Vault Immunotherapy

Abstract

The invention relates to compositions of vault complexes for use as adjuvants for stimulating a cellular immune response to an antigen, for example a tumor antigen, and methods of using the vault complexes in the treatment of diseases, such as cancer.

Description

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application 61/669,568 filed Jul. 9, 2013, which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] The present invention relates generally to the use of vault compositions as adjuvants for stimulating a cellular immune response to one or more antigens, for example, tumor antigens or cancer biomarkers. Also included in the invention is the use of the compositions for the treatment of diseases, such as cancer.

INTRODUCTION

[0005] With ongoing disease threats and the promise of emerging immunotherapies, demand for new vaccine technologies is growing. Developing effective and potent vaccines remains one of the most cost-effective strategies for preventing infectious diseases and cancers [1,2]. Vaccines containing killed or inactivated intact microbes elicit strong immune responses but also produce considerable inflammation at the site of vaccination [3-5]. Furthermore, engineered live vaccines, such as non-replicating recombinant viruses have been developed and also induce robust immune responses [6-8]. However, the potential for break-through replication of live vectors and anti-vector immunity further discourage the development of live vector vaccines due to safety concerns [9,10]. To further vaccine development, non-replicating adjuvants are needed which induce robust immunity with minimal inflammation.

[0006] The immune-promoting activity of any given vaccination strategy is determined by the presence of the relevant antigenic components in the vaccine formulation, enhanced by the addition of suitable adjuvants capable of activating and promoting an efficient immune response against infectious agents or cancers [1,2]. One approach for tailoring vaccines to elicit certain types of immune responses while avoiding inflammation is to develop subunit vaccines by combining non-living or synthetic antigens with adjuvants [9]. This type of vaccine can deliver defined antigens with reduced inflammatory cytokine production but is dependent on the adjuvant formulation to stimulate cell-mediated immune responses and protection from infectious challenge or prevent tumor growth [11,12]. Most licensed vaccines promote immunity by eliciting humoral immune responses and weak cellular immune responses. Current efforts are directed to producing adjuvants which elicit cell-mediated immunity [13,14].

[0007] A major limiting factor in the development of subunit vaccines is engineering immune adjuvants to induce cell-mediated immunity and encourage CD8.sup.+ T cell responses through major histocompatibility complex (MHC) class I presentation (MHC-I, cross presentation). Previous work has shown that it is difficult to achieve antigen presentation through MHC-I molecules unless the antigen is specifically targeted to the MHC-I processing machinery [15-17]. A wide range of approaches has been explored including CpG-DNA or toll-like receptor (TLR) ligands, recombinant viral vectors, fusion with bacterial toxins and others [18,19]. Adjuvants can also be designed to elicit specific immunity, such as promoting cellular immunity which is important for protection against many pathogens [20]. Currently none have been successfully developed for use in humans.

[0008] Nanoparticle pharmaceutical carriers can be engineered to elicit various types of immunity and are increasingly investigated as adjuvants for vaccines. Different types of nanocarriers, such as polymers (polymeric nanoparticles, micelles, or dendrimers), lipids (liposomes), viruses (viral nanoparticles), and organometallic compounds (carbon nanotubes) have been employed for immunotherapeutic applications [21-23]. We have engineered vaults using a recombinant technique to function as a nanocarrier. Natural vaults are barrel-shaped, hollow, 13 mDa ribonucleoprotein particles that exist in nearly all eukaryotic cells [24,25]. Their precise function is unknown but they have been associated with multidrug resistance, cell signaling, nuclear-cytoplasmic transport and innate immunity [26]. We have shown that recombinant vaults can be produced to contain a bacterial antigen and induce adaptive immune responses and protective immunity following immunization [27]. In addition, vault nanocapsules can also be engineered to promote anti-tumor responses [28]. These studies show that recombinant vault nanocapsules act as adjuvants, are versatile for eliciting various types of immunity and have outstanding potential for compound encapsulation, protection, and delivery.

[0009] 2. Description of the Related Art

[0010] Vaults are cytoplasmic ubiquitous ribonucleoprotein particles first described in 1986 that are found in all eukaryotic cells (Kedersha et al., J Cell Biol, 103(3):699-709 (1986)). Native vaults are 12.9.+-.1 MDa ovoid spheres with overall dimensions of approximately 40 nm in width and 70 nm in length (Kong et al., Structure, 7(4):371-379 (1999); Kedersha et al., J Cell Biol, 112(2):225-235 (1991)), present in nearly all-eukaryotic organisms with between 10.sup.4 and 10.sup.7 particles per cell (Suprenant, Biochemistry, 41(49):14447-14454 (2002)). Despite their cellular abundance, vault function remains elusive although they have been linked to many cellular processes, including the innate immune response, multidrug resistance in cancer cells, multifaceted signaling pathways, and intracellular transport (Berger et al., Cell Mol Life Sci, 66(1):43-61 (2009)).

[0011] Vaults are highly stable structures in vitro, and a number of studies indicate that the particles are non-immunogenic (Champion et al., PLoS One, 4(4):e5409 (2009)). Vaults can be engineered and expressed using a baculovirus expression system and heterologous proteins can be encapsulated inside of these recombinant particles using a protein-targeting domain termed INT for vault INTeraction. Several heterologous proteins have been fused to the INT domain (e.g. fluorescent and enzymatic proteins) and these fusion proteins are expressed in the recombinant vaults and retain their native characteristics, thus conferring new properties onto these vaults (Stephen et al., J Biol Chem, 276(26):23217-23220 (2001); Kickhoefer et al., Proc Natl Acad Sci USA, 102(12):4348-4352 (2005)).

[0012] Vaults are generally described in U.S. Pat. No. 7,482,319, filed on Mar. 10, 2004; U.S. application Ser. No. 12/252,200, filed on Oct. 15, 2008; International Application No. PCT/US2004/007434, filed on Mar. 10, 2004; U.S. Provisional Application No. 60/453,800, filed on Mar. 20, 2003; U.S. Pat. No. 6,156,879, filed on Jun. 3, 1998; U.S. Pat. No. 6,555,347, filed on Jun. 28, 2000; U.S. Pat. No. 6,110,740, filed on Mar. 26, 1999; International Application No. PCT/US1999/06683, filed on Mar. 26, 1999; U.S. Provisional App. No. 60/079,634, filed on Mar. 27, 1998; and International Application No. PCT/US1998/011348, filed on Jun. 3, 1998. Vault compositions for immunization against chlamydia genital infection are described in U.S. application Ser. No. 12/467,255, filed on May 15, 2009. The entire contents of these applications are incorporated by reference in their entirety for all purposes.

SUMMARY OF THE INVENTION

[0013] As shown herein, we have characterized the types of immune responses elicited by engineered vault nanocapsules compared to another type of nanocarrier, liposomes, using a well-characterized model antigen, ovalbumin (OVA). Ovalbumin is a highly immunogenic antigen and has often been used as a proof of principle for numerous vaccination strategies [29,30]. We show that immunization of mice with OVA encapsulated in vault nanocapsules efficiently stimulates the immune response to elicit robust CD8.sup.+, CD4.sup.+ memory T cell responses and antibody titers to OVA. Accordingly, as also shown herein, vault nanocapsules can be used as subunit vaccines which can generate both cellular and humoral immunity against antigens for human pathogens and cancer, which we have demonstrated for a number of tumor associated antigens.

[0014] In one aspect, the present invention provides a method for stimulating a cellular immune response in a subject, comprising administering to the subject an effective amount of an antigenic peptide or an antigenic fragment or variant thereof incorporated within a vault complex.

[0015] In a second aspect, the present invention provides a pharmaceutical composition for preventing or treating a subject for cancer, comprising a tumor antigen or an antigenic fragment or variant thereof incorporated within a vault complex, and optionally at least one pharmaceutically acceptable excipient, sufficient to stimulate a cellular immune response.

[0016] In a yet third aspect, the present invention provides a method of preventing or treating cancer in a subject, comprising administering to the subject an effective amount of a tumor antigen or an antigenic fragment or variant thereof incorporated within a vault complex, sufficient to stimulate a cellular immune response. In some embodiments, the administering reduces tumor volume or tumor growth.

[0017] In various embodiments of the above aspects, the antigenic peptide is a tumor antigen. In other embodiments, the vault complex comprises two or more vault complexes, in which each vault complex comprises two or more different antigenic peptides or antigenic fragments or variants.

[0018] In other embodiments, one or multiple copies of the antigenic peptide can be fused to INT or MVP. If fused to MVP, the antigenic peptide can be fused to the N-terminus of MVP or to the C-terminus of MVP. In some embodiments, the INT comprises the amino acid sequence of SEQ ID NO: 2.

[0019] In further embodiments, the vault complex comprises MVP, in which the number of MVP is 1-78. In some embodiments, the number of MVP is 78.

[0020] In additional embodiments, the vault complex further comprises VPARP or modified VPARP, or a portion of VPARP, or a modified portion of VPARP.

