggacc tgagctggtg aagcctgggg cttcagtgaa gatgtcctgc 120aaggcttctg gatacacatt tactgactat gttataagtt gggtgaagca gagaactgga 180cagggccttg agtggattgg agatatttat cctggaagtg gttattcttt ctacaatgag 240aacttcaagg gcaaggccac actgactgca gacaaatcct ccaccacagc ctacatgcag 300ctcagcagcc tgacatctga ggactctgcg gtctatttct gtgcaaccta ctataactac 360ccttttgctt actggggcca agggactctg gtcactgtct ctgcagccaa aacaacgggc 420ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agccgccctg 480ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 540ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 600agcagcgtgg tgaccgtgcc ctccagcagc ttgggcacga agacctacac ctgcaacgta 660gatcacaagc ccagcaacac caaggtggac aagagagttg agtccaaata tggtccccca 720tgcccaccct gcccagcacc tgagttcgaa gggggaccat cagtcttcct gttcccccca 780aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 840gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 900aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 960ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 1020aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 1080ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 1140acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1200cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1260ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 1320tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 1380ggtaaagcta gctga 13952446PRTArtificial SequenceSynthetic peptide. 2Gln Val Gln Leu Arg Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Ala Thr Tyr Tyr Asn Tyr Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 4453705DNAArtificial SequenceSyntehtic oligonucleotide. 3atggcctgga tttcacttat actctctctc ctggctctca gctcaggggc catttcccag 60gctgttgtga ctcaggaatc tgcactcacc acatcacctg gtgaaacagt cacactcact 120tgtcgctcaa gtactggggc tgttacaact agtaactatg ccaactgggt ccaagaaaaa 180ccagatcatt tattcactgg tctaataggt ggtaccaaca accgagtttc aggtgttcct 240gccagattct caggctccct gattggagac aaggctgccc tcaccatcac aggggcacag 300actgaggatg aggcaatata tttctgtgct ctatggtaca gcaaccattg ggtgttcggt 360ggaggaacca aactgactgt cctaggccag cccaagtctt cgccatcagt caccctgttt 420ccaccttcct ctgaagagct cgagactaac aaggccacac tggtgtgtac gatcactgat 480ttctacccag gtgtggtgac agtggactgg aaggtagatg gtacccctgt cactcagggt 540atggagacaa cccagccttc caaacagagc aacaacaagt acatggctag cagctacctg 600accctgacag caagagcatg ggaaaggcat agcagttaca gctgccaggt cactcatgaa 660ggtcacactg tggagaagag tttgtcccgt gctgactgtt cctag 7054215PRTArtificial SequenceSynthetic peptide. 4Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu1 5 10 15Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45Leu Ile Gly Gly Thr Asn Asn Arg Val Ser Gly Val Pro Ala Arg Phe 50 55 60Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala65 70 75 80Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro 100 105 110Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr Pro 130 135 140Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr Gln145 150 155 160Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr Met 165 170 175Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His Ser 180 185 190Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys Ser 195 200 205Leu Ser Arg Ala Asp Cys Ser 210 21551401DNAArtificial SequenceSynthetic oligonucleotide. 5atgacattga acatgctgtt ggggctgaag tgggttttct ttgttgtttt ttatcaaggt 60gtgcattgtg aggtgcagct tgttgagtct ggtggaggat tggtgcagcc taaagggtca 120ttgaaactct catgtgcagc ctctggatta accttcaata tctacgccat gaactgggtc 180cgccaggctc caggaaaggg tttggaatgg gttgctcgca taagaaataa aagtaataat 240tatgcaacat attatgccga ttcagtgaaa gacaggttca ccatctccag agatgattca 300caaagcttgc tctatctgca aatgaacaac ttgaaaactg aggacacagc catgtattac 360tgtgtgggac gggactggtt tgattactgg ggccaaggga ctctggtcac tgtctctgca 420gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380tctcctggta aagctagctg a 14016443PRTArtificial SequenceSynthetic peptide. 6Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asn Ile Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Arg Ile Arg Asn Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Leu65 70 75 80Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95Tyr Cys Val Gly Arg Asp Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser145 150 155 160Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys225 230 235 240Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala305 310 315 320Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val385 390 395 400Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430Lys Ser Leu Ser His Ser Pro Gly Lys Ala Ser 435 44071635DNAArtificial SequenceSyntehtic oligonucleotide. 7atgacattga acatgctgtt ggggctgagg tgggttttct ttgttgtttt ttatcaaggt 60gtgcattgtg aggtgcagct tgttgagtct ggtggaggat tggtgcagcc taaagggtca 120ttgaaactct catgtgcagc ctctggatta accttcaata tctacgccat gaactgggtc 180cgccaggctc caggaaaggg tttggaatgg gttgctcgca taagaaataa aagtaataat 240tatgcaacat attatgccga ttcagtgaaa gacaggttca ccatctccag agatgattca 300caaagcttgc tctatctgca aatgaacaac ttgaaaactg aggacacagc catgtattac 360tgtgtgggac gggactggtt tgattactgg ggccaaggga ctctggtcac tgtctctgca 420gccaaaacga agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 480agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 660tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 720aaatatggtc ccccatgccc accctgccca gcacctgagt tcgaaggggg accatcagtc 780ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 840tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 900ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 960cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 1020tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1080gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1140aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1200tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1320aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1380ctctccctgt ctctgggtaa agctagcaat tctcctcaaa atgaagtact gtacggagat 1440gtgaatgatg acggaaaagt aaactccact gacttgactt tgttaaaaag atatgttctt 1500aaagccgtct caactctccc ttcttccaaa gctgaaaaga acgcagatgt aaatcgtgac 1560ggaagagtta attccagtga tgtcacaata ctttcaagat atttgataag ggtaatcgag 1620aaattaccaa tataa 16358521PRTArtificial SequenceSynthetic peptide. 8Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asn Ile Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Arg Ile Arg Asn Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Leu65 70 75 80Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95Tyr Cys Val Gly Arg Asp Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu

Gly Lys Ala Ser Asn Ser 435 440 445Pro Gln Asn Glu Val Leu Tyr Gly Asp Val Asn Asp Asp Gly Lys Val 450 455 460Asn Ser Thr Asp Leu Thr Leu Leu Lys Arg Tyr Val Leu Lys Ala Val465 470 475 480Ser Thr Leu Pro Ser Ser Lys Ala Glu Lys Asn Ala Asp Val Asn Arg 485 490 495Asp Gly Arg Val Asn Ser Ser Asp Val Thr Ile Leu Ser Arg Tyr Leu 500 505 510Ile Arg Val Ile Glu Lys Leu Pro Ile 515 520960PRTArtificial SequenceSynthetic peptide. 9Met Trp Val Pro Val Val Phe Leu Thr Leu Ser Val Thr Trp Ile Gly1 5 10 15Ala Ala Pro Leu Ile Leu Ser Arg Ile Val Gly Gly Trp Glu Cys Glu 20 25 30Lys His Ser Gln Pro Trp Gln Val Leu Val Ala Ser Arg Gly Arg Ala 35 40 45Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val 50 55 601060PRTArtificial SequenceSyhthetic peptide. 10Leu Thr Ala Ala His Cys Ile Arg Asn Lys Ser Val Ile Leu Leu Gly1 5 10 15Arg His Ser Leu Phe His Pro Glu Asp Thr Gly Gln Val Phe Gln Val 20 25 30Ser His Ser Phe Pro His Pro Leu Tyr Asp Met Ser Leu Leu Lys Asn 35 40 45Arg Phe Leu Arg Pro Gly Asp Asp Ser Ser His Asp 50 55 601160PRTArtificial SequenceSynthetic peptide. 11Leu Met Leu Leu Arg Leu Ser Glu Pro Ala Glu Leu Thr Asp Ala Val1 5 10 15Lys Val Met Asp Leu Pro Thr Gln Glu Pro Ala Leu Gly Thr Thr Cys 20 25 30Tyr Ala Ser Gly Trp Gly Ser Ile Glu Pro Glu Glu Phe Leu Thr Pro 35 40 45Lys Lys Leu Gln Cys Val Asp Leu His Val Ile Ser 50 55 601260PRTArtificial SequenceSynthetic peptide. 12Asn Asp Val Cys Ala Gln Val His Pro Gln Lys Val Thr Lys Phe Met1 5 10 15Leu Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser Thr Cys Ser Gly Asp 20 25 30Ser Gly Gly Pro Leu Val Cys Asn Gly Val Leu Gln Gly Ile Thr Ser 35 40 45Trp Gly Ser Glu Pro Cys Ala Leu Pro Glu Arg Pro 50 55 601321PRTArtificial SequenceSynthetic peptide. 13Ser Leu Tyr Thr Lys Val Val His Tyr Arg Lys Trp Ile Lys Asp Thr1 5 10 15Ile Val Ala Asn Pro 20149PRTArtificial SequenceSynthetic peptide. 14Ile Met Asp Gln Val Pro Phe Ser Val1 5159PRTArtificial SequenceSynthetic peptide. 15Ile Thr Asp Gln Val Pro Phe Ser Val1 5169PRTArtificial SequenceSynthetic peptide. 16Tyr Leu Glu Pro Gly Pro Val Thr Val1 5179PRTArtificial SequenceSynthetic peptide. 17Tyr Leu Glu Pro Gly Pro Val Thr Ala1 5189PRTArtificial SequenceSyntehtic peptide. 18Lys Thr Trp Gly Gln Tyr Trp Gln Val1 519244PRTArtificial SequenceSynthetic peptide. 19Ala Pro Leu Ile Leu Ser Arg Ile Val Gly Gly Trp Glu Cys Glu Lys1 5 10 15His Ser Gln Pro Trp Gln Val Leu Val Ala Ser Arg Gly Arg Ala Val 20 25 30Cys Gly Gly Val Leu Val His Pro Gln Trp Val Leu Thr Ala Ala His 35 40 45Cys Ile Arg Asn Lys Ser Val Ile Leu Leu Gly Arg His Ser Leu Phe 50 55 60His Pro Glu Asp Thr Gly Gln Val Phe Gln Val Ser His Ser Phe Pro65 70 75 80His Pro Leu Tyr Asp Met Ser Leu Leu Lys Asn Arg Phe Leu Arg Pro 85 90 95Gly Asp Asp Ser Ser His Asp Leu Met Leu Leu Arg Leu Ser Glu Pro 100 105 110Ala Glu Leu Thr Asp Ala Val Lys Val Met Asp Leu Pro Thr Gln Glu 115 120 125Pro Ala Leu Gly Thr Thr Cys Tyr Ala Ser Gly Trp Gly Ser Ile Glu 130 135 140Pro Glu Glu Phe Leu Thr Pro Lys Lys Leu Gln Cys Val Asp Leu His145 150 155 160Val Ile Ser Asn Asp Val Cys Ala Gln Val His Pro Gln Lys Val Thr 165 170 175Lys Phe Met Leu Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser Thr Cys 180 185 190Ser Gly Asp Ser Gly Gly Pro Leu Val Cys Asn Gly Val Leu Gln Gly 195 200 205Ile Thr Ser Trp Gly Ser Glu Pro Cys Ala Leu Pro Glu Arg Pro Ser 210 215 220Leu Tyr Thr Lys Val Val His Tyr Arg Lys Trp Ile Lys Asp Thr Ile225 230 235 240Val Ala Asn Pro20230PRTArtificial SequenceSynthetic peptide. 20Asp Thr Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Pro Thr1 5 10 15Thr Thr Lys Val Pro Arg Asn Gln Asp Trp Leu Gly Val Ser Arg Gln 20 25 30Leu Arg Thr Lys Ala Trp Asn Arg Gln Leu Tyr Pro Glu Trp Thr Glu 35 40 45Ala Gln Arg Leu Asp Cys Trp Arg Gly Gly Gln Val Ser Leu Lys Val 50 55 60Ser Asn Asp Gly Pro Thr Leu Ile Gly Ala Asn Ala Ser Phe Ser Ile65 70 75 80Ala Leu Asn Phe Pro Gly Ser Gln Lys Val Leu Pro Asp Gly Gln Val 85 90 95Ile Trp Val Asn Asn Thr Ile Ile Asn Gly Ser Gln Val Trp Gly Gly 100 105 110Gln Pro Val Tyr Pro Gln Glu Thr Asp Asp Ala Cys Ile Phe Pro Asp 115 120 125Gly Gly Pro Cys Pro Ser Gly Ser Trp Ser Gln Lys Arg Ser Phe Val 130 135 140Tyr Val Trp Lys Thr Trp Gly Gln Tyr Trp Gln Val Leu Gly Gly Pro145 150 155 160Val Ser Gly Leu Ser Ile Gly Thr Gly Arg Ala Met Leu Gly Thr His 165 170 175Thr Met Glu Val Thr Val Tyr His Arg Arg Gly Ser Gln Ser Tyr Val 180 185 190Pro Leu Ala His Ser Ser Ser Ala Phe Thr Ile Thr Asp Gln Val Pro 195 200 205Phe Ser Val Ser Val Ser Gln Leu Arg Ala Leu Asp Gly Gly Asn Lys 210 215 220His Phe Leu Arg Asn Gln225 2302173PRTArtificial SequenceSynthetic peptide. 21Pro Leu Thr Phe Ala Leu Gln Leu His Asp Pro Ser Gly Tyr Leu Ala1 5 10 15Glu Ala Asp Leu Ser Tyr Thr Trp Asp Phe Gly Asp Ser Ser Gly Thr 20 25 30Leu Ile Ser Arg Ala Xaa Val Val Thr His Thr Tyr Leu Glu Pro Gly 35 40 45Pro Val Thr Ala Gln Val Val Leu Gln Ala Ala Ile Pro Leu Thr Ser 50 55 60Cys Gly Ser Ser Pro Val Pro Ala Ser65 7022109PRTArtificial SequenceSynthetic peptide. 22Gly Thr Thr Asp Gly His Arg Pro Thr Ala Glu Ala Pro Asn Thr Thr1 5 10 15Ala Gly Gln Val Pro Thr Thr Glu Val Val Gly Thr Thr Pro Gly Gln 20 25 30Ala Pro Thr Ala Glu Pro Ser Gly Thr Thr Ser Val Gln Val Pro Thr 35 40 45Thr Glu Val Ile Ser Thr Ala Pro Val Gln Met Pro Thr Ala Glu Ser 50 55 60Thr Gly Met Thr Pro Glu Lys Val Pro Val Ser Glu Val Met Gly Thr65 70 75 80Thr Leu Ala Glu Met Ser Thr Pro Glu Ala Thr Gly Met Thr Pro Ala 85 90 95Glu Val Ser Ile Val Val Leu Ser Gly Thr Thr Ala Ala 100 1052375PRTArtificial SequenceSynthetic peptide. 23Gln Val Thr Thr Thr Glu Trp Val Glu Thr Thr Ala Arg Glu Leu Pro1 5 10 15Ile Pro Glu Pro Glu Gly Pro Asp Ala Ser Ser Ile Met Ser Thr Glu 20 25 30Ser Ile Thr Gly Ser Leu Gly Pro Leu Leu Asp Gly Thr Ala Thr Leu 35 40 45Arg Leu Val Lys Arg Gln Val Pro Leu Asp Cys Val Leu Tyr Arg Tyr 50 55 60Gly Ser Phe Ser Val Thr Leu Asp Ile Val Gln65 70 7524109PRTArtificial SequenceSynthetic peptide. 24Gly Ile Glu Ser Ala Glu Ile Leu Gln Ala Val Pro Ser Gly Glu Gly1 5 10 15Asp Ala Phe Glu Leu Thr Val Ser Cys Gln Gly Gly Leu Pro Lys Glu 20 25 30Ala Cys Met Glu Ile Ser Ser Pro Gly Cys Gln Pro Pro Ala Gln Arg 35 40 45Leu Cys Gln Pro Val Leu Pro Ser Pro Ala Cys Gln Leu Val Leu His 50 55 60Gln Ile Leu Lys Gly Gly Ser Gly Thr Tyr Cys Leu Asn Val Ser Leu65 70 75 80Ala Asp Thr Asn Ser Leu Ala Val Val Ser Thr Gln Leu Ile Val Pro 85 90 95Gly Ile Leu Leu Thr Gly Gln Glu Ala Gly Leu Gly Gln 100 1052550PRTARtificial SequenceSynthetic peptide. 25Met Glu Met Lys Ile Leu Arg Ala Leu Asn Phe Gly Leu Gly Arg Pro1 5 10 15Leu Pro Leu His Phe Leu Arg Arg Ala Ser Lys Ile Gly Glu Val Asp 20 25 30Val Glu Gln His Thr Leu Ala Lys Tyr Leu Met Glu Leu Thr Met Leu 35 40 45Asp Tyr 502636PRTArtificial SequenceSynthetic peptide. 26Asp Trp Leu Val Gln Val Gln Met Lys Phe Arg Leu Leu Gln Glu Thr1 5 10 15Met Tyr Met Thr Val Ser Ile Ile Asp Arg Phe Met Gln Asn Asn Cys 20 25 30Val Pro Lys Lys 352748PRTArtificial SequenceSyntehtic peptide. 27Met Glu His Gln Leu Leu Cys Cys Glu Val Glu Thr Ile Arg Arg Ala1 5 10 15Tyr Pro Asp Ala Asn Leu Leu Asn Asp Arg Val Leu Arg Ala Met Leu 20 25 30Lys Ala Glu Glu Thr Cys Ala Pro Ser Val Ser Tyr Phe Lys Cys Val 35 40 452895PRTArtificial SequenceSynthetic peptide. 28Gln Lys Glu Val Leu Pro Ser Met Arg Lys Ile Val Ala Thr Trp Met1 5 10 15Leu Glu Val Cys Glu Glu Gln Lys Cys Glu Glu Glu Val Phe Pro Leu 20 25 30Ala Met Asn Tyr Leu Asp Arg Phe Leu Ser Leu Glu Pro Val Lys Lys 35 40 45Ser Arg Leu Gln Leu Leu Gly Ala Thr Cys Met Phe Val Ala Ser Lys 50 55 60Met Lys Glu Thr Ile Pro Leu Thr Ala Glu Lys Leu Cys Ile Tyr Thr65 70 75 80Asp Asn Ser Ile Arg Pro Glu Glu Leu Leu Gln Met Glu Leu Leu 85 90 952960PRTArtificial SequenceSynthetic peptide. 29Leu Val Asn Lys Leu Lys Trp Asn Leu Ala Ala Met Thr Pro His Asp1 5 10 15Phe Ile Glu His Phe Leu Ser Lys Met Pro Glu Ala Glu Glu Asn Lys 20 25 30Gln Ile Ile Arg Lys His Ala Gln Thr Phe Val Ala Leu Cys Ala Thr 35 40 45Asp Val Lys Phe Ile Ser Asn Pro Pro Ser Met Val 50 55 603092PRTArtificial SequenceSynthetic peptide. 30Ala Ala Gly Ser Val Val Ala Ala Val Gln Gly Leu Asn Leu Arg Ser1 5 10 15Pro Asn Asn Phe Leu Ser Tyr Tyr Arg Leu Thr Arg Phe Leu Ser Arg 20 25 30Val Ile Lys Cys Asp Pro Asp Cys Leu Arg Ala Cys Gln Glu Gln Ile 35 40 45Glu Ala Leu Leu Glu Ser Ser Leu Arg Gln Ala Gln Gln Asn Met Asp 50 55 60Pro Lys Ala Ala Glu Glu Glu Glu Glu Glu Glu Glu Glu Val Asp Leu65 70 75 80Ala Cys Thr Pro Thr Asp Val Arg Asp Val Asp Ile 85 903132PRTArtificial SequenceSynthetic peptide. 31Val Gly Phe Pro Val Thr Pro Gln Val Pro Leu Arg Pro Met Thr Tyr1 5 10 15Lys Ala Ala Val Asp Leu Ser His Phe Leu Lys Glu Lys Gly Gly Leu 20 25 303230PRTArtificial SequenceSynthetic peptide. 32His Thr Gln Gly Tyr Phe Pro Asp Trp Gln Asn Tyr Thr Pro Gly Pro1 5 10 15Gly Val Arg Tyr Pro Leu Thr Phe Gly Trp Leu Tyr Lys Leu 20 25 303319PRTArtificial SequenceSynthetic peptide. 33Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys Tyr Lys Leu Lys1 5 10 15His Ile Val3432PRTArtificial SequenceSyntehtic peptide. 34Asn Pro Pro Ile Pro Val Gly Glu Ile Tyr Lys Arg Trp Ile Ile Leu1 5 10 15Gly Leu Asn Lys Ile Val Arg Met Tyr Ser Pro Thr Ser Ile Leu Asp 20 25 303531PRTArtificial SequenceSyntehtic peptide. 35Ala Ile Phe Gln Ser Ser Met Thr Lys Ile Leu Glu Pro Phe Arg Lys1 5 10 15Gln Asn Pro Asp Ile Val Ile Tyr Gln Tyr Met Asp Asp Leu Tyr 20 25 3036314PRTArtificial SequenceSyntehtic peptide. 36Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val1 5 10 15Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu 20 25 30Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile Ala 35 40 45Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Leu Leu Gly Asn 50 55 60Pro Glu Cys Asp Pro Leu Leu Pro Val Arg Ser Trp Ser Tyr Ile Val65 70 75 80Glu Thr Pro Asn Ser Glu Asn Gly Ile Cys Tyr Pro Gly Asp Phe Ile 85 90 95Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu 100 105 110Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Asn Thr 115 120 125Asn Gly Val Thr Ala Ala Cys Ser His Glu Gly Lys Ser Ser Phe Tyr 130 135 140Arg Asn Leu Leu Trp Leu Thr Glu Lys Glu Gly Ser Tyr Pro Lys Leu145 150 155 160Lys Asn Ser Tyr Val Asn Lys Lys Gly Lys Glu Val Leu Val Leu Trp 165 170 175Gly Ile His His Pro Pro Asn Ser Lys Glu Gln Gln Asn Leu Tyr Gln 180 185 190Asn Glu Asn Ala Tyr Val Ser Val Val Thr Ser Asn Tyr Asn Arg Arg 195 200 205Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Asp Gln Ala Gly 210 215 220Arg Met Asn Tyr Tyr Trp Thr Leu Leu Lys Pro Gly Asp Thr Ile Ile225 230 235 240Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Met Tyr Ala Phe Ala Leu 245 250 255Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser Met His 260 265 270Glu Cys Asn Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Ser Ser 275 280 285Leu Pro Tyr Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro Lys 290 295 300Tyr Val Arg Ser Ala Lys Leu Arg Met Val305 31037314PRTArtificial SequenceSyntehtic peptide. 37Asp Gln Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val1 5 10 15Asp Thr Ile Met Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile 20 25 30Leu Glu Lys Lys His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys 35 40 45Pro Leu Ile Leu Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn 50 55 60Pro Met Cys Asp Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val65 70 75 80Glu Lys Ala Asn Pro Val Asn Asp Leu Cys Tyr Pro Gly Asp Phe Asn 85 90 95Asp Tyr Glu Glu Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu 100 105 110Lys Ile Gln Ile Ile Pro Lys Ser Ser Trp Ser Ser His Glu Ala Ser 115 120 125Leu Gly Val Ser Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe 130 135 140Arg Asn Val Val Trp Leu Ile Lys Lys Asn Ser Thr Tyr Pro Thr Ile145 150 155 160Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp 165 170 175Gly Ile His His Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln 180 185 190Asn Pro Thr Thr Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg 195 200 205Leu Val Pro Arg Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly 210 215 220Arg Met Glu Phe Phe

Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn225 230 235 240Phe Glu Ser Asn Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile 245 250 255Val Lys Lys Gly Asp Ser Thr Ile Met Lys Ser Glu Leu Glu Tyr Gly 260 265 270Asn Cys Asn Thr Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser 275 280 285Met Pro Phe His Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys 290 295 300Tyr Val Lys Ser Asn Arg Leu Val Leu Ala305 31038231PRTArtificial SequenceSyntehtic peptide. 38Pro Ile Val Gln Asn Ile Gln Gly Gln Met Val His Gln Ala Ile Ser1 5 10 15Pro Arg Thr Leu Asn Ala Trp Val Lys Val Val Glu Glu Lys Ala Phe 20 25 30Ser Pro Glu Val Ile Pro Met Phe Ser Ala Leu Ser Glu Gly Ala Thr 35 40 45Pro Gln Asp Leu Asn Thr Met Leu Asn Thr Val Gly Gly His Gln Ala 50 55 60Ala Met Gln Met Leu Lys Glu Thr Ile Asn Glu Glu Ala Ala Glu Trp65 70 75 80Asp Arg Val His Pro Val His Ala Gly Pro Ile Ala Pro Gly Gln Met 85 90 95Arg Glu Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr Ser Thr Leu Gln 100 105 110Glu Gln Ile Gly Trp Met Thr Asn Asn Pro Pro Ile Pro Val Gly Glu 115 120 125Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys Ile Val Arg Met 130 135 140Tyr Ser Pro Thr Ser Ile Leu Asp Ile Arg Gln Gly Pro Lys Glu Pro145 150 155 160Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu Arg Ala Glu Gln 165 170 175Ala Ser Gln Glu Val Lys Asn Trp Met Thr Glu Thr Leu Leu Val Gln 180 185 190Asn Ala Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala Leu Gly Pro Ala 195 200 205Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly Val Gly Gly Pro 210 215 220Gly His Lys Ala Arg Val Leu225 2303925PRTArtificial SequenceSynthetic peptide. 39Ser Ser Val Ser Pro Thr Thr Ser Val His Pro Thr Pro Thr Ser Val1 5 10 15Pro Pro Thr Pro Thr Lys Ser Ser Pro 20 254025PRTArtificial SequenceSynthetic peptide. 40Pro Thr Ser Thr Pro Ala Asp Ser Ser Thr Ile Thr Pro Thr Ala Thr1 5 10 15Pro Thr Ala Thr Pro Thr Ile Lys Gly 20 254125PRTArtificial SequenceSynthetic peptide. 41Thr Val Thr Pro Thr Ala Thr Ala Thr Pro Ser Ala Ile Val Thr Thr1 5 10 15Ile Thr Pro Thr Ala Thr Thr Lys Pro 20 254225PRTArtificial SequenceSynthetic peptide. 42Thr Asn Gly Ser Ile Thr Val Ala Ala Thr Ala Pro Thr Val Thr Pro1 5 10 15Thr Val Asn Ala Thr Pro Ser Ala Ala 20 25439PRTArtificial SequenceSynthetic peptide. 43Gly Ile Leu Gly Phe Val Phe Thr Leu1 5449PRTArtificial SequenceSynthetic peptide. 44Lys Leu Gln Cys Val Asp Leu His Val1 54576PRTArtificial SequenceSynthetic peptide. 45Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly1 5 10 15Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys 20 25 30Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg 35 40 45Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile Ser Arg 50 55 60Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser65 70 754681PRTArtificial SequenceSynthetic peptide. 46Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr1 5 10 15Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 20 25 30Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 35 40 45Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr 50 55 60Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys65 70 75 80Ala4774PRTArtificial SequenceSynthetic peptide. 47Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn1 5 10 15Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly Leu 20 25 30Ile Gly Gly Thr Asn Asn Arg Val Ser Gly Val Pro Ala Arg Phe Ser 35 40 45Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln 50 55 60Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala65 704882PRTArtificial SequenceSynthetic peptide. 48Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asn Ile Tyr1 5 10 15Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 20 25 30Ala Arg Ile Arg Asn Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 35 40 45Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Leu 50 55 60Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr65 70 75 80Tyr Cys49717DNAArtificial SequenceSyntehtic oligonucleotide. 49atgaagttgc ctgttaggct gttggtgctg atgttctgga ttcctgcttc cagcagtgat 60gttgtgatga cccaaactcc actctccctg cctgtccgtc ttggagatca agcctccatc 120tcttgcagat ctagtcagag ccttgtacac agtaatggaa acacctattt acattggtac 180ctgcagaagc caggccagtc tccaaagctc ctgatctaca aagtttccaa ccgattttct 240ggggtcccag acaggttcag tggcagtgga tcagggacaa atttcacact caagatcagc 300agagtggagg ctgaggatct gggactttat ttctgctctc aaagtacaca tgttccgtac 360acgttcggag gggggaccaa gctggaaata aaacgggctg atgctgcacc aactgtatcc 420atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 480aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 540aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgaac 600agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 660actcacaaga catcaacttc acccatcgtc aagagcttca acaggaatga gtgttag 71750219PRTArtificial SequenceSyntehtic peptide. 50Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Arg Leu Gly1 5 10 15Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser 85 90 95Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 115 120 125Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 130 135 140Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg145 150 155 160Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Met Asn Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 180 185 190Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 195 200 205Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 21551714DNAArtificial SequenceSynthetic oligonucleotide. 51atggattttc agatgcagat tatcagcttg ctgctaatca gtgtcacagt catagtgtct 60aatggagaaa ttgtgctcac ccagtctcca accaccatgg ctgcatctcc cggggagaag 120atcactatca cctgcagtgc cagctcaagt ataagttccc attacttaca ttggtatcag 180cagaagccag gattctcccc taaactcttg atttatagga catccaatct ggcttctgga 240gtcccagctc gcttcagtgg cagtgggtct gggacctctt actctctcac aattgacacc 300atggaggctg aagatgttgc cacttactac tgccagcagg gtagtagtat accattcacg 360ttcggctcgg ggacaaagtt ggaaataaaa cgggctgatg ctgcaccaac tgtatccatc 420ttcccaccat ccagtgagca gttaacatct ggaggtgcct cagtcgtgtg cttcttgaac 480aacttctacc ccaaagacat caatgtcaag tggaagattg atggcagtga acgacaaaat 540ggcgtcctga acagttggac tgatcaggac agcaaagaca gcacctacag catgagcagc 600accctcacgt tgaccaagga cgagtatgaa cgacataaca gctatacctg tgaggccact 660cacaagacat caacttcacc catcgtcaag agcttcaaca ggaatgagtg ttag 71452215PRTArtificial SequenceSynthetic peptide. 52Glu Ile Val Leu Thr Gln Ser Pro Thr Thr Met Ala Ala Ser Pro Gly1 5 10 15Glu Lys Ile Thr Ile Thr Cys Ser Ala Ser Ser Ser Ile Ser Ser His 20 25 30Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Phe Ser Pro Lys Leu Leu 35 40 45Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Asp Thr Met Glu65 70 75 80Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Ser Ile Pro 85 90 95Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala 100 105 110Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser 115 120 125Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp 130 135 140Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val145 150 155 160Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met 165 170 175Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser 180 185 190Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys 195 200 205Ser Phe Asn Arg Asn Glu Cys 210 215531479DNAArtificial SequenceSynthetic oligonucleotide. 53atgagatcac tgttctcttt acagttactg agcacacagg acctcgccat gggatggagc 60tgtatcatcc tcttcttggt agcaacagct acaggtgtcc actctcaggt ccaactgcag 120cagcctgggg ctgaacttgt gaagcctggg gcttcagtga agctgtcctg caaggcttct 180ggctacacct tcaccagtta ctggatgcag tgggtaaagc agaggcctgg acagggcctt 240gagtggatcg gagagattga tccttctgat agctatacta actacaatca aaggttcaag 300ggcaaggcca cattgactgt ggacacatcc tccagcacag cctacataca gctcagcagc 360ctgacgtctg aggactctgc ggtctgtttc tgtgcaagac gctactatgg taactacgat 420gggtttgctt actggggcca agggactctg gtcactgtct ctgcagccaa aacaacagcc 480ccatcggtct atccactggc ccctgtgtgt ggaggtacaa ctggctcctc ggtgactcta 540ggatgcctgg tcaagggtta tttccctgag ccagtgacct tgacctggaa ctctggatcc 600ctgtccagtg gtgtgcacac cttcccagct ctcctgcagt ctggcctcta caccctcagc 660agctcagtga ctgtaacctc gaacacctgg cccagccaga ccatcacctg caatgtggcc 720cacccggcaa gcagcaccaa agtggacaag aaaattgagc ccagagtgcc cataacacag 780aacccctgtc ctccactcaa agagtgtccc ccatgcgcag ctccagacct cttgggtgga 840ccatccgtct tcatcttccc tccaaagatc aaggatgtac tcatgatctc cccgagcccc 900atggtcacat gtgtggtggt ggatgtgagc gaggatgacc cagacgtcca gatcagctgg 960tttgtgaaca acgtggaagt acacacagct cagacacaaa cccatagaga ggattacaac 1020agtactctcc gggtggtcag tgccctcccc atccagcacc aggactggat gagtggcaag 1080gagttcaaat gcaaggtcaa caacagagcc ctcccatccc ccatcgagaa aaccatctca 1140aaacccagag ggccagtaag agctccacag gtatatgtct tgcctccacc agcagaagag 1200atgactaaga aagagttcag tctgacctgc atgatcacag gcttcttacc tgccgaaatt 1260gctgtggact ggaccagcaa tgggcgtaca gagcaaaact acaagaacac cgcaacagtc 1320ctggactctg atggttctta cttcatgtac agcaagctca gagtacaaaa gagcacttgg 1380gaaagaggaa gtcttttcgc ctgctcagtg gtccacgagg gtctgcacaa tcaccttacg 1440actaagacca tctcccggtc tctgggtaaa gctagctga 147954457PRTArtificial SequenceSynthetic peptide. 54Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Arg Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr65 70 75 80Ile Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Cys Phe Cys 85 90 95Ala Arg Arg Tyr Tyr Gly Asn Tyr Asp Gly Phe Ala Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val 115 120 125Tyr Pro Leu Ala Pro Val Cys Gly Gly Thr Thr Gly Ser Ser Val Thr 130 135 140Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr145 150 155 160Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Leu 165 170 175Leu Gln Ser Gly Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser 180 185 190Asn Thr Trp Pro Ser Gln Thr Ile Thr Cys Asn Val Ala His Pro Ala 195 200 205Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Val Pro Ile Thr 210 215 220Gln Asn Pro Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro225 230 235 240Asp Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys 245 250 255Asp Val Leu Met Ile Ser Pro Ser Pro Met Val Thr Cys Val Val Val 260 265 270Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn 275 280 285Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr 290 295 300Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp305 310 315 320Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu 325 330 335Pro Ser Pro Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg 340 345 350Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys 355 360 365Lys Glu Phe Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu 370 375 380Ile Ala Val Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys385 390 395 400Asn Thr Ala Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser 405 410 415Lys Leu Arg Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala 420 425 430Cys Ser Val Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr 435 440 445Ile Ser Arg Ser Leu Gly Lys Ala Ser 450 45555705DNAArtificial SequenceSynthetic oligonucleotide. 55atgagggccc ctgctcagtt ttttgggatc ttgttgctct ggtttccagg tatcagatgt 60gacatcaaga tgacccagtc tccatcctcc atgtatgcat cgctgggaga gagagtcact 120attacttgca aggcgagtca ggacattaaa agctatttaa cttggtacca gcagaaacca 180tggaaatctc ctaagaccct gatcaattat gcaacaagct tggcagatgg ggtcccatca 240agattcagtg gcagtggatc tggacaagat tattctctaa ccatcagcag cctggagtct 300gacgatacag caacttatta ctgtctacag catggtcaga gtccgttcac gttcggaggg 360gggaccaggc tggagataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420tccagtgagc agttaacatc tggaggtgcc tcggtcgtgt gcttcttgaa caacttctac 480cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660tcaacttcac ccatcgtcaa gagcttcaac aggaatgagt gttag 70556214PRTArtificial SequenceSynthetic peptide. 56Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Lys Ser Tyr 20 25 30Leu Thr Trp Tyr Gln Gln Lys Pro Trp Lys Ser Pro Lys Thr Leu Ile 35 40 45Asn Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser65 70 75 80Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Gln Ser Pro Phe 85 90 95Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105

110Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu145 150 155 160Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205Phe Asn Arg Asn Glu Cys 210571479DNAArtificial SequenceSynthetic peptide. 57atgagatcac tgttctcttt acagttactg agcacacagg acctcgccat gggatggagc 60tgtatcatcc tcttcttggt agcaacagct acaggtgtcc actctcaggt ccaactgcag 120cagcctgggg ctgagcttgt gaagcctggg gcttcagtga agctgtcctg caaggcttct 180ggctacacct tcaccagtta ctggatgcag tgggtaaagc agaggcctgg acagggcctt 240gagtggaccg gagagattga tccttctgat agctatacta actacaatca aaggttcaag 300ggcaaggcca cattgactgt ggacacatcc tccagcacag cctacacaca gctcagcagc 360ctgacgtctg aggactctgc ggtccatttc tgtgcaagac gctactatgg taactacgat 420gggtttgctt actggggcca agggactctg gtcactgtct ctgcagccaa aacaacagcc 480ccatcggtct atccactggc ccctgtgtgt ggaggtacaa ctggctcctc ggtgactcta 540ggatgcctgg tcaagggtta tttccctgag ccagtgacct tgacctggaa ctctggatcc 600ctgtccagtg gtgtgcacac cttcccagct ctcctgcagt ctggcctcta caccctcagc 660agctcagtga ctgtaacctc gaacacctgg cccagccaga ccatcacctg caatgtggcc 720cacccggcaa gcagcaccaa agtggacaag aaaattgagc ccagagtgcc cataacacag 780aacccctgtc ctccactcaa agagtgtccc ccatgcgcag ctccagacct cttgggtgga 840ccatccgtct tcatcttccc tccaaaggtc aaggatgtac tcatgatctc cctgagcccc 900atggtcacat gtgtggtggt ggatgtgagc gaggatgacc cagacgtcca gatcagctgg 960tttgtgaaca acgtggaagt acacacagct cagacacaaa cccatagaga ggattacaac 1020agtactctcc gggtggtcag tgccctcccc atccagcacc aggactggat gagtggcaag 1080gagttcaaat gcaaggtcaa caacagagcc ctcccatccc ccatcgagaa aaccatctca 1140aaacccagag ggccagtaag agctccacag gtatatgtct tgcctccacc agcagaagag 1200atgactaaga aagagttcag tctgacctgc atgatcacag gcttcttacc tgccgaaatt 1260gctgtggact ggaccagcaa tgggcgtaca gagcaaaact acaagaacac cgcaacagtc 1320ctggactctg atggttctta cttcatgtac agcaagctca gagtacaaaa gagcacttgg 1380gaaagaggaa gtcttttcgc ctgctcagtg gtccacgagg gtctgcacaa tcaccttacg 1440actaagacca tctcccggtc tctgggtaaa gctagctga 147958457PRTArtificial SequenceSynthetic peptide. 58Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Thr 35 40 45Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Arg Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr65 70 75 80Thr Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val His Phe Cys 85 90 95Ala Arg Arg Tyr Tyr Gly Asn Tyr Asp Gly Phe Ala Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val 115 120 125Tyr Pro Leu Ala Pro Val Cys Gly Gly Thr Thr Gly Ser Ser Val Thr 130 135 140Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr145 150 155 160Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Leu 165 170 175Leu Gln Ser Gly Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser 180 185 190Asn Thr Trp Pro Ser Gln Thr Ile Thr Cys Asn Val Ala His Pro Ala 195 200 205Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Val Pro Ile Thr 210 215 220Gln Asn Pro Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro225 230 235 240Asp Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Val Lys 245 250 255Asp Val Leu Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val 260 265 270Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn 275 280 285Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr 290 295 300Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp305 310 315 320Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu 325 330 335Pro Ser Pro Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg 340 345 350Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys 355 360 365Lys Glu Phe Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu 370 375 380Ile Ala Val Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys385 390 395 400Asn Thr Ala Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser 405 410 415Lys Leu Arg Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala 420 425 430Cys Ser Val Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr 435 440 445Ile Ser Arg Ser Leu Gly Lys Ala Ser 450 455592412DNAArtificial SequenceSynthetic oligonucleotide. 59atgacattga acatgctgtt ggggctgagg tgggttttct ttgttgtttt ttatcaaggt 60gtgcattgtg aggtgcagct tgttgagtct ggtggaggat tggtgcagcc taaagggtca 120ttgaaactct catgtgcagc ctctggatta accttcaata tctacgccat gaactgggtc 180cgccaggctc caggaaaggg tttggaatgg gttgctcgca taagaaataa aagtaataat 240tatgcaacat attatgccga ttcagtgaaa gacaggttca ccatctccag agatgattca 300caaagcttgc tctatctgca aatgaacaac ttgaaaactg aggacacagc catgtattac 360tgtgtgggac gggactggtt tgattactgg ggccaaggga ctctggtcac tgtctctgca 420gccaaaacga agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 480agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 660tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 720aaatatggtc ccccatgccc accctgccca gcacctgagt tcgaaggggg accatcagtc 780ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 840tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 900ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 960cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 1020tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1080gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1140aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1200tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1320aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1380ctctccctgt ctctgggtaa agctagcgat acaacagaac ctgcaacacc tacaacacct 1440gtaacaacag acacaatatg tataggctac catgcgaaca attcaaccga cactgttgac 1500acagtactcg agaagaatgt gacagtgaca cactctgtta acctgctcga agacagccac 1560aacggaaaac tatgtagatt aaaaggaata gccccactac aattggggaa atgtaacatc 1620gccggatggc tcttgggaaa cccagaatgc gacccactgc ttccagtgag atcatggtcc 1680tacattgtag aaacaccaaa ctctgagaat ggaatatgtt atccaggaga tttcatcgac 1740tatgaggagc tgagggagca attgagctca gtgtcatcat tcgaaagatt cgaaatattt 1800cccaaagaaa gctcatggcc caaccacaac acaaacggag taacggcagc atgctcccat 1860gaggggaaaa gcagttttta cagaaatttg ctatggctga cggagaagga gggctcatac 1920ccaaagctga aaaattctta tgtgaacaaa aaagggaaag aagtccttgt actgtggggt 1980attcatcacc cgcctaacag taaggaacaa cagaatctct atcagaatga aaatgcttat 2040gtctctgtag tgacttcaaa ttataacagg agatttaccc cggaaatagc agaaagaccc 2100aaagtaagag atcaagctgg gaggatgaac tattactgga ccttgctaaa acccggagac 2160acaataatat ttgaggcaaa tggaaatcta atagcaccaa tgtatgcttt cgcactgagt 2220agaggctttg ggtccggcat catcacctca aacgcatcaa tgcatgagtg taacacgaag 2280tgtcaaacac ccctgggagc tataaacagc agtctccctt accagaatat acacccagtc 2340acaataggag agtgcccaaa atacgtcagg agtgccaaat tgaggatggt tcaccatcac 2400catcaccatt ga 241260780PRTArtificial SequenceSynthetic peptide. 60Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asn Ile Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Arg Ile Arg Asn Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Leu65 70 75 80Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95Tyr Cys Val Gly Arg Asp Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asp Thr 435 440 445Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Asp Thr Ile Cys 450 455 460Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val Asp Thr Val Leu465 470 475 480Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu Leu Glu Asp Ser 485 490 495His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile Ala Pro Leu Gln Leu 500 505 510Gly Lys Cys Asn Ile Ala Gly Trp Leu Leu Gly Asn Pro Glu Cys Asp 515 520 525Pro Leu Leu Pro Val Arg Ser Trp Ser Tyr Ile Val Glu Thr Pro Asn 530 535 540Ser Glu Asn Gly Ile Cys Tyr Pro Gly Asp Phe Ile Asp Tyr Glu Glu545 550 555 560Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu Arg Phe Glu Ile 565 570 575Phe Pro Lys Glu Ser Ser Trp Pro Asn His Asn Thr Asn Gly Val Thr 580 585 590Ala Ala Cys Ser His Glu Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu 595 600 605Trp Leu Thr Glu Lys Glu Gly Ser Tyr Pro Lys Leu Lys Asn Ser Tyr 610 615 620Val Asn Lys Lys Gly Lys Glu Val Leu Val Leu Trp Gly Ile His His625 630 635 640Pro Pro Asn Ser Lys Glu Gln Gln Asn Leu Tyr Gln Asn Glu Asn Ala 645 650 655Tyr Val Ser Val Val Thr Ser Asn Tyr Asn Arg Arg Phe Thr Pro Glu 660 665 670Ile Ala Glu Arg Pro Lys Val Arg Asp Gln Ala Gly Arg Met Asn Tyr 675 680 685Tyr Trp Thr Leu Leu Lys Pro Gly Asp Thr Ile Ile Phe Glu Ala Asn 690 695 700Gly Asn Leu Ile Ala Pro Met Tyr Ala Phe Ala Leu Ser Arg Gly Phe705 710 715 720Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser Met His Glu Cys Asn Thr 725 730 735Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Ser Ser Leu Pro Tyr Gln 740 745 750Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro Lys Tyr Val Arg Ser 755 760 765Ala Lys Leu Arg Met Val His His His His His His 770 775 780612412DNAArtificial SequenceSyntehtic oligonucleotide. 61atgacattga acatgctgtt ggggctgagg tgggttttct ttgttgtttt ttatcaaggt 60gtgcattgtg aggtgcagct tgttgagtct ggtggaggat tggtgcagcc taaagggtca 120ttgaaactct catgtgcagc ctctggatta accttcaata tctacgccat gaactgggtc 180cgccaggctc caggaaaggg tttggaatgg gttgctcgca taagaaataa aagtaataat 240tatgcaacat attatgccga ttcagtgaaa gacaggttca ccatctccag agatgattca 300caaagcttgc tctatctgca aatgaacaac ttgaaaactg aggacacagc catgtattac 360tgtgtgggac gggactggtt tgattactgg ggccaaggga ctctggtcac tgtctctgca 420gccaaaacga agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 480agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 660tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 720aaatatggtc ccccatgccc accctgccca gcacctgagt tcgaaggggg accatcagtc 780ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 840tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 900ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 960cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 1020tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1080gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1140aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1200tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1320aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1380ctctccctgt ctctgggtaa agctagcgat acaacagaac ctgcaacacc tacaacacct 1440gtaacaacag atcagatttg cattggttac catgcaaaca actcgacaga gcaggttgac 1500acaataatgg aaaagaacgt tactgttaca catgcccaag acatactgga aaagaaacac 1560aacgggaagc tctgcgatct agatggagtg aagcctctaa ttttgagaga ttgtagcgta 1620gctggatggc tcctcggaaa cccaatgtgt gacgaattca tcaatgtgcc ggaatggtct 1680tacatagtgg agaaggccaa tccagtcaat gacctctgtt acccagggga tttcaatgac 1740tatgaagaat tgaaacacct attgagcaga ataaaccatt ttgagaaaat tcagatcatc 1800cccaaaagtt cttggtccag tcatgaagcc tcattagggg tgagctcagc atgtccatac 1860cagggaaagt cctccttttt cagaaatgtg gtatggctta tcaaaaagaa cagtacatac 1920ccaacaataa agaggagcta caataatacc aaccaagaag atcttttggt actgtggggg 1980attcaccatc ctaatgatgc ggcagagcag acaaagctct atcaaaaccc aaccacctat 2040atttccgttg ggacatcaac actaaaccag agattggtac caagaatagc tactagatcc 2100aaagtaaacg ggcaaagtgg aaggatggag ttcttctgga caattttaaa gccgaatgat 2160gcaatcaact tcgagagtaa tggaaatttc attgctccag aatatgcata caaaattgtc 2220aagaaagggg actcaacaat tatgaaaagt gaattggaat atggtaactg caacaccaag 2280tgtcaaactc caatgggggc gataaactct agcatgccat tccacaatat acaccctctc 2340accattgggg aatgccccaa atatgtgaaa tcaaacagat tagtccttgc gcaccatcac 2400catcaccatt ga 241262780PRTArtificial SequenceSyntehtic peptide. 62Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asn Ile Tyr 20 25

30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Arg Ile Arg Asn Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Leu65 70 75 80Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95Tyr Cys Val Gly Arg Asp Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asp Thr 435 440 445Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Asp Gln Ile Cys 450 455 460Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val Asp Thr Ile Met465 470 475 480Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile Leu Glu Lys Lys 485 490 495His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys Pro Leu Ile Leu 500 505 510Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn Pro Met Cys Asp 515 520 525Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val Glu Lys Ala Asn 530 535 540Pro Val Asn Asp Leu Cys Tyr Pro Gly Asp Phe Asn Asp Tyr Glu Glu545 550 555 560Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu Lys Ile Gln Ile 565 570 575Ile Pro Lys Ser Ser Trp Ser Ser His Glu Ala Ser Leu Gly Val Ser 580 585 590Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val 595 600 605Trp Leu Ile Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr 610 615 620Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His625 630 635 640Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Pro Thr Thr 645 650 655Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Arg 660 665 670Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly Arg Met Glu Phe 675 680 685Phe Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn Phe Glu Ser Asn 690 695 700Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile Val Lys Lys Gly705 710 715 720Asp Ser Thr Ile Met Lys Ser Glu Leu Glu Tyr Gly Asn Cys Asn Thr 725 730 735Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser Met Pro Phe His 740 745 750Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys Ser 755 760 765Asn Arg Leu Val Leu Ala His His His His His His 770 775 780632202DNAArtificial SequenceSynthetic oligonucleotide. 63atgacattga acatgctgtt ggggctgaag tgggttttct ttgttgtttt ttatcaaggt 60gtgcattgtg aggtgcagct tgttgagtct ggtggaggat tggtgcagcc taaagggtca 120ttgaaactct catgtgcagc ctctggatta accttcaata tctacgccat gaactgggtc 180cgccaggctc caggaaaggg tttggaatgg gttgctcgca taagaaataa aagtaataat 240tatgcaacat attatgccga ttcagtgaaa gacaggttca ccatctccag agatgattca 300caaagcttgc tctatctgca aatgaacaac ttgaaaactg aggacacagc catgtattac 360tgtgtgggac gggactggtt tgattactgg ggccaaggga ctctggtcac tgtctctgca 420gccaaaacga agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 480agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 660tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 720aaatatggtc ccccatgccc accctgccca gcacctgagt tcgaaggggg accatcagtc 780ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 840tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 900ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 960cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 1020tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1080gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1140aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1200tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1320aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1380ctctccctgt ctctgggtaa agctagcgat acaacagaac ctgcaacacc tacaacacct 1440gtaacaacac cgacaacaac acttctagcg cccctcatcc tgtctcggat tgtgggaggc 1500tgggagtgcg agaagcattc ccaaccctgg caggtgcttg tggcctctcg tggcagggca 1560gtctgcggcg gtgttctggt gcacccccag tgggtcctca cagctgccca ctgcatcagg 1620aacaaaagcg tgatcttgct gggtcggcac agcctgtttc atcctgaaga cacaggccag 1680gtatttcagg tcagccacag cttcccacac ccgctctacg atatgagcct cctgaagaat 1740cgattcctca ggccaggtga tgactccagc cacgacctca tgctgctccg cctgtcagag 1800cctgccgagc tcacggatgc tgtgaaggtc atggacctgc ccacccagga gccagcactg 1860gggaccacct gctacgcctc aggctggggc agcattgaac cagaggagtt cttgacccca 1920aagaaacttc agtgtgtgga cctccatgtt atttccaatg acgtgtgtgc gcaagttcac 1980cctcagaagg tgaccaagtt catgctgtgt gctggacgct ggacaggggg caaaagcacc 2040tgctcgggtg attctggggg cccacttgtc tgtaatggtg tgcttcaagg tatcacgtca 2100tggggcagtg aaccatgtgc cctgcccgaa aggccttccc tgtacaccaa ggtggtgcat 2160taccggaagt ggatcaagga caccatcgtg gccaacccct ga 220264710PRTArtificial SequenceSynthetic peptide. 64Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly1 5 10 15Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asn Ile Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Arg Ile Arg Asn Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Leu65 70 75 80Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95Tyr Cys Val Gly Arg Asp Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asp Thr 435 440 445Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Pro Thr Thr Thr 450 455 460Leu Leu Ala Pro Leu Ile Leu Ser Arg Ile Val Gly Gly Trp Glu Cys465 470 475 480Glu Lys His Ser Gln Pro Trp Gln Val Leu Val Ala Ser Arg Gly Arg 485 490 495Ala Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val Leu Thr Ala 500 505 510Ala His Cys Ile Arg Asn Lys Ser Val Ile Leu Leu Gly Arg His Ser 515 520 525Leu Phe His Pro Glu Asp Thr Gly Gln Val Phe Gln Val Ser His Ser 530 535 540Phe Pro His Pro Leu Tyr Asp Met Ser Leu Leu Lys Asn Arg Phe Leu545 550 555 560Arg Pro Gly Asp Asp Ser Ser His Asp Leu Met Leu Leu Arg Leu Ser 565 570 575Glu Pro Ala Glu Leu Thr Asp Ala Val Lys Val Met Asp Leu Pro Thr 580 585 590Gln Glu Pro Ala Leu Gly Thr Thr Cys Tyr Ala Ser Gly Trp Gly Ser 595 600 605Ile Glu Pro Glu Glu Phe Leu Thr Pro Lys Lys Leu Gln Cys Val Asp 610 615 620Leu His Val Ile Ser Asn Asp Val Cys Ala Gln Val His Pro Gln Lys625 630 635 640Val Thr Lys Phe Met Leu Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser 645 650 655Thr Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Cys Asn Gly Val Leu 660 665 670Gln Gly Ile Thr Ser Trp Gly Ser Glu Pro Cys Ala Leu Pro Glu Arg 675 680 685Pro Ser Leu Tyr Thr Lys Val Val His Tyr Arg Lys Trp Ile Lys Asp 690 695 700Thr Ile Val Ala Asn Pro705 710652415DNAArtificial SequenceSyntehtic oligonucleotide. 65atggacccca aaggctccct ttcctggaga atacttctgt ttctctccct ggcttttgag 60ttgtcgtacg gacaggttca gctgcggcag tctggacctg agctggtgaa gcctggggct 120tcagtgaaga tgtcctgcaa ggcttctgga tacacattta ctgactatgt tataagttgg 180gtgaagcaga gaactggaca gggccttgag tggattggag atatttatcc tggaagtggt 240tattctttct acaatgagaa cttcaagggc aaggccacac tgactgcaga caaatcctcc 300accacagcct acatgcagct cagcagcctg acatctgagg actctgcggt ctatttctgt 360gcaacctact ataactaccc ttttgcttac tggggccaag ggactctggt cactgtctct 420gcagccaaaa caacgggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 480gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 600tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 660acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 720tccaaatatg gtcccccatg cccaccctgc ccagcacctg agttcgaagg gggaccatca 780gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 840acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 900gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 960taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 1020aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1080aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1140aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1200gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1260tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1320gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1380agcctctccc tgtctctggg taaagctagc gatacaacag aacctgcaac acctacaaca 1440cctgtaacaa cagatcagat ttgcattggt taccatgcaa acaactcgac agagcaggtt 1500gacacaataa tggaaaagaa cgttactgtt acacatgccc aagacatact ggaaaagaaa 1560cacaacggga agctctgcga tctagatgga gtgaagcctc taattttgag agattgtagc 1620gtagctggat ggctcctcgg aaacccaatg tgtgacgaat tcatcaatgt gccggaatgg 1680tcttacatag tggagaaggc caatccagtc aatgacctct gttacccagg ggatttcaat 1740gactatgaag aattgaaaca cctattgagc agaataaacc attttgagaa aattcagatc 1800atccccaaaa gttcttggtc cagtcatgaa gcctcattag gggtgagctc agcatgtcca 1860taccagggaa agtcctcctt tttcagaaat gtggtatggc ttatcaaaaa gaacagtaca 1920tacccaacaa taaagaggag ctacaataat accaaccaag aagatctttt ggtactgtgg 1980gggattcacc atcctaatga tgcggcagag cagacaaagc tctatcaaaa cccaaccacc 2040tatatttccg ttgggacatc aacactaaac cagagattgg taccaagaat agctactaga 2100tccaaagtaa acgggcaaag tggaaggatg gagttcttct ggacaatttt aaagccgaat 2160gatgcaatca acttcgagag taatggaaat ttcattgctc cagaatatgc atacaaaatt 2220gtcaagaaag gggactcaac aattatgaaa agtgaattgg aatatggtaa ctgcaacacc 2280aagtgtcaaa ctccaatggg ggcgataaac tctagcatgc cattccacaa tatacaccct 2340ctcaccattg gggaatgccc caaatatgtg aaatcaaaca gattagtcct tgcgcaccat 2400caccatcacc attga 241566780PRTArtificial SequenceSynthetic peptide. 66Gln Val Gln Leu Arg Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Ala Thr Tyr Tyr Asn Tyr Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro

Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asp Thr 435 440 445Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Asp Gln Ile Cys 450 455 460Ile Gly Tyr His Ala Asn Asn Ser Thr Glu Gln Val Asp Thr Ile Met465 470 475 480Glu Lys Asn Val Thr Val Thr His Ala Gln Asp Ile Leu Glu Lys Lys 485 490 495His Asn Gly Lys Leu Cys Asp Leu Asp Gly Val Lys Pro Leu Ile Leu 500 505 510Arg Asp Cys Ser Val Ala Gly Trp Leu Leu Gly Asn Pro Met Cys Asp 515 520 525Glu Phe Ile Asn Val Pro Glu Trp Ser Tyr Ile Val Glu Lys Ala Asn 530 535 540Pro Val Asn Asp Leu Cys Tyr Pro Gly Asp Phe Asn Asp Tyr Glu Glu545 550 555 560Leu Lys His Leu Leu Ser Arg Ile Asn His Phe Glu Lys Ile Gln Ile 565 570 575Ile Pro Lys Ser Ser Trp Ser Ser His Glu Ala Ser Leu Gly Val Ser 580 585 590Ser Ala Cys Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val 595 600 605Trp Leu Ile Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr 610 615 620Asn Asn Thr Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His625 630 635 640Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Pro Thr Thr 645 650 655Tyr Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Arg 660 665 670Ile Ala Thr Arg Ser Lys Val Asn Gly Gln Ser Gly Arg Met Glu Phe 675 680 685Phe Trp Thr Ile Leu Lys Pro Asn Asp Ala Ile Asn Phe Glu Ser Asn 690 695 700Gly Asn Phe Ile Ala Pro Glu Tyr Ala Tyr Lys Ile Val Lys Lys Gly705 710 715 720Asp Ser Thr Ile Met Lys Ser Glu Leu Glu Tyr Gly Asn Cys Asn Thr 725 730 735Lys Cys Gln Thr Pro Met Gly Ala Ile Asn Ser Ser Met Pro Phe His 740 745 750Asn Ile His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys Ser 755 760 765Asn Arg Leu Val Leu Ala His His His His His His 770 775 780671638DNAArtificial SequenceSyntehtic oligonucleotide. 67atggacccca aaggctccct ttcctggaga atacttctgt ttctctccct ggcttttgag 60ttgtcgtacg gacaggttca gctgcggcag tctggacctg agctggtgaa gcctggggct 120tcagtgaaga tgtcctgcaa ggcttctgga tacacattta ctgactatgt tataagttgg 180gtgaagcaga gaactggaca gggccttgag tggattggag atatttatcc tggaagtggt 240tattctttct acaatgagaa cttcaagggc aaggccacac tgactgcaga caaatcctcc 300accacagcct acatgcagct cagcagcctg acatctgagg actctgcggt ctatttctgt 360gcaacctact ataactaccc ttttgcttac tggggccaag ggactctggt cactgtctct 420gcagccaaaa caacgggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 480gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 600tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 660acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 720tccaaatatg gtcccccatg cccaccctgc ccagcacctg agttcgaagg gggaccatca 780gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 840acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 900gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 960taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 1020aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1080aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1140aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1200gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1260tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1320gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1380agcctctccc tgtctctggg taaagctagc aattctcctc aaaatgaagt actgtacgga 1440gatgtgaatg atgacggaaa agtaaactcc actgacttga ctttgttaaa aagatatgtt 1500cttaaagccg tctcaactct cccttcttcc aaagctgaaa agaacgcaga tgtaaatcgt 1560gacggaagag ttaattccag tgatgtcaca atactttcaa gatatttgat aagggtaatc 1620gagaaattac caatataa 163868521PRTArtificial SequenceSynthetic peptide. 68Gln Val Gln Leu Arg Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Ala Thr Tyr Tyr Asn Tyr Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asn Ser 435 440 445Pro Gln Asn Glu Val Leu Tyr Gly Asp Val Asn Asp Asp Gly Lys Val 450 455 460Asn Ser Thr Asp Leu Thr Leu Leu Lys Arg Tyr Val Leu Lys Ala Val465 470 475 480Ser Thr Leu Pro Ser Ser Lys Ala Glu Lys Asn Ala Asp Val Asn Arg 485 490 495Asp Gly Arg Val Asn Ser Ser Asp Val Thr Ile Leu Ser Arg Tyr Leu 500 505 510Ile Arg Val Ile Glu Lys Leu Pro Ile 515 520692415DNAArtificial SequenceSyntehtic oligonucleotide. 69atggacccca aaggctccct ttcctggaga atacttctgt ttctctccct ggcttttgag 60ttgtcgtacg gacaggttca gctgcggcag tctggacctg agctggtgaa gcctggggct 120tcagtgaaga tgtcctgcaa ggcttctgga tacacattta ctgactatgt tataagttgg 180gtgaagcaga gaactggaca gggccttgag tggattggag atatttatcc tggaagtggt 240tattctttct acaatgagaa cttcaagggc aaggccacac tgactgcaga caaatcctcc 300accacagcct acatgcagct cagcagcctg acatctgagg actctgcggt ctatttctgt 360gcaacctact ataactaccc ttttgcttac tggggccaag ggactctggt cactgtctct 420gcagccaaaa caacgggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 480gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 600tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 660acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 720tccaaatatg gtcccccatg cccaccctgc ccagcacctg agttcgaagg gggaccatca 780gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 840acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 900gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 960taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 1020aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1080aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1140aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1200gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1260tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1320gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1380agcctctccc tgtctctggg taaagctagc gatacaacag aacctgcaac acctacaaca 1440cctgtaacaa cagacacaat atgtataggc taccatgcga acaattcaac cgacactgtt 1500gacacagtac tcgagaagaa tgtgacagtg acacactctg ttaacctgct cgaagacagc 1560cacaacggaa aactatgtag attaaaagga atagccccac tacaattggg gaaatgtaac 1620atcgccggat ggctcttggg aaacccagaa tgcgacccac tgcttccagt gagatcatgg 1680tcctacattg tagaaacacc aaactctgag aatggaatat gttatccagg agatttcatc 1740gactatgagg agctgaggga gcaattgagc tcagtgtcat cattcgaaag attcgaaata 1800tttcccaaag aaagctcatg gcccaaccac aacacaaacg gagtaacggc agcatgctcc 1860catgagggga aaagcagttt ttacagaaat ttgctatggc tgacggagaa ggagggctca 1920tacccaaagc tgaaaaattc ttatgtgaac aaaaaaggga aagaagtcct tgtactgtgg 1980ggtattcatc acccgcctaa cagtaaggaa caacagaatc tctatcagaa tgaaaatgct 2040tatgtctctg tagtgacttc aaattataac aggagattta ccccggaaat agcagaaaga 2100cccaaagtaa gagatcaagc tgggaggatg aactattact ggaccttgct aaaacccgga 2160gacacaataa tatttgaggc aaatggaaat ctaatagcac caatgtatgc tttcgcactg 2220agtagaggct ttgggtccgg catcatcacc tcaaacgcat caatgcatga gtgtaacacg 2280aagtgtcaaa cacccctggg agctataaac agcagtctcc cttaccagaa tatacaccca 2340gtcacaatag gagagtgccc aaaatacgtc aggagtgcca aattgaggat ggttcaccat 2400caccatcacc attga 241570780PRTArtificial SequenceSynthetic peptide. 70Gln Val Gln Leu Arg Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Ala Thr Tyr Tyr Asn Tyr Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asp Thr 435 440 445Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Asp Thr Ile Cys 450 455 460Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val Asp Thr Val Leu465 470 475 480Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu Leu Glu Asp Ser 485 490 495His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile Ala Pro Leu Gln Leu 500 505 510Gly Lys Cys Asn Ile Ala Gly Trp Leu Leu Gly Asn Pro Glu Cys Asp 515 520 525Pro Leu Leu Pro Val Arg Ser Trp Ser Tyr Ile Val Glu Thr Pro Asn 530 535 540Ser Glu Asn Gly Ile Cys Tyr Pro Gly Asp Phe Ile Asp Tyr Glu Glu545 550 555 560Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu Arg Phe Glu Ile 565 570 575Phe Pro Lys Glu Ser Ser Trp Pro Asn His Asn Thr Asn Gly Val Thr 580 585 590Ala Ala Cys Ser His Glu Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu 595 600 605Trp Leu Thr Glu Lys Glu Gly Ser Tyr Pro Lys Leu Lys Asn Ser Tyr 610 615 620Val Asn Lys Lys Gly Lys Glu Val Leu Val Leu Trp Gly Ile His His625 630 635 640Pro Pro Asn Ser Lys Glu Gln Gln Asn Leu Tyr Gln Asn Glu Asn Ala 645 650 655Tyr Val Ser Val Val Thr Ser Asn Tyr Asn Arg Arg Phe Thr Pro Glu 660 665 670Ile Ala Glu Arg Pro Lys Val Arg Asp Gln Ala