[0021] In particular embodiments, the cellular immune response is induction of CD8.sup.+ and CD4.sup.+ memory T-cells. In other embodiments, the cellular immune response is production of INF.gamma..

[0022] Further embodiments comprise administering to the subject a vault complex containing a chemokine, in which the chemokine can be CCL21. The administration can be with or without an antigen.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0024] FIG. 1: Analysis of purified recombinant vault particles containing OVA-INT. (A) Representative gel image showing co-purification of the protein species MVP and OVA-INT. Sucrose gradients of 40% to 60% run in SDS-PAGE (4%-15%). Lane: M: protein molecular weight markers, 40: 40% fractions of sucrose gradient and 45% fractions of sucrose gradient. (B) The gradient fractions were probed with either anti-MVP rabbit polyclonal antisera or (C) anti-OVA rabbit polyclonal antisera. (D) Negative stain EM of CP-OVA recombinant vaults Bar, 100 nm.

[0025] FIG. 2: Vault nanocapsules induce cross presentation to CD8 cells. B3Z cells (1.times.10.sup.5 cells/200 uL/well) were co cultured with DC 2.4 (5.times.10.sup.4 cells/200 .mu.L/well) in the presence or absence of CP-OVA (3.3 .mu.g/200 uL/well) for 24 hrs. Control vaults (CP) were also used at concentration of 3.3 .mu.g/200 uL/well. Following 24 hrs, T cell activation was analyzed by measuring IL-2 production. Data in all panels are representative of 3 independent experiments. Student's t-test was used to determine statistical significance between the CP-OVA and control CP-vaults. * p<0.05.

[0026] FIG. 3: Vault nanocapsules induce CD4 T cell activation. T cells (2.times.10.sup.5 cells/mL) were co-cultured with DC (2.times.10.sup.4 cells/mL) in the presence of PBS, recombinant OVA protein (2.5 .mu.g/mL), control CP-vaults and CP-OVA with the indicated concentrations. DC-induced T cell proliferation was assessed by incorporation of [.sup.3H] thymidine. The graphs show mean (SEM) values from a representative experiment (n=6 replicates) of three independent experiments. Student's t test was used to determine the p value by comparing appropriate control. *p<0.05.

[0027] FIG. 4. Quantitation of OVA in delivery vehicles and immunization regimen. (A) Images of representative 4-15% SDS polyacrylamide gel showing standards, CP-OVA, CPZ-OVA and OVA-liposomes. The amount of OVA incorporated into the delivery vehicles were quantitated using a Typhoon 9410 Typhoon Variable Mode Scanner of Coomassie blue stained SDS-PAGE gels. (B) Schematic representation of vaccination schedules and subcutaneous immunizations with saline (), unencapsulated OVA with saline (.box-solid.), CP (), CP-OVA (.tangle-solidup.), CPZ (), CPZ-OVA (.diamond-solid.), liposome (), or liposome-OVA ( ). The immunization regimen involved three vaccinations (day -28, -14 and 0).

[0028] FIG. 5: Vault nanocapsules enhance priming of endogenous CD8+ T cells. Mice were injected with various immunogens as shown on the x-axis; saline () unencapsulated OVA with saline (.box-solid.), CP () CP-OVA (.tangle-solidup.), CPZ (), CPZ-OVA (.diamond-solid.), liposome (), or liposome-OVA ( ) Splenocytes were harvested, stained and gated on lymphocytes as described in the methods section. The frequency of CD8 subpopulations are shown on the y-axis. (A) Total CD8+ cells, (B) CD8+ memory cells (CD8+CD44.sup.hi), (C) IFN.gamma.-producing CD8+ cells, (D) Perforin-expressing CD8+ cells and (E) IL-4 producing CD8 cells. The cell populations from immunized groups were compared using one-way ANOVA and Bonferroni's post-hoc test). ***p<0.001, **p<0.01, *p<0.05. Representative of 3 independent experiments.

[0029] FIG. 6. Vault nanocapsules encourage production of CD4+ T cells upon vaccination. Mice were injected with various immunogens as shown on the x-axis; saline () unencapsulated OVA with saline (.box-solid.), CP (), CP-OVA (.tangle-solidup.), CPZ (), CPZ-OVA (.diamond-solid.), liposome () or liposome-OVA ( ). Splenocytes were harvested, stained and gated on lymphocytes as described in the methods section. The frequency of CD4 subpopulations are shown on the y-axis. (A) Total CD4+ cells, (B) CD4+ memory cells (CD4+CD44.sup.hi), (C) IFN.gamma.-producing CD4+ cells, (D) IL-17 producing CD4+ cells and (E) IL-4 producing CD4 cells. The cell populations from immunized groups were compared using one-way ANOVA and Bonferroni's post-hoc test). ***p<0.001, **p<0.01, *p<0.05. Representative of 2 independent experiments.

[0030] FIG. 7: Vault nanocapsules produce lower anti-OVA antibody titers. Antibody titers after vaccination schedule, composed of 3 weekly s.c. injections with control saline (), unencapsulated OVA in saline (.box-solid.), CP-OVA (.tangle-solidup.), CPZ-OVA (.diamond-solid.) or Liposome-OVA ( ) Total anti-OVA-IgG1 titers and (B) Total anti-OVA-IgG2c titers. Significance was determined by ANOVA (p<0.001) with Bonferroni post-hoc test (***p<0.001). (C) Ratio of anti-OVA IgG1 to IgG2c antibody. The ratio of Liposome-OVA immunized mice were compared to the other OVA-immunized groups using Mann Whitney t-test (*p<0.001). Data are representative of 2 independent experiments.

[0031] FIG. 8: Flow cytometry gating scheme used to define cell populations. (A) A representative dotplot from a CPZ-OVA immunized mouse was gated on lymphocytes using SSC versus FSC. The percent of CD3.sup.+CD8.sup.+ memory T cells was determined from the events in the lymphocyte gate. (B) The lymphocyte gated population was further gated on CD3.sup.+ T cells and CD3.sup.+ T cells were separated into CD8.sup.+ or CD4.sup.+ T cells. Memory cell population was determined by hi expression of CD44 and a gate drawn. This was applied to all experimental mice to determine the percentage of CD8.sup.+ memory cells. The scheme was applied to CD8.sup.+ or CD4.sup.+ T cells producing cytokines or expressing perforin by gating on the CD3.sup.+CD8.sup.+ or CD3.sup.+CD4.sup.+ population.

[0032] FIG. 9: OVA-vault vaccination inhibited tumor growth. C57BL/6 mice bearing 7 day 3LL-OVA established tumors (s.c.) were treated with diluent normal saline (NS), control vaults (20 .mu.g) and OVA-vaults (2-20 .mu.g) by sc or ip injection. Bisecting tumor diameters were measured with calipers. Tumor growth (9A) and tumor weights (9B) were inhibited in the OVA-vault treatments compared to controls. Data; Mean.+-.SEM, *p<0.05 between OVA-vault and controls, n=8 mice/group.

[0033] FIG. 10: OVA-vault vaccination on the contralateral flank of tumor inoculation inhibited tumor growth. C57BL/6 mice bearing 7 day 3LL-OVA established tumors (s.c.) were treated with diluent normal saline (NS), control vaults (40 .mu.g) and OVA-vaults (20-40 .mu.g) by sc injection. Bisecting tumor diameters were measured with calipers. Tumor growth was inhibited in the OVA-vault vaccination group compared to controls (10A). H&E of tumor sections showed that the Ova vault vaccination groups have diffuse tumor burden with leukocytic infiltrates compared to control vaults that have solid tumor mass and few infiltrates (10B). Data; Mean.+-.SEM, *p<0.05 between OVA-vault and controls, n=8 mice/group.

[0034] FIG. 11: OVA-vault, CCL21 vault, or combined CCL21vault+OVA-vault treatment on the contralateral flank of tumor inoculation inhibited tumor growth and induced systemic immune responses. C57BL/6 mice bearing 7 day 3LL-OVA established tumors (s.c.) were treated with diluent normal saline (NS), control vaults (20 .mu.g), OVA-vaults (20 .mu.g), CCL21 (5 .mu.g), and CCL21 (5 .mu.g) +OVA (20 .mu.g) by sc injection. Tumor growth was inhibited in the treatment groups compared to controls (11A) with 40-50% of treated mice completely rejecting tumors (Table 2). Cytolysis of CFSE labeled 3LL-OVA following incubation with splenocytes from treated mice at effector to target ratio of 1:1 for 4 hours showed enhanced tumor cytolysis compared to controls (11B). Data; Mean.+-.SEM, *p<0.05 between OVA-vault and controls, n=6 mice/group.

[0035] FIG. 12: NYESO-vault vaccination inhibited tumor growth. C57BL/6 mice bearing 7 day 3LL-NYESO established tumors (s.c.) were treated with control vaults (20 .mu.g), CCL21-vaults (5 .mu.g) and NYESO vaults (20-40 .mu.g) by sc injection on the contralateral flank. Tumor growth (12A) and tumor weights (12B) were inhibited in the CCL21 vault and NYESO-vault treatments compared to control. Data; Mean.+-.SEM, *p<0.05 between OVA-vault and controls, n=6 mice/group.

[0036] FIG. 13: Efficient uptake of vault nanoparticles housing NYESO by dentritic cells. Fluorescent microscopy images demonstrating DC integration of INT vaults. DCs stained in green with either media alone or our vaults stained in red. At zero minutes and T60 for the media (A and B), auto-fluorescence surrounding the exterior of the DC. After 60 minutes of incubation with vaults, clear concentration of vaults within the confines of the DCs (C and D).

[0037] FIG. 14: Increased dentritic cell activation and maturation as measured by CD86 expression by treatment with NYESO vaults. Flow cytometry for DC maturation following 20 hours of incubation with NY-ESO-1 vaults, vaults with a red fluorescent protein, or media alone. CD86 median fluorescence intensity for the NY-ESO-1 vaults demonstrated a statistically significant 43% increase in MFI.

[0038] FIG. 15: Dendritic cells treated with GP100 vaults have demonstrated efficacy in stimulating CD8 T cells as shown by elevated levels of interferon gamma. In vitro ELISA demonstrating a significant increase in interferon gamma in T cells incubated with dendritic cells treated with GP100 vaults at 4 hours and for 24 hours.

DETAILED DESCRIPTION OF THE INVENTION

[0039] The descriptions of various aspects of the invention are presented for purposes of illustration, and are not intended to be exhaustive or to limit the invention to the forms disclosed. Persons skilled in the relevant art can appreciate that many modifications and variations are possible in light of the embodiment teachings.

[0040] It should be noted that the language used herein has been principally selected for readability and instructional purposes, and it may not have been selected to delineate or circumscribe the inventive subject matter. Accordingly, the disclosure is intended to be illustrative, but not limiting, of the scope of invention.

[0041] It must be noted that, as used in the specification, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0042] Any terms not directly defined herein shall be understood to have the meanings commonly associated with them as understood within the art of the invention. Certain terms are discussed herein to provide additional guidance to the practitioner in describing the compositions, devices, methods and the like of embodiments of the invention, and how to make or use them. It will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms can be used for any one or more of the terms discussed herein. No significance is to be placed upon whether or not a term is elaborated or discussed herein. Some synonyms or substitutable methods, materials and the like are provided. Recital of one or a few synonyms or equivalents does not exclude use of other synonyms or equivalents, unless it is explicitly stated. Use of examples, including examples of terms, is for illustrative purposes only and does not limit the scope and meaning of the embodiments of the invention herein.

DEFINITIONS

[0043] Terms used in the claims and specification are defined as set forth below unless otherwise specified.

[0044] As used herein, the term "vault" or "vault particle" refers to a large cytoplasmic ribonucleoprotein (RNP) particle found in eukaryotic cells. The vault or vault particle is composed of MVP, VPARP, and/or TEP1 proteins and one or more untranslated vRNA molecules.

[0045] As used herein, the term "vault complex" refers to a vault or recombinant vault that encapsulates a small molecule or protein of interest. A vault complex can include all the components of a vault or vault particle or just a subset. A vault complex with just a subset of the components found in vaults or vault particles can also be termed a "vault-like particle". Examples of vault-like particles include: 1) MVP without VPARP, TEP1 and vRNA; 2) MVP and either VPARP or a portion of VPARP, without TEP1 and vRNA; 3) MVP and TEP 1 or a portion of TEP 1 with or without the one or more than one vRNA, and without VPARP; 4) MVP without VPARP, TEP1 and vRNA, where the MVP is modified to attract a specific substance within the vault-like particle, or modified to attract the vault complex to a specific tissue, cell type or environmental medium, or modified both to attract a specific substance within the vault complex and to attract the vault particle to a specific tissue, cell type or environmental medium; and 5) MVP, and either VPARP or a portion of VPARP, or TEP 1 or a portion of TEP 1 with or without the one or more than one vRNA, or with both VPARP or a portion of VPARP, and TEP1, with or without the one or more than one vRNA, where one or more than one of the MVP, VPARP or portion of VPARP and TEP 1 is modified to attract a specific substance within the vault-like particle, or modified to attract the vault particle to a specific tissue, cell type or environmental medium, or modified both to attract a specific substance within the vault complex and to attract the vault complex to a specific tissue, cell type or environmental medium. As used herein, a vault complex is sometimes referred to as a "vault nanoparticle".

[0046] As used herein, the term "vault targeting domain" or "vault interaction domain" is a domain that is responsible for interaction or binding of a heterologous fusion protein with a vault protein, or interaction of a VPARP with a vault protein, such as a MVP. As used herein, the term "INT domain" is a vault interaction domain from a vault poly ADP-ribose polymerase (VPARP) that is responsible for the interaction of VPARP with a major vault protein (MVP). The term "INT domain" refers to a major vault protein (MVP) interaction domain comprising amino acids 1563-1724 of VPARP.

[0047] As used herein, the term "MVP" is major vault protein. The term "cp-MVP" is a cysteine-rich peptide major vault protein.

[0048] The term "VPARP" refers to a vault poly ADP-ribose polymerase.

[0049] As used herein, the term "TEP-1" is a telomerase/vault associated protein 1.

[0050] As used herein, the term "vRNA" is an untranslated RNA molecule found in vaults.

[0051] As used herein, the term "vector" is a DNA or RNA molecule used as a vehicle to transfer foreign genetic material into a cell. The four major types of vectors are plasmids, bacteriophages and other viruses, cosmids, and artificial chromosomes. Vectors can include an origin of replication, a multi-cloning site, and a selectable marker.

[0052] As used herein, a "cell" includes eukaryotic and prokaryotic cells.

[0053] As used herein, the terms "organism", "tissue" and "cell" include naturally occurring organisms, tissues and cells, genetically modified organisms, tissues and cells, and pathological tissues and cells, such as tumor cell lines in vitro and tumors in vivo.

[0054] As used herein, the term "extracellular environment" is the environment external to the cell.

[0055] As used herein, the term "in vivo" refers to processes that occur in a living organism.

[0056] A "subject" referred to herein can be any animal, including a mammal (e.g., a laboratory animal such as a rat, mouse, guinea pig, rabbit, primates, etc.), a farm or commercial animal (e.g., a cow, horse, goat, donkey, sheep, etc.), a domestic animal (e.g., cat, dog, ferret, etc.), an avian species, or a human.

[0057] The term "mammal" as used herein includes both humans and non-humans and include but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0058] As used herein, the term "human" refers to "Homo sapiens."

[0059] As used herein, the term "sufficient amount" is an amount sufficient to produce a desired effect, e.g., an amount sufficient to stimulate a cellular immune response.

[0060] As used herein, the term "therapeutically effective amount" is an amount that is effective to ameliorate a symptom of a disease, such as cancer.

[0061] A "prophylactically effective amount" refers to an amount that is effective for prophylaxis.

[0062] As used herein, the term "stimulating" refers to activating, increasing, or triggering a molecular, cellular or enzymatic activity or response in a cell or organism, e.g. a cellular immune response.

[0063] As used herein, the term "inhibiting" refers to deactivating, decreasing, or shutting down a molecular, cellular or enzymatic activity or response in a cell or organism.

[0064] As used herein, the term "administering" includes any suitable route of administration, as will be appreciated by one of ordinary skill in the art with reference to this disclosure, including direct injection into a solid organ, direct injection into a cell mass such as a tumor, inhalation, intraperitoneal injection, intravenous injection, topical application on a mucous membrane, or application to or dispersion within an environmental medium, and a combination of the preceding.

[0065] As used herein, the term "treating" or "treatment" refers to the reduction or elimination of symptoms of a disease, e.g., cancer.

[0066] As used herein, the term "preventing" or "prevention" refers to the reduction or elimination of the onset of symptoms of a disease, e.g., cancer.

[0067] As used herein, the term "regressing" or "regression" refers to the reduction or reversal of symptoms of a disease after its onset, e.g., cancer remission.

[0068] As used in this disclosure, the term "modified" and variations of the term, such as "modification," means one or more than one change to the naturally occurring sequence of MVP, VPARP or TEP1 selected from the group consisting of addition of a polypeptide sequence to the C-terminal, addition of a polypeptide sequence to the N-terminal, deletion of between about 1 and 100 amino acid residues from the C-terminal, deletion of between about 1 and 100 amino acid residues from the N-terminal, substitution of one or more than one amino acid residue that does not change the function of the polypeptide, as will be appreciated by one of ordinary skill in the art with reference to this disclosure, such as for example, an alanine to glycine substitution, and a combination of the preceding.

[0069] As used herein, the term percent "identity," in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to persons of skill) or by visual inspection. Depending on the application, the percent "identity" can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0070] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0071] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0072] One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov/).