Gly Arg Met Asn Tyr 675 680 685Tyr Trp Thr Leu Leu Lys Pro Gly Asp Thr Ile Ile Phe Glu Ala Asn 690 695 700Gly Asn Leu Ile Ala Pro Met Tyr Ala Phe Ala Leu Ser Arg Gly Phe705 710 715 720Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser Met His Glu Cys Asn Thr 725 730 735Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Ser Ser Leu Pro Tyr Gln 740 745 750Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro Lys Tyr Val Arg Ser 755 760 765Ala Lys Leu Arg Met Val His His His His His His 770 775 780712154DNAArtificial SequenceSyntehtic oligonucleotide. 71atggacccca aaggctccct ttcctggaga atacttctgt ttctctccct ggcttttgag 60ttgtcgtacg gacaggttca gctgcggcag tctggacctg agctggtgaa gcctggggct 120tcagtgaaga tgtcctgcaa ggcttctgga tacacattta ctgactatgt tataagttgg 180gtgaagcaga gaactggaca gggccttgag tggattggag atatttatcc tggaagtggt 240tattctttct acaatgagaa cttcaagggc aaggccacac tgactgcaga caaatcctcc 300accacagcct acatgcagct cagcagcctg acatctgagg actctgcggt ctatttctgt 360gcaacctact ataactaccc ttttgcttac tggggccaag ggactctggt cactgtctct 420gcagccaaaa caacgggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 480gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 600tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 660acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 720tccaaatatg gtcccccatg cccaccctgc ccagcacctg agttcgaagg gggaccatca 780gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 840acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 900gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 960taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 1020aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1080aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1140aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1200gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1260tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1320gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1380agcctctccc tgtctctggg taaagctagc gacatggcca agaaggagac agtctggagg 1440ctcgaggagt tcggtaggcc tatagtgcag aacatccagg ggcaaatggt acatcaggcc 1500atatcaccta gaactttaaa tgcatgggta aaagtagtag aagagaaggc tttcagccca 1560gaagtaatac ccatgttttc agcattatca gaaggagcca ccccacaaga tttaaacacc 1620atgctaaaca cagtgggggg acatcaagca gccatgcaaa tgttaaaaga gaccatcaat 1680gaggaagctg cagaatggga tagagtacat ccagtgcatg cagggcctat tgcaccaggc 1740cagatgagag aaccaagggg aagtgacata gcaggaacta ctagtaccct tcaggaacaa 1800ataggatgga tgacaaataa tccacctatc ccagtaggag aaatttataa aagatggata 1860atcctgggat taaataaaat agtaagaatg tatagcccta ccagcattct ggacataaga 1920caaggaccaa aagaaccttt tagagactat gtagaccggt tctataaaac tctaagagcc 1980gagcaagctt cacaggaggt aaaaaattgg atgacagaaa ccttgttggt ccaaaatgcg 2040aacccagatt gtaagactat tttaaaagca ttgggaccag cggctacact agaagaaatg 2100atgacagcat gtcagggagt aggaggaccc ggccataagg caagagtttt gtga 215472693PRTArtificial SequenceSynthetic peptide. 72Gln Val Gln Leu Arg Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Ala Thr Tyr Tyr Asn Tyr Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asp Met 435 440 445Ala Lys Lys Glu Thr Val Trp Arg Leu Glu Glu Phe Gly Arg Pro Ile 450 455 460Val Gln Asn Ile Gln Gly Gln Met Val His Gln Ala Ile Ser Pro Arg465 470 475 480Thr Leu Asn Ala Trp Val Lys Val Val Glu Glu Lys Ala Phe Ser Pro 485 490 495Glu Val Ile Pro Met Phe Ser Ala Leu Ser Glu Gly Ala Thr Pro Gln 500 505 510Asp Leu Asn Thr Met Leu Asn Thr Val Gly Gly His Gln Ala Ala Met 515 520 525Gln Met Leu Lys Glu Thr Ile Asn Glu Glu Ala Ala Glu Trp Asp Arg 530 535 540Val His Pro Val His Ala Gly Pro Ile Ala Pro Gly Gln Met Arg Glu545 550 555 560Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr Ser Thr Leu Gln Glu Gln 565 570 575Ile Gly Trp Met Thr Asn Asn Pro Pro Ile Pro Val Gly Glu Ile Tyr 580 585 590Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys Ile Val Arg Met Tyr Ser 595 600 605Pro Thr Ser Ile Leu Asp Ile Arg Gln Gly Pro Lys Glu Pro Phe Arg 610 615 620Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu Arg Ala Glu Gln Ala Ser625 630 635 640Gln Glu Val Lys Asn Trp Met Thr Glu Thr Leu Leu Val Gln Asn Ala 645 650 655Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala Leu Gly Pro Ala Ala Thr 660 665 670Leu Glu Glu Met Met Thr Ala Cys Gln Gly Val Gly Gly Pro Gly His 675 680 685Lys Ala Arg Val Leu 690732187DNAArtificial SequenceSyntehtic oligonucleotide. 73atggaatgga ggatctttct cttcatcctg tcaggaactg caggtgtcca ctcccaggtt 60cagctgcggc agtctggacc tgagctggtg aagcctgggg cttcagtgaa gatgtcctgc 120aaggcttctg gatacacatt tactgactat gttataagtt gggtgaagca gagaactgga 180cagggccttg agtggattgg agatatttat cctggaagtg gttattcttt ctacaatgag 240aacttcaagg gcaaggccac actgactgca gacaaatcct ccaccacagc ctacatgcag 300ctcagcagcc tgacatctga ggactctgcg gtctatttct gtgcaaccta ctataactac 360ccttttgctt actggggcca agggactctg gtcactgtct ctgcagccaa aacaacgggc 420ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agccgccctg 480ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 540ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 600agcagcgtgg tgaccgtgcc ctccagcagc ttgggcacga agacctacac ctgcaacgta 660gatcacaagc ccagcaacac caaggtggac aagagagttg agtccaaata tggtccccca 720tgcccaccct gcccagcacc tgagttcgaa gggggaccat cagtcttcct gttcccccca 780aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 840gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 900aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 960ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 1020aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 1080ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 1140acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1200cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1260ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 1320tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 1380ggtaaagcta gcgatacaac agaacctgca acacctacaa cacctgtaac aacaccgaca 1440acaacacttc tagcgcccct catcctgtct cggattgtgg gaggctggga gtgcgagaag 1500cattcccaac cctggcaggt gcttgtggcc tctcgtggca gggcagtctg cggcggtgtt 1560ctggtgcacc cccagtgggt cctcacagct gcccactgca tcaggaacaa aagcgtgatc 1620ttgctgggtc ggcacagcct gtttcatcct gaagacacag gccaggtatt tcaggtcagc 1680cacagcttcc cacacccgct ctacgatatg agcctcctga agaatcgatt cctcaggcca 1740ggtgatgact ccagccacga cctcatgctg ctccgcctgt cagagcctgc cgagctcacg 1800gatgctgtga aggtcatgga cctgcccacc caggagccag cactggggac cacctgctac 1860gcctcaggct ggggcagcat tgaaccagag gagttcttga ccccaaagaa acttcagtgt 1920gtggacctcc atgttatttc caatgacgtg tgtgcgcaag ttcaccctca gaaggtgacc 1980aagttcatgc tgtgtgctgg acgctggaca gggggcaaaa gcacctgctc gggtgattct 2040gggggcccac ttgtctgtaa tggtgtgctt caaggtatca cgtcatgggg cagtgaacca 2100tgtgccctgc ccgaaaggcc ttccctgtac accaaggtgg tgcattaccg gaagtggatc 2160aaggacacca tcgtggccaa cccctga 218774710PRTArtificial SequenceSynthetic peptide. 74Gln Val Gln Leu Arg Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Ala Thr Tyr Tyr Asn Tyr Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Asp Thr 435 440 445Thr Glu Pro Ala Thr Pro Thr Thr Pro Val Thr Thr Pro Thr Thr Thr 450 455 460Leu Leu Ala Pro Leu Ile Leu Ser Arg Ile Val Gly Gly Trp Glu Cys465 470 475 480Glu Lys His Ser Gln Pro Trp Gln Val Leu Val Ala Ser Arg Gly Arg 485 490 495Ala Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val Leu Thr Ala 500 505 510Ala His Cys Ile Arg Asn Lys Ser Val Ile Leu Leu Gly Arg His Ser 515 520 525Leu Phe His Pro Glu Asp Thr Gly Gln Val Phe Gln Val Ser His Ser 530 535 540Phe Pro His Pro Leu Tyr Asp Met Ser Leu Leu Lys Asn Arg Phe Leu545 550 555 560Arg Pro Gly Asp Asp Ser Ser His Asp Leu Met Leu Leu Arg Leu Ser 565 570 575Glu Pro Ala Glu Leu Thr Asp Ala Val Lys Val Met Asp Leu Pro Thr 580 585 590Gln Glu Pro Ala Leu Gly Thr Thr Cys Tyr Ala Ser Gly Trp Gly Ser 595 600 605Ile Glu Pro Glu Glu Phe Leu Thr Pro Lys Lys Leu Gln Cys Val Asp 610 615 620Leu His Val Ile Ser Asn Asp Val Cys Ala Gln Val His Pro Gln Lys625 630 635 640Val Thr Lys Phe Met Leu Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser 645 650 655Thr Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Cys Asn Gly Val Leu 660 665 670Gln Gly Ile Thr Ser Trp Gly Ser Glu Pro Cys Ala Leu Pro Glu Arg 675 680 685Pro Ser Leu Tyr Thr Lys Val Val His Tyr Arg Lys Trp Ile Lys Asp 690 695 700Thr Ile Val Ala Asn Pro705 710752268DNAArtificial SequenceSyntehtic oligonucleotide. 75atggaatgga ggatctttct cttcatcctg tcaggaactg caggtgtcca ctcccaggtt 60cagctgcggc agtctggacc tgagctggtg aagcctgggg cttcagtgaa gatgtcctgc 120aaggcttctg gatacacatt tactgactat gttataagtt gggtgaagca gagaactgga 180cagggccttg agtggattgg agatatttat cctggaagtg gttattcttt ctacaatgag 240aacttcaagg gcaaggccac actgactgca gacaaatcct ccaccacagc ctacatgcag 300ctcagcagcc tgacatctga ggactctgcg gtctatttct gtgcaaccta ctataactac 360ccttttgctt actggggcca agggactctg gtcactgtct ctgcagccaa aacaacgggc 420ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agccgccctg 480ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 540ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 600agcagcgtgg tgaccgtgcc ctccagcagc ttgggcacga agacctacac ctgcaacgta 660gatcacaagc ccagcaacac caaggtggac aagagagttg agtccaaata tggtccccca 720tgcccaccct gcccagcacc tgagttcgaa gggggaccat cagtcttcct gttcccccca 780aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 840gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 900aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 960ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 1020aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 1080ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 1140acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1200cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1260ctctacagca ggctaaccgt ggacaagagc

aggtggcagg aggggaatgt cttctcatgc 1320tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 1380ggtaaagcta gtcagacccc caccaacacc atcagcgtga cccccaccaa caacagcacc 1440cccaccaaca acagcaaccc caagcccaac cccgctagtg agaagatccg gctgcggccc 1500ggcggcaaga agaagtacaa gctgaagcac atcgtggcta gtagcagcgt gagccccacc 1560accagcgtgc accccacccc caccagcgtg ccccccaccc ccaccaagag cagccccgct 1620agtaaccccc ccatccccgt gggcgagatc tacaagcggt ggatcatcct gggcctgaac 1680aagatcgtgc ggatgtacag ccccaccagc atcctggacg ctagtcccac cagcaccccc 1740gccgacagca gcaccatcac ccccaccgcc acccccaccg ccacccccac catcaagggc 1800gctagtcaca cccagggcta cttccccgac tggcagaact acacccccgg ccccggcgtg 1860cggtaccccc tgaccttcgg ctggctgtac aagctggcta gtaccgtgac ccccaccgcc 1920accgccaccc ccagcgccat cgtgaccacc atcaccccca ccgccaccac caagcccgct 1980agtgtgggct tccccgtgac cccccaggtg cccctgcggc ccatgaccta caaggccgcc 2040gtggacctga gccacttcct gaaggagaag ggcggcctgg ctagtaccaa cggcagcatc 2100accgtggccg ccaccgcccc caccgtgacc cccaccgtga acgccacccc cagcgccgcc 2160gctagtgcca tcttccagag cagcatgacc aagatcctgg agcccttccg gaagcagaac 2220cccgacatcg tgatctacca gtacatggac gacctgtacg ctagctga 226876737PRTArtificial SequenceSynthetic peptide. 76Gln Val Gln Leu Arg Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Asp Ile Tyr Pro Gly Ser Gly Tyr Ser Phe Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Ala Thr Tyr Tyr Asn Tyr Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe225 230 235 240Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val305 310 315 320Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser385 390 395 400Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Gln Thr 435 440 445Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser Thr Pro Thr 450 455 460Asn Asn Ser Asn Pro Lys Pro Asn Pro Ala Ser Glu Lys Ile Arg Leu465 470 475 480Arg Pro Gly Gly Lys Lys Lys Tyr Lys Leu Lys His Ile Val Ala Ser 485 490 495Ser Ser Val Ser Pro Thr Thr Ser Val His Pro Thr Pro Thr Ser Val 500 505 510Pro Pro Thr Pro Thr Lys Ser Ser Pro Ala Ser Asn Pro Pro Ile Pro 515 520 525Val Gly Glu Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys Ile 530 535 540Val Arg Met Tyr Ser Pro Thr Ser Ile Leu Asp Ala Ser Pro Thr Ser545 550 555 560Thr Pro Ala Asp Ser Ser Thr Ile Thr Pro Thr Ala Thr Pro Thr Ala 565 570 575Thr Pro Thr Ile Lys Gly Ala Ser His Thr Gln Gly Tyr Phe Pro Asp 580 585 590Trp Gln Asn Tyr Thr Pro Gly Pro Gly Val Arg Tyr Pro Leu Thr Phe 595 600 605Gly Trp Leu Tyr Lys Leu Ala Ser Thr Val Thr Pro Thr Ala Thr Ala 610 615 620Thr Pro Ser Ala Ile Val Thr Thr Ile Thr Pro Thr Ala Thr Thr Lys625 630 635 640Pro Ala Ser Val Gly Phe Pro Val Thr Pro Gln Val Pro Leu Arg Pro 645 650 655Met Thr Tyr Lys Ala Ala Val Asp Leu Ser His Phe Leu Lys Glu Lys 660 665 670Gly Gly Leu Ala Ser Thr Asn Gly Ser Ile Thr Val Ala Ala Thr Ala 675 680 685Pro Thr Val Thr Pro Thr Val Asn Ala Thr Pro Ser Ala Ala Ala Ser 690 695 700Ala Ile Phe Gln Ser Ser Met Thr Lys Ile Leu Glu Pro Phe Arg Lys705 710 715 720Gln Asn Pro Asp Ile Val Ile Tyr Gln Tyr Met Asp Asp Leu Tyr Ala 725 730 735Ser77708DNAArtificial SequenceSynthetic oligonucleotide. 77atggattttc aagtgcagat tttcagcttc ctgctaatca gtgcttcagt cataatgtcc 60agaggacaaa ttgttctctc ccagtctcca gcaatcctgt ctgcatctcc aggggagaag 120gtcacaatga cttgcagggc cagctcaagt gtaagttaca tgcactggta ccagcggaag 180ccaggatcct cccccaaacc ctggatttat gccacatcca acctggcttc tggagtccct 240gctcgcttca gtggcagtgg gtctgggacc tcttattctc tcacaatcag cagagtggag 300gctgaagatg ctgccactta ttactgccag cagtggagta gtaacccgct cacgttcggt 360gctgggacca agctggagct gaaacgggct gatgctgcac caactgtatc catcttccca 420ccatccagtg agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 480taccccaaag acatcaatgt caagtggaag attgatggca gtgaacgaca aaatggcgtc 540ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 600acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cactcacaag 660acatcaactt cacccatcgt caagagcttc aacaggaatg agtgttag 70878213PRTArtificial SequenceSynthetic peptide. 78Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly1 5 10 15Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30His Trp Tyr Gln Arg Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu65 70 75 80Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr 85 90 95Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro 100 105 110Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 130 135 140Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn145 150 155 160Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 195 200 205Asn Arg Asn Glu Cys 210791428DNAArtificial SequenceSynthetic oligonucleotide. 79atggaatgga gctgggtctt tctcttcctc ctgtcagtaa ttgcaggtgt ccaatcccag 60gttcagctgc agcagtctgg ggctgagctg gtgaggcctg gggcttcagt gacgctgtcc 120tgcaaggctt cgggctacac atttattgac catgatatgc actgggtgca gcagacacct 180gtgtatggcc tggaatggat cggagctatt gatcctgaaa ctggtgatac tggctacaat 240cagaagttca agggcaaggc catactgact gcagacaaat cctccaggac agcctacatg 300gaactccgca gcctgacatc tgaggactct gccgtctatt actgtacaat ccccttctac 360tatagtaact acagcccgtt tgcttactgg ggccaagggg ctctggtcac tgtctctgca 420gccaaaacaa cagccccatc ggtctatcca ctggcccctg tgtgtggagg tacaactggc 480tcctcggtga ctctaggatg cctggtcaag ggttatttcc ctgagccagt gaccttgacc 540tggaactctg gatccctgtc cagtggtgtg cacaccttcc cagctctcct gcagtctggc 600ctctacaccc tcagcagctc agtgactgta acctcgaaca cctggcccag ccagaccatc 660acctgcaatg tggcccaccc ggcaagcagc accaaagtgg acaagaaaat tgagcccaga 720gtgcccataa cacagaaccc ctgtcctcca ctcaaagagt gtcccccatg cgcagacctc 780ttgggtggac catccgtctt catcttccct ccaaagatca aggatgtact catgatctcc 840ctgagcccca tggtcacatg tgtggtggtg gatgtgagcg aggatgaccc agacgcccag 900atcagctggt ttgtgaacaa cgtggaagta cacacagctc agacacaaac ccatagagag 960gattacaaca gtactctccg ggtggtcagt gccctcccca tccagcacca ggactggatg 1020agtggcaagg agttcaaatg caaggtcaac aacagagccc tcccatcccc catcgagaaa 1080accatctcaa aacccagagg gccagtaaga gctccacagg tatatgtctt gcctccacca 1140gcagaagaga tgactaagaa agagttcagt ctgacctgca tgatcacagg cttcttacct 1200gccgaaattg ctgtggactg gaccagcaat gggcgtacag agcaaaacta caagaacacc 1260gcaacagtcc tggactctga tggttcttac ttcatgtaca gcaagctcag agtacaaaag 1320agcacttggg aaagaggaag tcttttcgcc tgctcagtgg tccacgaggg tctgcacaat 1380caccttacga ctaagaccat ctcccggtct ctgggtaaag ctagctga 142880456PRTArtificial SequenceSynthetic peptide. 80Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala1 5 10 15Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Asp His 20 25 30Asp Met His Trp Val Gln Gln Thr Pro Val Tyr Gly Leu Glu Trp Ile 35 40 45Gly Ala Ile Asp Pro Glu Thr Gly Asp Thr Gly Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Ala Ile Leu Thr Ala Asp Lys Ser Ser Arg Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95Thr Ile Pro Phe Tyr Tyr Ser Asn Tyr Ser Pro Phe Ala Tyr Trp Gly 100 105 110Gln Gly Ala Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser 115 120 125Val Tyr Pro Leu Ala Pro Val Cys Gly Gly Thr Thr Gly Ser Ser Val 130 135 140Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu145 150 155 160Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175Leu Leu Gln Ser Gly Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr 180 185 190Ser Asn Thr Trp Pro Ser Gln Thr Ile Thr Cys Asn Val Ala His Pro 195 200 205Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Val Pro Ile 210 215 220Thr Gln Asn Pro Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Asp225 230 235 240Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp 245 250 255Val Leu Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp 260 265 270Val Ser Glu Asp Asp Pro Asp Ala Gln Ile Ser Trp Phe Val Asn Asn 275 280 285Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn 290 295 300Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp305 310 315 320Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro 325 330 335Ser Pro Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala 340 345 350Pro Gln Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys 355 360 365Glu Phe Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile 370 375 380Ala Val Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn385 390 395 400Thr Ala Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys 405 410 415Leu Arg Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys 420 425 430Ser Val Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile 435 440 445Ser Arg Ser Leu Gly Lys Ala Ser 450 455