[0073] As used in this disclosure, the term "comprise" and variations of the term, such as "comprising" and "comprises," are not intended to exclude other additives, components, integers or steps.

[0074] It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0075] Compositions of the Invention

[0076] As described in more detail below, the invention includes compositions and methods of using vault complexes. An embodiment of the invention has recombinant vaults having a MVP and an antigen, e.g., a tumor antigen. The vault complex can be used as an adjuvant for stimulating a cellular immune response to the antigen.

[0077] Vaults and Vault Complexes

[0078] The compositions of the invention comprise a vault complex. A vault complex is a recombinant particle that encapsulates a small molecule (drug, sensor, toxin, etc.), or a protein of interest, e.g., a peptide, or a protein, including an endogenous protein, a heterologous protein, a recombinant protein, or recombinant fusion protein. Vault complexes of the invention can include a tumor antigen.

[0079] Vaults, e.g., vault particles are ubiquitous, highly conserved ribonucleoprotein particles found in nearly all eukaryotic tissues and cells, including dendritic cells (DCs), endometrium, and lung, and in phylogeny as diverse as mammals, avians, amphibians, the slime mold Dictyostelium discoideum, and the protozoan Trypanosoma brucei (Izquierdo et al., Am. J. Pathol., 148(3):877-87 (1996)). Vaults have a hollow, barrel-like structure with two protruding end caps, an invaginated waist, and regular small openings surround the vault cap. These openings are large enough to allow small molecules and ions to enter the interior of the vault. Vaults have a mass of about 12.9.+-.1 MDa (Kedersha et al., J. Cell Biol., 112(2):225-35 (1991)) and overall dimensions of about 42.times.42.times.75 nm (Kong et al., Structure, 7(4):371-9 (1999)). The volume of the internal vault cavity is approximately 50.times.10.sup.3 nm.sup.3, which is large enough to enclose an entire ribosomal protein.

[0080] Vaults comprise three different proteins, designated MVP, VPARP and TEP1, and comprise one or more different untranslated RNA molecules, designated vRNAs. The number of vRNA can vary. For example, the rat Rattus norvegicus has only one form of vRNA per vault, while humans have three forms of vRNA per vault. The most abundant protein, major vault protein (MVP), is a 95.8 kDa protein in Rattus norvegicus and a 99.3 kDa protein in humans which is present in 96 copies per vault and accounts for about 75% of the total protein mass of the vault particle. The two other proteins, the vault poly-ADP ribose polymerase, VPARP, a 193.3 kDa protein in humans, and the telomerase/vault associated protein 1, TEP 1, a 292 kDa protein in Rattus norvegicus and a 290 kDa protein in humans, are each present in between about 2 and 16 copies per vault.

[0081] VPARP, INT Domain, and INT Fusion Proteins

[0082] A vault poly ADP-ribose polymerase (VPARP) includes a region of about 350 amino acids that shares 28% identity with the catalytic domain of poly ADP-ribosyl polymerase, PARP, a nuclear protein that catalyzes the formation of ADP-ribose polymers in response to DNA damage. VPARP catalyzes an NAD-dependent poly ADP-ribosylation reaction, and purified vaults have poly ADP-ribosylation activity that targets MVP, as well as VPARP itself. VPARP includes a INT domain (major vault protein (MVP) interaction domain). The INT domain is responsible for the interaction of VPARP with a major vault protein (MVP).

[0083] A vault complex of the invention can include a INT domain. The INT domain, also referred to as mINT domain for minimal INT domain, is responsible for interaction of a protein of interest with a vault protein such as a MVP. In some embodiments, the INT domain is expressed as a fusion protein with a protein of interest. Alternatively, a protein of interest can be covalently or non-covalently attached. The INT of the vault complexes of the invention are derived from VPARP sequences. Exemplary VPARP sequences and INT sequences can be found in Table 1. One of skill in the art understands that the INT can have the entire naturally occurring sequence or portions of the sequence or fragments thereof. In other embodiments, the INT has at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any of the VPARP and/or INT sequences disclosed in Table 1.

[0084] In one embodiment, the INT is derived from a human VPARP, SEQ ID NO:3, GenBank accession number AAD47250, encoded by the cDNA, SEQ ID NO:5, GenBank accession number AF158255. In some embodiments, the vault targeting domain comprises or consists of the INT domain corresponding to residues 1473-1724 of human VPARP protein sequence (full human VPARP amino acid sequence is SEQ ID NO:3). In other embodiments, the vault targeting domain comprises or consists of the mINT domain comprising residues 1563-1724 (SEQ ID NO: 2) of the human VPARP protein sequence. In certain embodiments, the vault targeting domain is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 or 3.

[0085] In alternative embodiments, as with VPARP, a major vault protein (MVP) interaction domain can be derived from TEP 1 sequences. Such interaction domains can be termed, for example INT2, to distinguish them from a VPARP interaction domain. One of skill in the art understands that the INT can have the entire naturally occurring sequence of the vault interaction domain in TEP 1 or portions of the sequence or fragments thereof.

[0086] MVP

[0087] A vault complex of the invention can include an MVP. Exemplary MVP sequences can be found in Table 1. One of skill in the art understands that the MVP can have the entire naturally occurring sequence or portions of the sequence or fragments thereof. In other embodiments, the MVP has at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any of the MVP sequences disclosed in Table 1.

[0088] In one embodiment, the MVP is human MVP, SEQ ID NO:6, GenBank accession number CAA56256, encoded by the cDNA, SEQ ID NO:7, GenBank accession number X79882. In other embodiments, the MVP is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the MVP sequences described herein.

[0089] In one embodiment, there is provided a vault complex comprising, consisting essentially of, or consisting of an MVP modified by adding a peptide to the N-terminal to create a one or more than one of heavy metal binding domains. In a preferred embodiment, the heavy metal binding domains bind a heavy metal selected from the group consisting of cadmium, copper, gold and mercury. In a preferred embodiment, the peptide added to the N-terminal is a cysteine-rich peptide (CP), such as for example, SEQ ID NO:8, the MVP is human MVP, SEQ ID NO:6, and the modification results in CP-MVP, SEQ ID NO:9, encoded by the cDNA, SEQ ID NO:10. These embodiments are particularly useful because vault particles consisting of CP-MVP are stable without the presence of other vault proteins.

[0090] Any of the vault complexes described herein can include MVPs or modified MVPs disclosed herein.

[0091] TEP1

[0092] In some embodiments, a vault complex of the invention can include a TEP1 protein. Exemplary TEP1 sequences can be found in Table 1. One of skill in the art understands that the TEP1 can have the entire naturally occurring sequence or portions of the sequence or fragments thereof. In other embodiments, the TEP1 has at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any of the TEP1 sequences disclosed in Table 1.

[0093] The TEP1 can be human TEP1, SEQ ID NO:11, GenBank accession number AAC51107, encoded by the cDNA, SEQ ID NO:12, GenBank accession number U86136. Any of the vault complexes described herein can include TEP 1 or modifications thereof

[0094] vRNA

[0095] A vault complex of the invention can include a vRNA. Exemplary vRNA sequences can be found in Table 1. One of skill in the art understands that the vRNA can have the entire naturally occurring sequence or portions of the sequence or fragments thereof. In other embodiments, the vRNA has at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any of the vRNA sequences disclosed in Table 1.

[0096] In one embodiment, the vRNA can be a human vRNA, SEQ ID NO:13, GenBank accession number AF045143, SEQ ID NO:14, GenBank accession number AF045144, or SEQ ID NO:15, GenBank accession number AF045145, or a combination of the preceding.

[0097] As will be appreciated by one of ordinary skill in the art with reference to this disclosure, the actual sequence of any of MVP, VPARP, TEP1 and vRNAs can be from any species suitable for the purposes disclosed in this disclosure, even though reference or examples are made to sequences from specific species. Further, as will be appreciated by one of ordinary skill in the art with reference to this disclosure, there are some intraspecies variations in the sequences of MVP, VPARP, TEP 1 and vRNAs that are not relevant to the purposes of the present invention. Therefore, references to MVP, VPARP, TEP 1 and vRNAs are intended to include such intraspecies variants.

[0098] Isolated Nucleic Acids and Vectors

[0099] Suitable expression vectors generally include DNA plasmids or viral vectors. Expression vectors compatible with eukaryotic cells, preferably those compatible with vertebrate cells, can be used to produce recombinant constructs for the expression of an iRNA as described herein. Eukaryotic cell expression vectors are well known in the art and are available from a number of commercial sources. Typically, such vectors are provided containing convenient restriction sites for insertion of the desired nucleic acid segment. Delivery of expression vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that allows for introduction into a desired target cell.

[0100] Plasmids expressing a nucleic acid sequence can be transfected into target cells as a complex with cationic lipid carriers (e.g., Oligofectamine) or non-cationic lipid-based carriers (e.g., Transit-TKO.TM.). Successful introduction of vectors into host cells can be monitored using various known methods. For example, transient transfection can be signaled with a reporter, such as a fluorescent marker, such as Green Fluorescent Protein (GFP). Stable transfection of cells ex vivo can be ensured using markers that provide the transfected cell with resistance to specific environmental factors (e.g., antibiotics and drugs), such as hygromycin B resistance.

[0101] Viral vector systems which can be utilized with the methods and compositions described herein include, but are not limited to, (a) adenovirus vectors; (b) retrovirus vectors, including but not limited to lentiviral vectors, moloney murine leukemia virus, etc.; (c) adeno-associated virus vectors; (d) herpes simplex virus vectors; (e) SV 40 vectors; (f) polyoma virus vectors; (g) papilloma virus vectors; (h) picornavirus vectors; (i) pox virus vectors such as an orthopox, e.g., vaccinia virus vectors or avipox, e.g. canary pox or fowl pox; and (j) a helper-dependent or gutless adenovirus. Replication-defective viruses can also be advantageous. Different vectors will or will not become incorporated into the cells' genome. The constructs can include viral sequences for transfection, if desired. Alternatively, the construct may be incorporated into vectors capable of episomal replication, e.g., EPV and EBV vectors. Constructs for the recombinant expression of a nucleic acid encoding a fusion protein will generally require regulatory elements, e.g., promoters, enhancers, etc., to ensure the expression of the fusion nucleic acid in target cells. Other aspects to consider for vectors and constructs are further described below.

[0102] Vectors useful for the delivery of a nucleic acid can include regulatory elements (promoter, enhancer, etc.) sufficient for expression of the nucleic acid in the desired target cell or tissue. The regulatory elements can be chosen to provide either constitutive or regulated/inducible expression. A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the transgene.

[0103] In a specific embodiment, viral vectors that contain the recombinant gene can be used. For example, a retroviral vector can be used (see Miller et al., Meth. Enzymol. 217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding a fusion protein are cloned into one or more vectors, which facilitates delivery of the nucleic acid into a patient. More detail about retroviral vectors can be found, for example, in Boesen et al., Biotherapy 6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdrl gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest. 93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson, Curr. Opin. in Genetics and Devel. 3:110-114 (1993). Lentiviral vectors contemplated for use include, for example, the HIV based vectors described in U.S. Pat. Nos. 6,143,520; 5,665,557; and 5,981,276, which are herein incorporated by reference.

[0104] Adenoviruses are also contemplated for use in delivery of isolated nucleic acids encoding fusion proteins into a cell. Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia or for use in adenovirus-based delivery systems such as delivery to the liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, Current Opinion in Genetics and Development 3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992); Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993); PCT Publication WO94/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). A suitable AV vector for expressing a nucleic acid molecule featured in the invention, a method for constructing the recombinant AV vector, and a method for delivering the vector into target cells, are described in Xia H et al. (2002), Nat. Biotech. 20: 1006-1010.

[0105] Use of Adeno-associated virus (AAV) vectors is also contemplated (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Pat. No. 5,436,146). Suitable AAV vectors for expressing the dsRNA featured in the invention, methods for constructing the recombinant AV vector, and methods for delivering the vectors into target cells are described in Samulski R et al. (1987), J. Virol. 61: 3096-3101; Fisher K J et al. (1996), J. Virol, 70: 520-532; Samulski R et al. (1989), J. Virol. 63: 3822-3826; U.S. Pat. No. 5,252,479; U.S. Pat. No. 5,139,941; International Patent Application No. WO 94/13788; and International Patent Application No. WO 93/24641, the entire disclosures of which are herein incorporated by reference.

[0106] Another preferred viral vector is a pox virus such as a vaccinia virus, for example an attenuated vaccinia such as Modified Virus Ankara (MVA) or NYVAC, an avipox such as fowl pox or canary pox.

[0107] The pharmaceutical preparation of a vector can include the vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system.

[0108] Examples of additional expression vectors that can be used in the invention include pFASTBAC expression vectors and E. coli pET28a expression vectors.

[0109] Generally, recombinant vectors capable of expressing genes for recombinant fusion proteins are delivered into and persist in target cells. The vectors or plasmids can be transfected into target cells by a transfection agent, such as Lipofectamine. Examples of cells useful for expressing the nucleic acids encoding the fusion proteins of the invention include Sf9 cells or insect larvae cells. Recombinant vaults based on expression of the MVP protein alone can be produced in insect cells. Stephen, A. G. et al. (2001). J. Biol. Chem. 276:23217:23220; Poderycki, M. J., et al. (2006). Biochemistry (Mosc). 45: 12184-12193.

[0110] Pharmaceutical Compositions of the Invention

[0111] In one embodiment, the invention provides methods using pharmaceutical compositions comprising the vault complexes of the invention. These compositions can comprise, in addition to one or more of the vault complexes, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.

[0112] In certain embodiments, the pharmaceutical compositions that are injected intra-tumorally comprise an isotonic or other suitable carrier fluid or solution.

[0113] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required.

[0114] In other embodiments, pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.

[0115] In some embodiments, administration of the pharmaceutical compositions may be topical, pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intraparenchymal, intrathecal or intraventricular, administration. Formulations for parenteral administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Formulations may be reconstituted from freeze-dried (lyophilized) preparations. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic.

[0116] Methods of Use

[0117] Vault complexes described herein can be used to deliver a protein of interest (e.g., a tumor antigen) to a cell, a tissue, an environment outside a cell, a tumor, an organism or a subject. In one embodiment, the vault complex comprises a tumor antigen, and the vault complex is introduced to the cell, tissue, or tumor. In some embodiments, the vault complex is introduced into the extracellular environment surrounding the cell. In other embodiments, the vault complex is introduced into an organism or subject. Delivery of the vault complex of the invention can include administering the vault complex to a specific tissue, specific cells, an environmental medium, or to the organism.

[0118] The methods of the invention comprise delivering a biomolecule to a cell by contacting the cell with any of the vault complexes described herein. Cells of the invention can include, but are not limited to, any eukaryotic cell, mammalian cell, or human cells, including tumor cells.

[0119] Methods of the invention include delivery of the vault complex to a subject. The delivery of a vault complex to a subject in need thereof can be achieved in a number of different ways. In vivo delivery can be performed directly by administering a vault complex to a subject. Alternatively, delivery can be performed indirectly by administering one or more vectors that encode and direct the expression of the vault complex or components of the vault complex. In one embodiment, the vault complex is administered to a mammal, such as a mouse or rat. In another embodiment, the vault complex is administered to a human.

[0120] In another embodiment, the methods of delivery of the invention include systemic injection of vaults. In other embodiments, the methods of delivery of the invention include oral ingestion of vaults.

[0121] Methods of Treatment

[0122] The invention features a method of treating or managing disease, such as cancer, by administering the vault complex of the invention to a subject (e.g., patient). In some embodiments, the method of the invention comprises treating or cancer in a subject in need of such treatment or management, comprising administering to the subject a therapeutically effective amount of the vault complexes described herein.

[0123] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. For any compound used in the methods featured in the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range of the vault complex. Such information can be used to more accurately determine useful doses in humans.

[0124] The pharmaceutical composition according to the present invention to be given to a subject, administration is preferably in a "therapeutically effective amount" or "prophylactically effective amount" (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of protein aggregation disease being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980. A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

[0125] In certain embodiments, the dosage of vault complexes is between about 0.1 and 10,000 micrograms per kilogram of body weight or environmental medium. In another embodiment, the dosage of vault complexes is between about 1 and 1,000 micrograms per kilogram of body weight or environmental medium. In another embodiment, the dosage of vault complexes is between about 10 and 1,000 micrograms per kilogram of body weight or environmental medium. For intravenous injection and intraperitoneal injection, the dosage is preferably administered in a final volume of between about 0.1 and 10 ml. For inhalation the dosage is preferably administered in a final volume of between about 0.01 and 1 ml. As will be appreciated by one of ordinary skill in the art with reference to this disclosure, the dose can be repeated a one or multiple times as needed using the same parameters to effect the purposes disclosed in this disclosure.

[0126] For instance, the pharmaceutical composition may be administered once to a subject, or the vault complex may be administered as two, three, or more sub-doses or injections at appropriate intervals. In that case, the vault complexes can be injected in sub-doses in order to achieve the total required dosage.

[0127] The vault complexes featured in the invention can be administered in combinations of vault complexes containing different tumor antigens, or in combination with other known agents effective in treatment of cancer. An administering physician can adjust the amount and timing of vault complex administration or injection on the basis of results observed using standard measures of efficacy known in the art or described herein. The skilled artisan will also appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.

[0128] Methods of Preparing Vault Complexes

[0129] The methods of the invention include preparing the vault complexes described herein.