Claims

1. A vaccine comprising an isolated anti-Langerin antibody or binding fragment thereof and one or more antigenic peptides at the carboxy-terminus of the anti-Langerin antibody, wherein when two or more antigens are present, they are separated by one or more linker peptides that comprise at least one glycosylation site.

2. The vaccine of claim 1, wherein the antibody binding fragment is selected from an Fv, Fab, Fab', F(ab').sub.2, Fc, or a ScFv fragment.

3. The vaccine of claim 1, wherein the antibody comprises one or more complementarity determining regions selected from: ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); or a direct equivalent thereof.

4. The vaccine of claim 1, wherein the antigenic peptide is a cancer antigen selected from: MWVPVVFLTLSVTWIGAAPLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHP QWV (SEQ ID NO.: 9); LTAAHCIRNKSVILLGRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSH D (SEQ ID NO.: 10); LMLLRLSEPAELTDAVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVI S (SEQ ID NO.: 11); NDVCAQVHPQKVTKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALP ERP (SEQ ID NO.: 12); SLYTKVVHYRKWIKDTIVANP (SEQ ID NO.: 13); IMDQVPFSV (SEQ ID NO.: 14); ITDQVPFSV (SEQ ID NO.: 15); YLEPGPVTV (SEQ ID NO.: 16); YLEPGPVTA (SEQ ID NO.: 17); KTWGQYWQV (SEQ ID NO.: 18); APLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHPQWVLTAAHCIRNKSVILL GRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSHDLMLLRLSEPAELTD AVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVISNDVCAQVHPQKV TKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALPERPSLYTKVVHYR KWIKDTIVANP (SEQ ID NO.: 19); DTTEPATPTTPVTTPTTTKVPRNQDWLGVSRQLRTKAWNRQLYPEWTEAQRLDCWRG GQVSLKVSNDGPTLIGANASFSIALNFPGSQKVLPDGQVIWVNNTIINGSQVWGGQPVY PQETDDACIFPDGGPCPSGSWSQKRSFVYVWKTWGQYWQVLGGPVSGLSIGTGRAML GTHTMEVTVYHRRGSQSYVPLAHSSSAFTITDQVPFSVSVSQLRALDGGNKHFLRNQ (SEQ ID NO.: 20); PLTFALQLHDPSGYLAEADLSYTWDFGDSSGTLISRAXVVTHTYLEPGPVTAQVVLQA AIPLTSCGSSPVPAS (SEQ ID NO.: 21); GTTDGHRPTAEAPNTTAGQVPTTEVVGTTPGQAPTAEPSGTTSVQVPTTEVISTAPVQM PTAESTGMTPEKVPVSEVMGTTLAEMSTPEATGMTPAEVSIVVLSGTTAA (SEQ ID NO.: 22); QVTTTEWVETTARELPIPEPEGPDASSIMSTESITGSLGPLLDGTATLRLVKRQVPLDCVL YRYGSFSVTLDIVQ (SEQ ID NO.: 23); GIESAEILQAVPSGEGDAFELTVSCQGGLPKEACMEISSPGCQPPAQRLCQPVLPSPACQ LVLHQILKGGSGTYCLNVSLADTNSLAVVSTQLIVPGILLTGQEAGLGQ (SEQ ID NO.: 24); MEMKILRALNFGLGRPLPLHFLRRASKIGEVDVEQHTLAKYLMELTMLDY (SEQ ID NO.: 25); DWLVQVQMKFRLLQETMYMTVSIIDRFMQNNCVPKK (SEQ ID NO.: 26); MEHQLLCCEVETIRRAYPDANLLNDRVLRAMLKAEETCAPSVSYFKCV (SEQ ID NO.: 27); QKEVLPSMRKIVATWMLEVCEEQKCEEEVFPLAMNYLDRFLSLEPVKKSRLQLLGATC MFVASKMKETIPLTAEKLCIYTDNSIRPEELLQMELL (SEQ ID NO.: 28); LVNKLKWNLAAMTPHDFIEHFLSKMPEAEENKQIIRKHAQTFVALCATDVKFISNPPSM V (SEQ ID NO.: 29); or AAGSVVAAVQGLNLRSPNNFLSYYRLTRFLSRVIKCDPDCLRACQEQIEALLESSLRQA QQNMDPKAAEEEEEEEEEVDLACTPTDVRDVDI (SEQ ID NO.: 30), or binding fragments thereof.

5. The vaccine of claim 1, wherein the antigenic peptide is a viral antigen selected from: TABLE-US-00032 (SEQ ID NO.: 31) VGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGL; (SEQ ID NO.: 32) HTQGYFPDWQNYTPGPGVRYPLTFGWLYKL; (SEQ ID NO.: 33) EKIRLRPGGKKKYKLKHIV; (SEQ ID NO.: 34) NPPIPVGEIYKRWIILGLNKIVRMYSPTSILD; (SEQ ID NO.: 35) AIFQSSMTKILEPFRKQNPDIVIYQYMDDLY; (SEQ ID NO.: 36) DTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDSHNGKLCRLKGIA PLQLGKCNIAGWLLGNPECDPLLPVRSWSYIVETPNSENGICYPGDFI DYEELREQLSSVSSFERFEIFPKESSWPNHNTNGVTAACSHEGKSSFY RNLLWLTEKEGSYPKLKNSYVNKKGKEVLVLWGIHHPPNSKEQQNLYQ NENAYVSVVTSNYNRRFTPEIAERPKVRDQAGRMNYYWTLLKPGDTII FEANGNLIAPMYAFALSRGFGSGIITSNASMHECNTKCQTPLGAINSS LPYQNIHPVTIGECPKYVRSAKLRMV; (SEQ ID NO.: 37) DQICIGYHANNSTEQVDTIMEKNVTVTHAQDILEKKHNGKLCDLDGVK PLILRDCSVAGWLLGNPMCDEFINVPEWSYIVEKANPVNDLCYPGDFN DYEELKHLLSRINHFEKIQIIPKSSWSSHEASLGVSSACPYQGKSSFF RNVVWLIKKNSTYPTIKRSYNNTNQEDLLVLWGIHHPNDAAEQTKLYQ NPTTYISVGTSTLNQRLVPRIATRSKVNGQSGRMEFFWTILKPNDAIN FESNGNFIAPEYAYKIVKKGDSTIMKSELEYGNCNTKCQTPMGAINSS MPFHNIHPLTIGECPKYVKSNRLVLA; or (SE0 ID NO.: 38) PIVQNIQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGAT PQDLNTMLNTVGGHQAAMQMLKETINEEAAEWDRVHPVHAGPIAPGQM REPRGSDIAGTTSTLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRM YSPTSILDIRQGPKEPFRDYVDRFYKTLRAEQASQEVKNWMTETLLVQ NANPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVL.

6. The vaccine of claim 1, wherein the one or more peptide linkers are selected from: TABLE-US-00033 SSVSPTTSVHPTPTSVPPTPTKSSP; (SEQ ID NO.: 39) PTSTPADSSTITPTATPTATPTIKG; (SEQ ID NO.: 40) TVTPTATATPSAIVTTITPTATTKP; (SEQ ID NO.: 41) or TNGSITVAATAPTVTPTVNATPSAA. (SEQ ID NO.: 42)

7. The vaccine of claim 1, wherein the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80 or binding fragments thereof.

8. The vaccine of claim 1, wherein the anti-Langerin antibody is the expression product of the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79.

9. The vaccine of claim 1, wherein the anti-Langerin antibody or binding fragment thereof is at least one of 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7 and humanized derivatives thereof.

10. The vaccine of claim 1, wherein the anti-Langerin antibody or binding fragment thereof and the antigenic peptide are a fusion protein.

11. An isolated nucleic acid vector that expresses an anti-Langerin antibody or binding fragment thereof and two or more antigenic peptides at the carboxy-terminus of the light chain, the heavy chain or both the light and heavy chains of the anti-Langerin antibody, wherein when two or more antigenic peptides are present, the antigenic peptides are separated by the one or more peptide linkers that comprise at least one glycosylation site.

12. The vector of claim 11, wherein the antigenic peptides are cancer peptides selected from tumor associated antigens selected from CEA, prostate specific antigen (PSA), HER-2/neu, BAGE, GAGE, MAGE 1-4, 6 and 12, MUC (Mucin) (e.g., MUC-1, MUC-2, etc.), GM2 and GD2 gangliosides, ras, myc, tyrosinase, MART (melanoma antigen), MARCO-MART, cyclin B1, cyclin D, Pmel 17(gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate Ca psm, prostate serum antigen (PSA), PRAME (melanoma antigen), .beta.-catenin, MUM-1-B (melanoma ubiquitous mutated gene product), GAGE (melanoma antigen)1, BAGE (melanoma antigen) 2-10, c-ERB2 (Her2/neu), EBNA (Epstein-Barr Virus nuclear antigen) 1-6, gp75, human papilloma virus (HPV) E6 and E7, p53, lung resistance protein (LRP), Bcl-2, and Ki-67.

13. The vector of claim 11, wherein the antigenic peptides are cancer peptides are selected from tumor associated antigens comprising antigens from leukemias and lymphomas, neurological tumors such as astrocytomas or glioblastomas, melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors, gastric cancer, colon cancer, liver cancer, pancreatic cancer, genitourinary tumors such cervix, uterus, ovarian cancer, vaginal cancer, testicular cancer, prostate cancer or penile cancer, bone tumors, vascular tumors, or cancers of the lip, nasopharynx, pharynx and oral cavity, esophagus, rectum, gall bladder, biliary tree, larynx, lung and bronchus, bladder, kidney, brain and other parts of the nervous system, thyroid, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and leukemia.

14. The vector of claim 11, wherein the antigenic peptides are selected from Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain, HLA-A201-FluMP (58-66) peptide (GILGFVFTL) tetramer, Avian Flu (HA5-1), dockerin domain from C. thermocellum (doc), HIV gag p24 (gag), or a string of HIV peptides (Lipo5), PSA (KLQCVDLHV)-tetramer, or an HIVgag-derived p24-PLA.

15. The vector of claim 11, wherein the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80 or binding fragments thereof.

16. The vector of claim 11, wherein the anti-Langerin antibody is the expression product of the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79.

17. The vector of claim 11, wherein the anti-Langerin antibody or binding fragment thereof is at least one of 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7 and humanized derivatives thereof.

18. The vector of claim 11, wherein the anti-Langerin antibody or binding fragment thereof and the antigenic peptide are a fusion protein.

19. A method of enhancing T and B cell responses comprising: immunizing a subject in need of vaccination with an effective amount of a vaccine comprising an isolated fusion protein comprising an anti-Langerin antibody or binding portion thereof and one or more antigenic peptides linked to the carboxy-terminus of the anti-Langerin antibody.