[0130] In one embodiment, the vault complexes are derived or purified from natural sources, such as mammalian liver or spleen tissue, using methods known to those with skill in the art, such as for example tissue homogenization, differential centrifugation, discontinuous sucrose gradient fractionation and cesium chloride gradient fractionation. In another embodiment, the vault complexes are made using recombinant technology.

[0131] In some embodiments, a target of interest, i.e., protein of interest, is selected for packaging in the vault complexes. The target of interest may be selected from the group consisting of an enzyme, a pharmaceutical agent, a plasmid, a polynucleotide, a polypeptide, a sensor and a combination of the preceding. In a preferred embodiment, the target of interest is a recombinant protein, e.g., a cell adhesion modifying substance, e.g., an RGD-containing peptide.

[0132] Preferably, if the target of interest is a recombinant protein, the polynucleotide sequences encoding the recombinant protein are used to generate a bacmid DNA, which is used to generate a baculovirus comprising the sequence. The baculovirus is then used to infect insect cells for protein production using an in situ assembly system, such as the baculovirus protein expression system, according to standard techniques, as will be appreciated by one of ordinary skill in the art with reference to this disclosure. Advantageously, the baculovirus protein expression system can be used to produce milligram quantities of vault complexes, and this system can be scaled up to allow production of gram quantities of vault complexes according to the present invention.

[0133] In another embodiment, the target of interest is incorporated into the provided vaults. In one embodiment, incorporation is accomplished by incubating the vaults with the target of interest at an appropriate temperature and for an appropriate time, as will be appreciated by one of ordinary skill in the art with reference to this disclosure. The vaults containing the protein of interest are then purified, such as, for example sucrose gradient fractionation, as will be appreciated by one of ordinary skill in the art with reference to this disclosure.

[0134] In other embodiments, the vaults comprising the target of interest are administered to an organism, to a specific tissue, to specific cells, or to an environmental medium. Administration is accomplished using any suitable route, as will be appreciated by one of ordinary skill in the art with reference to this disclosure.

[0135] In one embodiment, the method comprises preparing the composition of the invention by a) mixing a INT or INT fusion protein generated in insect Sf9 cells with a MVP or MVP fusion protein generated in insect Sf9 cells to generate a mixture; b) incubating the mixture for a sufficient period of time to allow formation of vault complexes, thereby generating the composition. For example, Sf9 cells are infected with pVI-MVP encoding recombinant baculoviruses. Lysates containing recombinant tumor antigen-INT and rat MVP generated in Sf-9 cells can be mixed to allow the formation of a macromolecular vault complex containing the tumor antigen-INT fusion protein.

EXAMPLES

[0136] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0137] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T. E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A. L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3.sup.rd Ed. (Plenum Press) Vols A and B (1992).

Example 1

Preparation of Recombinant Vaults Packaged with Chicken Ovalbumin

[0138] Recombinant vaults were produced using a baculovirus expression system in Sf9 insect cells that express a stabilized form of recombinant vaults (CP) and contain a cysteine rich peptide on the N terminus to increase stability [31]. Cryoelectron microscopy imaging of recombinant and tissue derived vaults revealed the localization of the MVP interacting domain, INT [31]. Another form of recombinant vaults (CPZ) contains a 33 amino acid mimic of the Ig binding domain of staphylococcal protein A (Z) in addition to the CP peptide [32]. CPZ vaults were shown to bind antibody and may direct uptake thorough FcRs [27]. These vaults (CP or CPZ) were packaged with chicken ovalbumin by fusion of OVA protein to the vault-targeting protein, INT to form OVA-INT. The OVA-containing vaults were purified and the majority of particles were found in the 40% and 45% sucrose fraction as previously described [33]. Analysis of these fractions by SDS-PAGE and Western blotting (FIG. 1) shows the co-purification of MVP and OVA-INT (FIG. 1 A). The identity of the components was confirmed by Western analysis with either an anti-MVP polyclonal antibody (FIG. 1B) or an anti-OVA antibody (FIG. 1C). Purified CP-OVA recombinant vaults were evaluated by negative stain electron microscopy (FIG. 1D). The addition of the OVA-INT protein to CP or CPZ did not alter recombinant vault morphology as compared to empty CP vaults when evaluated by transmission electron microcopy (data not shown) and as shown previously [27]. The presence of additional protein density or lighter staining area (arrow) near the waist of the vault barrel, which based on earlier structural studies, is the expected location of OVA-INT [34]. We used these CP and CPZ-vaults containing OVA-INT in vaccinations, henceforth referred to as CP-OVA and CPZ-OVA.

Example 2

Ovalbumin Packaged Inside Vault Nanocapsules can Induce a MHC-I Restricted Response

[0139] Dendritic cells (DCs) possess the unique ability to process particulate antigens efficiently into the MHC-I pathway, in a process known as cross-priming. Several approaches have been used to encourage cross priming such as adding exogenous antigenic proteins or peptides with adjuvants to stimulate cytotoxic T lymphocytes (CTLs) [35]. Therefore, we investigated whether recombinant vaults engineered to express OVA could be efficiently internalized, processed and presented by DC in an MHC-I restricted manner to activate CD8.sup.+ T cells. To this end, the DC2.4 cell line (H-2K.sup.b) was pulsed with CP-OVA and secretion of IL-2 was measured as an activation marker of the OVA-responsive CD8.sup.+ T cell hybridoma B3Z (H-2K.sup.b). The combination of DC2.4 cells, B3Z cells and CP that did not contain OVA-INT could not effectively stimulate IL-2 secretion. However, CP-OVA (produced by combining CP+OVA-INT) incubated with both DC2.4 cells and B3Z hybridoma cells induced secretion of IL-2 (FIG. 2). We examined different concentrations of CP-OVA vaults and determined that 3.3 .mu.g CP-OVA vaults per 200 .mu.L per well gave us the greatest IL-2 secretion (data not shown). Additional controls included the B3Z CD8+ T cell hybridoma incubated with CP-OVA alone which induced modest IL-2 levels and suggests that vaults interact with T cells and participate in autopresentation of MHC-I responses [36]. Finally, incubation of CP-OVA vaults with the DC2.4 cell line only produced baseline levels of IL-2. We concluded that exogenous antigen packaged within vault nanocapsules could be delivered and presented by the MHC-I pathway in DCs and possibly through autopresentation to enhance T cell responses.

Example 3

Ovalbumin Packaged Inside Vault Nanocapsules can Induce a MHC-II Restricted Response

[0140] We also examined the MHC class II pathway using bone-marrow-derived DCs from syngeneic BALB/c (H-2 IA/E.sup.d) mice pulsed with CP-OVA for 24 hours. These DCs were then used to stimulate naive OVA-responsive CD4.sup.+ T cells from DO11.10 (H-2 A/E.sup.d) mice. D11.10 cells are transgenic for the TCR recognizing the amino acid 323-339 peptide of OVA on MHC-II. As shown in FIG. 3, DC induced significant proliferation in the presence of OVA. However, OVA encased in vault nanoparticles at two concentrations; 2.5 .mu.g and 10.0 .mu.g, stimulated a greater degree of T cell proliferation at both concentrations compared to recombinant OVA protein alone and were not statistically different from each other (FIG. 3). These data show that OVA encased in vault nanocapsules was more effective at inducing CD4.sup.+ T cell proliferation than soluble OVA.

Example 4

Vaccination of Mice with OVA Packaged Vault Nanocapsules Induces CD8.sup.+ and CD4.sup.+ T Cells In Vivo

[0141] We characterized cell- and antibody-mediated immune responses to OVA encapsulated in vault nanocapsules and liposomes in vivo following subcutaneous administration. To evaluate the type of immune response we immunized mice with either CP-OVA or CPZ-OVA vaults containing equal amounts of endotoxin-free OVA (see material and methods). Liposomes where chosen as a control delivery method since they are a class of nanocarriers and have been utilized as delivery systems for drugs, peptides, proteins and DNA [29,37]. Liposomes are microscopic vesicles consisting of phospholipid bilayers which surround aqueous compartments and were prepared in this study by encapsulating OVA in DOTAP/DOPE as described in the methods section[38]. The amount of OVA within the vaults and liposomes was quantitated by SDS gel quantitation (FIG. 4A). Mice were immunized with equal amounts of delivery vehicle and OVA and the immunization regimen is described in FIG. 4B. The percentage of T cells responsive to the OVA CD8 peptide (SIINFEKL) or the OVA CD4 peptide 256-280 (TEWTSSNVMEERKIKV) were documented by surface, intracellular cytokine or perforin staining and FACS analysis after stimulation with each OVA peptide in C57BL/6 mice (H2.sup.b background) as described in the methods section. We also examined the anti-OVA-antibody responses following immunization by ELISA.

[0142] CD8+ T cells play a critical role in protection against viral and intracellular bacterial and protozoan infections and are important in tumor and graft rejection[39]. After activation, naive antigen (Ag)-responsive CD8.sup.+ T cells are able to proliferate quickly and differentiate into potent effector cells capable of rapid cytokine production and cytolytic killing of target cells [40,41]. We wanted to see if entrapment of OVA in vault nanocapsules facilitated cross-presentation of Ag to the MHC-I pathway, resulting in activation of a potent CD8.sup.+ T cell immunity in vivo as we observed previously in vitro. We evaluated induction of CD8.sup.+ T-cell responses among mice immunized with OVA-vaults (CP-OVA and CPZ-OVA), empty vaults (CP and CPZ) and Liposome-OVA as shown in FIG. 5. Control groups included soluble OVA and saline immunization. The induction of effector CD8.sup.+ T cell responses in the spleen was measured 2 weeks after the last immunization by measuring the number of total CD8.sup.+ T cells, CD8.sup.+ memory T cells (CD44.sup.hi), expression of the cytolytic marker perforin, and the production of IFN.gamma. and IL-4 after stimulation with the H2.sup.b restricted CD8 OVA peptide, SIINFEKL. All experimental controls were elevated over their respective controls. To simplify the graphs we only show statistical results for comparison of our control immunization group (Liposome-OVA) to the other OVA immunization groups. Our "control" group was Liposome-OVA group because we were interested to learn how vault immunization differed from liposome immunization.

[0143] As shown in FIG. 5A, we found a marked in increase of OVA-responsive SIINFEKL CD8.sup.+ T cells in the CPZ-OVA immunized group over that found in Liposome-OVA immunized mice in the lymphoid compartment. It was surprising that total CD8.sup.+ responses were only slightly elevated in the OVA and CP-OVA group and suggested that CD8.sup.+ T cell subset examination may be more revealing than examining total CD8.sup.+ T cells in the lymphoid compartment. We also saw an increase in CD8.sup.+ memory T cells (FIG. 5B) and CD8.sup.+ IFN.gamma. producing T cells (FIG. 5C) in mice immunized with OVA encased vault nanocapsules compared to OVA delivered in liposomes while OVA immunization in saline did not increase these responses compared to the Liposome-OVA group. This is consistent with previous studies finding that OVA alone and liposome delivery does not enhance memory CD8.sup.+ cytotoxic T cells [42]. Although we noted an increase in the number of CD8.sup.+ T cells expressing perforin in CPZ-OVA immunized mice compared to Liposome-OVA immunized mice we also found increased CD8.sup.+ perforin.sup.+ T cells in the OVA group but no increase in the CP-OVA immunized mice. Interestingly, the number of IL-4 producing cells in CP-OVA immunized mice had markedly lower numbers compared to other OVA immunized groups. As expected, vaccination with OVA in any delivery vehicle or dissolved in saline significantly increased SINFEKL-responsive CD8.sup.+ T cells over control groups for all immunization groups (FIG. 5). These findings demonstrate that immunization of antigen encased within vaults is cross-presented in vivo and stimulates a CD8.sup.+ T cell response characterized by memory T cells and IFN.gamma. producing T cells.

[0144] It has been documented that CD4.sup.+ T cell help is important for CD8.sup.+ T cell function. Since we observed increased numbers of OVA-responsive CD8.sup.+ memory and IFN.gamma. producing T cells in CP- and CPZ-OVA immunized mice, we investigated if the number of CD4.sup.+ T cells was also increased following vault immunization. To address this issue, splenocytes from each group were stimulated ex vivo with the class II peptide, OVA 265-280 and the CD4.sup.+ T cell response was characterized by FACS.

[0145] We found that immunization with CPZ-OVA but not CP-OVA vault nanocapsules induced a significant amount of total CD4.sup.+ T cells in the lymphoid compartment of the spleen when compared to Liposome-OVA group (FIG. 6A). Also, immunization with both forms of vault nanocapsules significantly elevated the number of CD4.sup.+ memory T cells compared to Liposome-OVA immunized mice (FIG. 6B). We did not see a significant increase in IFN.gamma. or IL-17 producing CD4.sup.+ T cells over that seen in Liposome-OVA immunized mice following vault or liposome immunization of OVA (FIGS. 6C & D). However, CPZ-OVA but not CP-OVA immunization induced similar numbers of IL-4 producing CD4+ T cells as mice immunized with Liposome-OVA (FIG. 6E). We also noted significant increases in subsets as well as total CD4.sup.+ T cells in all immunized groups when compared to control groups as expected (FIG. 6). Taken together, these data show that immunization with CPZ-OVA induces CD4.sup.+ T cells characterized by memory cells and IL-4 producing cells Immunization with CPZ vaults results in the combination CD8.sup.+ T cells and CD4.sup.+ helper T cells.

Example 5

Vault Nanocapsules can be Modified to Induce Select Antibody Ig Isotypes

[0146] Co-operation of CD4.sup.+ T helper cells with antigen specific B cells is crucial for inducing long-lived neutralizing antibody responses for protective immunity followed by vaccination [43]. We investigated whether OVA delivered in vault nanocapsules also induced anti-OVA antibody since they were capable of inducing CD4.sup.+ T cell memory and IL-4 producing cells. The serum titers of OVA-responsive IgG1 and IgG2c in each group were measured after immunization by ELISA. We found that mice immunized with Liposome-OVA induced significantly greater levels of anti-OVA IgG1 and IgG2c compared to CP-OVA, CPZ-OVA or OVA immunized mice (FIGS. 7A & B) indicating that liposomes induce high levels of anti-OVA antibody [44-46]. Further inspection revealed that the addition of the "Z" domain reduced mean anti-OVA IgG2c titers by 0.5 to 1 log in comparison to CP-OVA and OVA groups while IgG1 remained comparable. Comparison of the ratio of anti-OVA IgG1:IgG2c revealed that Liposome-OVA immunized mice produced equal levels of IgG1 and IgG2c resulting in a ratio near one while immunization with CP-OVA, CPZ-OVA or OVA increased the ratio of IgG1:IgG2. Moreover, mice immunized with vault nanocapsules modified to express the "Z" domain (CPZ-OVA) had a significantly increased this ratio compared to Liposome-OVA immunized group. In contrast, the OVA and CP-OVA groups were not significantly different compared to the Liposome-OVA group (FIG. 7C). As expected all OVA immunization groups induced significant IgG1 and IgG2c serum antibody titers compared to the corresponding controls (FIG. 7). These data show that modification of the vault body by addition of the "Z" domain modifies the antibody isotype and suggests that the vault nanocapsule can be modified to alter the humoral responses.

Example 6

Use of Vault Particles as an Adjuvant to Deliver an Antigen

[0147] When the vault particle is used as an adjuvant to deliver the model antigen ovalbumin (OVA) to mice harboring the solid tumor produced from Lewis lung carcinoma cells engineered to express ovalbumin, a cellular immune response directed against the tumor is induced resulting in immune attack on the tumor itself leading to reduction in the tumor size. This antitumor immune response can be induced with a contralateral subcutaneous injection of the vault encapsulated ovalbumin with equal efficacy. See FIGS. 9 A and B and 10 A and B.

Example 7

Use of CCL21 Chemokine Containing Vault Particles to Activate an Antitumor Response

[0148] The antitumor immune response to the vault adjuvant engineered to deliver specific antigens can be further activated by vault particles containing the CCL21 chemokine. See FIGS. 11 A and B and Table 2.

[0149] As one embodiment of this invention, the CCL21-vault can be combined with one or more than one vault containing tumor antigens to increase the cellular immune response induced toward the tumor. See FIG. 11A and Table 2.

Example 8

Use of Vault Particles to Deliver the Tumor Antigens

[0150] When the vault particle is used as an adjuvant to deliver the tumor antigen NYESO1 to mice harboring the solid tumor produced from Lewis lung carcinoma cells engineered to express NYESO1, immune responses directed against the tumor are induced resulting in immune attack on the tumor itself. This antitumor immune response can be induced with a contralateral subcutaneous injection of the vault encapsulated NYESO. See FIGS. 12 A and B.

[0151] These results have also been extended to glioblastoma by packaging the glioblastoma associated antigens (GAA): GP100, EGFRv3, NY-ESO, and TRP-2 onto the INT domain. All GAA-INT fusion proteins have been packaged into CP, CPZ, or pVIZ vaults. Vault nanoparticles housing NY-ESO have been shown efficient uptake by dendritic cells. See FIG. 13.

[0152] Furthermore, dendritic cell activation and maturation as measured by CD86 expression has also been shown to be significantly increased by treatment with NY-ESO vaults. See FIG. 14.

[0153] Additionally, dendritic cells treated with GP100 vaults have demonstrated efficacy in stimulating CD8 T cells shown by elevated levels of interferon gamma. See FIG. 15.

Example 9

Use of Vault Particle Delivery of Tumor Antigens for Personalized Therapeutics

[0154] The compositions and methods disclosed herein can be utilized for personalized therapeutics directed against a wide variety of tumors. For example a biopsy of a particular tumor (lung glioblastoma etc.) can analyzed using existing procedures to determine the presence of common tumor antigens (biomarkers). Vault particles can be produced and engineered to contain individual tumor antigens and a mixture of these particles can be formulated based on the biopsy results of an individual tumor. This mixture of vault particles can then be used to immunize the patient and stimulate a specific cellular immune response that will be directed against the patient's particular tumor.