20. The method of claim 19, wherein the antigenic peptides are cancer peptides selected from tumor associated antigens selected from CEA, prostate specific antigen (PSA), HER-2/neu, BAGE, GAGE, MAGE 1-4, 6 and 12, MUC (Mucin) (e.g., MUC-1, MUC-2, etc.), GM2 and GD2 gangliosides, ras, myc, tyrosinase, MART (melanoma antigen), MARCO-MART, cyclin B1, cyclin D, Pmel 17(gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate Ca psm, prostate serum antigen (PSA), PRAME (melanoma antigen), .beta.-catenin, MUM-1-B (melanoma ubiquitous mutated gene product), GAGE (melanoma antigen)1, BAGE (melanoma antigen) 2-10, c-ERB2 (Her2/neu), EBNA (Epstein-Barr Virus nuclear antigen) 1-6, gp75, human papilloma virus (HPV) E6 and E7, p53, lung resistance protein (LRP), Bcl-2, and Ki-67.

21. The method of claim 19, wherein the antigenic peptides are cancer peptides selected from tumor associated antigens comprising antigens from leukemias, lymphomas, neurological tumors such as astrocytomas or glioblastomas, melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors, gastric cancer, colon cancer, liver cancer, pancreatic cancer, genitourinary tumors such cervix, uterus, ovarian cancer, vaginal cancer, testicular cancer, prostate cancer or penile cancer, bone tumors, vascular tumors, or cancers of the lip, nasopharynx, pharynx and oral cavity, esophagus, rectum, gall bladder, biliary tree, larynx, lung and bronchus, bladder, kidney, brain and other parts of the nervous system, thyroid, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and leukemia.

22. The method of claim 19, wherein the antigenic peptides are selected from Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain, HLA-A201-FluMP (58-66) peptide (GILGFVFTL) tetramer, Avian Flu (HA5-1), Influenza A Hemagglutinin HA-1 from a H1N1 Flu strain (HA1-1), dockerin domain from C. thermocellum (doc), HIV gag p24 (gag), or a string of HIV peptides (Hipo5), PSA (KLQCVDLHV)-tetramer, or an HIVgag-derived p24-PLA.

23. A method of making an anti-Langerin-antigen fusion protein comprising: expressing an isolated fusion protein comprising an anti-Langerin antibody or binding fragment thereof in a host cell, the fusion protein comprising one or more antigenic peptides at the carboxy-terminus of the anti-Langerin antibody or binding fragment thereof, wherein when two or more cancer peptides are present, the cancer peptides are separated by one or more linkers, at least one linker comprising a glycosylation site; and isolating the fusion protein.

24. The method of claim 23, wherein the fusion protein expressed in the host is further purified.

25. The method of claim 23, wherein the host is a eukaryotic cell.

26. The method of claim 23, wherein the antigenic peptides are cancer peptides selected from tumor associated antigens selected from CEA, prostate specific antigen (PSA), HER-2/neu, BAGE, GAGE, MAGE 1-4, 6 and 12, MUC-related protein (Mucin) (MUC-1, MUC-2, etc.), GM2 and GD2 gangliosides, ras, myc, tyrosinase, MART (melanoma antigen), MARCO-MART, cyclin B1, cyclin D, Pmel 17(gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate Ca psm, prostate serum antigen (PSA), PRAME (melanoma antigen), .beta.-catenin, MUM-1-B (melanoma ubiquitous mutated gene product), GAGE (melanoma antigen).sub.1, BAGE (melanoma antigen) 2-10, c-ERB2 (Her2/neu), EBNA (Epstein-Barr Virus nuclear antigen) 1-6, gp75, human papilloma virus (HPV) E6 and E7, p53, lung resistance protein (LRP), Bcl-2, and Ki-67.

27. The method of claim 23, wherein the antigenic peptides are cancer peptides selected from tumor associated antigens comprising antigens from leukemias and lymphomas, neurological tumors such as astrocytomas or glioblastomas, melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors, gastric cancer, colon cancer, liver cancer, pancreatic cancer, genitourinary tumors such cervix, uterus, ovarian cancer, vaginal cancer, testicular cancer, prostate cancer or penile cancer, bone tumors, vascular tumors, or cancers of the lip, nasopharynx, pharynx and oral cavity, esophagus, rectum, gall bladder, biliary tree, larynx, lung and bronchus, bladder, kidney, brain and other parts of the nervous system, thyroid, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and leukemia.

28. The method of claim 23, wherein the cancer peptides are selected from at least one of: MWVPVVFLTLSVTWIGAAPLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHP QWV (SEQ ID NO.: 9); LTAAHCIRNKSVILLGRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSH D (SEQ ID NO.: 10); LMLLRLSEPAELTDAVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVI S (SEQ ID NO.: 11); NDVCAQVHPQKVTKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALP ERP (SEQ ID NO.: 12); SLYTKVVHYRKWIKDTIVANP (SEQ ID NO.: 13); IMDQVPFSV (SEQ ID NO.: 14); ITDQVPFSV (SEQ ID NO.: 15); YLEPGPVTV (SEQ ID NO.: 16); YLEPGPVTA (SEQ ID NO.: 17); KTWGQYWQV (SEQ ID NO.: 18); APLILSRIVGGWECEKHSQPWQVLVASRGRAVCGGVLVHPQWVLTAAHCIRNKSVILL GRHSLFHPEDTGQVFQVSHSFPHPLYDMSLLKNRFLRPGDDSSHDLMLLRLSEPAELTD AVKVMDLPTQEPALGTTCYASGWGSIEPEEFLTPKKLQCVDLHVISNDVCAQVHPQKV TKFMLCAGRWTGGKSTCSGDSGGPLVCNGVLQGITSWGSEPCALPERPSLYTKVVHYR KWIKDTIVANP (SEQ ID NO.: 19); DTTEPATPTTPVTTPTTTKVPRNQDWLGVSRQLRTKAWNRQLYPEWTEAQRLDCWRG GQVSLKVSNDGPTLIGANASFSIALNFPGSQKVLPDGQVIWVNNTIINGSQVWGGQPVY PQETDDACIFPDGGPCPSGSWSQKRSFVYVWKTWGQYWQVLGGPVSGLSIGTGRAML GTHTMEVTVYHRRGSQSYVPLAHSSSAFTITDQVPFSVSVSQLRALDGGNKHFLRNQ (SEQ ID NO.: 20); PLTFALQLHDPSGYLAEADLSYTWDFGDSSGTLISRAXVVTHTYLEPGPVTAQVVLQA AIPLTSCGSSPVPAS (SEQ ID NO.: 21); GTTDGHRPTAEAPNTTAGQVPTTEVVGTTPGQAPTAEPSGTTSVQVPTTEVISTAPVQM PTAESTGMTPEKVPVSEVMGTTLAEMSTPEATGMTPAEVSIVVLSGTTAA (SEQ ID NO.: 22); QVTTTEWVETTARELPIPEPEGPDASSIMSTESITGSLGPLLDGTATLRLVKRQVPLDCVL YRYGSFSVTLDIVQ (SEQ ID NO.: 23); GIESAEILQAVPSGEGDAFELTVSCQGGLPKEACMEISSPGCQPPAQRLCQPVLPSPACQ LVLHQILKGGSGTYCLNVSLADTNSLAVVSTQLIVPGILLTGQEAGLGQ (SEQ ID NO.: 24); MEMKILRALNFGLGRPLPLHFLRRASKIGEVDVEQHTLAKYLMELTMLDY (SEQ ID NO.: 25); DWLVQVQMKFRLLQETMYMTVSIIDRFMQNNCVPKK (SEQ ID NO.: 26); MEHQLLCCEVETIRRAYPDANLLNDRVLRAMLKAEETCAPSVSYFKCV (SEQ ID NO.: 27); QKEVLPSMRKIVATWMLEVCEEQKCEEEVFPLAMNYLDRFLSLEPVKKSRLQLLGATC MFVASKMKETIPLTAEKLCIYTDNSIRPEELLQMELL (SEQ ID NO.: 28); LVNKLKWNLAAMTPHDFIEHFLSKMPEAEENKQIIRKHAQTFVALCATDVKFISNPPSM V (SEQ ID NO.: 29); or AAGSVVAAVQGLNLRSPNNFLSYYRLTRFLSRVIKCDPDCLRACQEQIEALLESSLRQA QQNMDPKAAEEEEEEEEEVDLACTPTDVRDVDI (SEQ ID NO.: 30), or immunogenic fragments thereof.

29. A method of expanding antigen-specific T cells or B cells in vitro comprising: isolating peripheral blood mononuclear cells (PBMCs) from a cancer patient; incubating the isolated PBMCs with an immunogenic amount of an isolated anti-Langerin-(PL-Ag)x or anti-Langerin-(Ag-PL)x vaccine, wherein Ag is a tumor associated antigen and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of IL-2; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of anti-cancer specific T cells or B cells.

30. A tumor associated antigen-specific T cell or B cell made by the method comprising: isolating peripheral blood mononuclear cells (PBMCs) from a cancer patient; incubating the isolated PBMCs with an immunogenic amount of an anti-Langerin-(PL-Ag)x or anti-Langerin-(Ag-PL)x vaccine, wherein Ag is a tumor associated antigen and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of IL-2; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of tumor associated antigen-specific T cells or B cells.

31. A therapeutic vaccine comprising an isolated fusion protein comprising the formula: Ab-(PL-Ag)x; Ab-(Ag-PL)x; Ab-(PL-Ag-PL)x; Ab-(Ag-PL-Ag)x; Ab-(PL-Ag)x-PL; or Ab-(Ag-PL)x-Ag; wherein Ab is an anti-Langerin monoclonal antibody or binding fragment thereof; PL is at least one peptide linker comprising at least one glycosylation site; Ag is at least one infectious disease antigen; and x is an integer from 1 to 20.

32. A method of expanding antigen-specific T cells or B cells in vitro comprising: isolating peripheral blood mononuclear cells (PBMCs) from a patient suspected of having an infection; incubating the isolated PBMCs with an immunogenic amount of an isolated anti-Langerin-(PL-Ag)x or .alpha.Langerin-(Ag-PL)x vaccine, wherein Ag is an antigen of the infectious agent and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of one or more cytokines; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of anti-infections agent specific T cells or B cells.

33. A viral associated antigen-specific T cell or B cell made by the method comprising: isolating peripheral blood mononuclear cells (PBMCs) from a patient suspected of having a viral infection; incubating the isolated PBMCs with an immunogenic amount of an isolated anti-Langerin-(PL-Ag)x or anti-Langerin-(Ag-PL)x vaccine, wherein Ag is a viral associated antigen and x is an integer 1 to 20; expanding the PBMCs in the presence of an effective amount of one or more cytokines; harvesting the cells; and assessing the cytokine production by the cells to determine the presence of viral associated antigen-specific T cells or B cells.

34. A therapeutic vaccine comprising an isolated fusion protein comprising the formula: Ab-(PL-Ag)x; Ab-(Ag-PL)x; Ab-(PL-Ag-PL)x; Ab-(Ag-PL-Ag)x; Ab-(PL-Ag)x-PL; or Ab-(Ag-PL)x-Ag; wherein Ab is an anti-Langerin monoclonal antibody or binding fragment thereof; PL is at least one peptide linker comprising at least one glycosylation site; Ag is at least one viral antigen; and x is an integer from 1 to 20.

35. An isolated antibody comprising one or more of complementarity determining regions selected from: ASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTNFTL KISRVEAEDLGLYFCS (SEQ ID NO.: 45); SVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSGYSFYNENFKGKATLTADK SSTTAYMQLSSLTSEDSAVYFCA (SEQ ID NO.: 46); VTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNNRVSGVPARFSGSLIGDKAALT ITGAQTEDEAIYFCA (SEQ ID NO.: 47); SLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSNNYATYYADSVKDRFTISR DDSQSLLYLQMNNLKTEDTAMYYC (SEQ ID NO.: 48); or a direct equivalent thereof.

36. The antibody of claim 27, wherein the antibody is humanized.

37. The antibody of claim 27, wherein the antibody is 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7, and humanized derivatives thereof.

38. An isolated nucleic acid that encodes a 15B10, 2G3, 91E7, 37C1, or 4C7 antibody, antibody binding fragment or a humanized derivative thereof.

39. The nucleic acid of claim 38, wherein the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80; or binding fragments thereof.

40. The nucleic acid of claim 38, wherein the anti-Langerin antibody is the expression product from the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79; or binding fragments thereof.

41. A pharmaceutical composition comprising an isolated anti-Langerin antibody or binding fragment thereof and one or more antigenic peptides attached to the anti-Langerin antibody, wherein when two or more antigens are present, they are separated by one or more linker peptides that comprise at least one glycosylation site.

42. The composition of claim 41, wherein the antibody binding fragment is selected from an Fv, Fab, Fab', F(ab').sub.2, Fc, or a ScFv fragment.

43. The composition of claim 41, wherein the anti-Langerin antibody is selected from the following pairs of amino acid sequences SEQ ID NOS.: 2 and 4; 6 and 7; 52 and 54; 56 and 58; and 78 and 80 or binding fragments thereof.

44. The composition of claim 41, wherein the anti-Langerin antibody is the expression product of the following pairs of nucleic acid sequences SEQ ID NOS.: 1 and 3; 5 and 6; 51 and 53; 55 and 57; and 77 and 79.

45. The composition of claim 41, wherein the anti-Langerin antibody or binding fragment thereof is at least one of 15B10 having ATCC Accession No. PTA-9852, 2G3 having ATCC Accession No. PTA-9853, 91E7, 37C1, or 4C7 and humanized derivatives thereof.

46. The composition of claim 41, wherein the anti-Langerin antibody or binding fragment thereof and the antigenic peptide are a fusion protein.

47. The composition of claim 41, wherein the composition further comprises an adjuvant.

48. The composition of claim 41, wherein the composition further comprises one or more pharmaceutical excipients.