[0155] In other words, in lung cancer there are approximately 10 to 15 different antigens (tumor biomarkers) that are primarily expressed in nearly 99% of all lung tumors. Each of these 10 to 15 different antigens can be produced as fusion proteins with the vault packaging domain INT (antigen 1-INT, antigen 2-INT, antigen 3-INT etc.). These 10 to 15 different antigens-NT fusion proteins can be expressed, purified and stored either separately or mixed with recombinant vaults to form individual vault adjuvant antigen preparations that can be stored. Following biopsy, an individual's lung tumor can be analyzed for expression of the presence of the common biomarkers (the 10 to 15 different antigens) that are present in that tumor, thus allowing for tailored treatments for tumor eradication. For this example we will assume that antigens 3, 5 and 9 are present in an individual's tumor. A formulation of three different vault preparations (vaults containing antigen 3-INT, plus vaults containing antigen 5-INT plus vaults containing antigen 9-INT) can then be administered by subcutaneous injection to induce a cellular immune response to the individual tumor.

Example 10

Methods and Materials

[0156] Expression and Purification of Recombinant Vaults

[0157] Recombinant baculoviruses were generated using the Bac-to-Bac protocol (Invitrogen, Carlsbad, Calif.). The 385 amino acid coding region of ovalbumin was fused to major vault protein interaction domain (INT) derived from VPARP (amino acids 1563-1724) by PCR ligation[52,53]. Two PCR reactions were carried out: first=OVA-forward:CCCCACTAGTCCATGGGCTCCATCGG and OVA-INT reverse: TCCTGCCAGTGTTGTGTGCAGCTAGCAGGGGAAACACATCTGCC using plasmid pMFG-OVA as the template (plasmid pMFG-OVA was a kind gift from Dr Carlo Heirman, Laboratory of Molecular and Cellular Therapy, Department of Physiology-Immunology, Medical School of the Vrije Universiteit Brussel, Brussels, Belgium). The second PCR reaction with primer OVA-INT forward: TTGGCAGATGTGTTTCCCCTGCTAGCTGC ACACAACACTGGCAGGA and INT reverse: GGGCTCGAGTTAGCCTTGACTGTAATGGAG using INT in pET28 as the template. The PCR reactions were purified on a Qiagen column and a second round of PCR was carried out using the OVA-forward.times.INT reverse. The resultant PCR product containing the fused OVA-INT was purified on a Qiagen column, digested with Spe I and Xho I, gel purified, and ligated to pFastBac to form a pFastBac vector containing OVA-INT. Construction of cp-MVP-z, or cp-MVP in pFastBac has been described previously [32].

[0158] Sf9 cells were infected with Ova-INT, cp-MVP-z, or cp-MVP recombinant baculoviruses at a multiplicity of infection (MOI) of 0.01 for approximately 65 h and then pelleted and lysed on ice in buffer A [50 mM Tris-HCl (pH 7.4), 75 mM NaCl, and 0.5 mM MgCl2] with 1% Triton X-100, 1 mM dithiothreitol, 0.5 mM '.mu.g/ml chymostatin, 5 .mu.M leupeptin, 5 .mu.M pepstatin) (Sigma, St. Louis, Mo.). Lysates containing cp-MVP-z vaults were mixed with lysates containing either OVA-INT were incubated on ice for 30 min to allow the INT fusion proteins to package inside of vaults. Recombinant vaults were purified as previously described[33] and resuspended in 100-200 .mu.l of sterile phosphate buffered saline. The protein concentration was determined using the BCA assay (Pierce, Rockville, Ill.) and sample integrity was analyzed by negative stain electron microscopy and SDS-PAGE with Coomassie staining or transferred to hybond membrane (Amersham) for Western blot analysis. The density of the bands was determined by gel scanning and densitometry analysis using a 9410 Typhoon Variable Mode Scanner (GE Healthcare Life Sciences, Piscataway, N.J.).

[0159] Preparation of OVA-Liposomes

[0160] To generate OVA-liposomes, 10 mg lyophilized DOTAP/DOPE (1:1) (1,2-dioleoyl-3-trimethylammonium-propane/1,2-dioleoyl-sn-glycero-3-phosp- ho-ethanolamine) (Avanti Polar Lipids, Alabaster, Ala.) was re-hydrated in 1 mL endotoxin-free 5% glucose and mixed slowly (rotated) overnight at room temperature. Lyophilized EndoGrade Ovalbumin (<1 EU/mg=1 endotoxin unit has .about.0.1 .mu.g of endotoxin) (Profos AG, BioVender, LLC, Candler, N.C.) was reconstituted in endotoxin-free sterile saline (<0.1 EU/mL endotoxin, Sigma) to a stock solution of 10 mg/mL. Aliquots were stored frozen and thawed immediately before use. The entrapment of OVA was generated by combining 1.25 mg of resuspended ovalbumin with 2.5 mg of swollen DOTAP/DOPE lipids and further facilitated by brief sonication. OVA-liposomes were separated from unincorporated ovalbumin by ultracentrifugation at 100,000.times.g using an Optima XL-80K (Beckman Coulter, Fullerton, Calif.) ultracentrifuge and washed two additional times. Quantitation of encapsulated OVA was determined by subjecting OVA-liposomes (1, 2, 4 .mu.L) to SDS-PAGE electrophoresis in parallel with known amounts of ovalbumin (0.25, 0.5, 1.0, 2.5, 5 .mu.g) and visualized by Coomassie blue staining.

[0161] Gel Electrophoresis and Immunoblotting

[0162] Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was performed using the discontinuous buffer system and 4-15% acrylamide gels. Protein samples of OVA-liposome or OVA-vaults were transferred to an Immobilon-P transfer membrane (Millipore, city, Bedford, Mass.) and blocked with 5% (wt/vol) nonfat dry milk in PBS-0.1% Tween 20 (PBS-T). Membranes were incubated for 1 hr with anti-MVP (1:500, MAB 1023, Santa Cruz Biotechnology Inc, Santa Cruz, Calif.) or anti-INT followed by a 1 h incubation with the appropriate horseradish conjugate (1:5,000, Amersham Biosciences, Piscataway, N.J.). Bound conjugates were detected with ECL-Plus (GE Healthcare, Life Sciences, Piscataway, N.J.) and 9410 Typhoon Variable Mode Scanner (GE Healthcare Life Sciences, Piscataway, N.J.).

[0163] Antigen Processing and Presentation Assay

[0164] DC2.4 H-2Kb (5.times.10.sup.4/well) were plated in triplicates in 96-well plates and allowed to settle at 37.degree. C. Then, MHC Class I restricted CD8.sup.+ T cell line B3Z (10.sup.5/well) were added, in the presence of control vaults (200 .mu.g/mL) and OVA vaults (200 .mu.g/mL) for 24 hrs. After 24 h incubation at 37.degree. C., the plate was centrifuged at 1800 rpm, and the culture supernatant was collected and assayed for IL-2 using an IL-2 ELISA kit (BD Biosciences, San Jose, Calif.).

[0165] DC-Dependent T Cell Proliferation

[0166] DC cultures were generated by flushing the bone marrow (BM) from the bone shafts, washed and plated bacteriological Petri dishes (Falcon Plastics, Oxnard, Calif.). The cells were cultured at 2.times.10.sup.5 cells/mL in RPMI 1640 culture medium (10 mM HEPES/2 mM 1-glutamine/10% 0.22 um filtered FBS/50 uM .beta.-mercaptoethanol) supplemented with mGM-CSF (20 .mu.g/mL) and mIL-4 (20 .mu.g/mL) in an atmosphere of 5% CO.sub.2 at 37.degree. C. Fresh medium containing mGM-CSF (20 .mu.g/mL) and mIL-4 (20 .mu.g/mL) was added for 3-6 days after the start of culture. To induce maturation, cells were cultured for an additional 24 h in the presence of LPS (1 .mu.g/mL). The DC were harvested and purified with anti-CD11c magnetic beads, and suspended in complete RPMI-1640 medium and seeded at 5.times.10.sup.5/mL/well on 24-well culture plates followed by incubation with 25 and 100 .mu.g/mL of CP-OVA or recombinant OVA protein for 4 h at 37.degree. C., 5% CO.sub.2. Nonadherent cells consisting of mostly immature or mature DC were harvested for all the analyses performed in this study. Responder CD4.sup.+ T cells were separated from splenocytes with mouse CD4.sup.+ T-cell enrichment system (StemCell Technologies, Vancouver, Canada) according to the manufacturer's instructions. CD4.sup.+ T cells (2.times.10.sup.4/well) were added to OVA protein or CP-OVA pulsed DC and cultured for an additional 4 days. During the last 16-18 h of the 4-day culture, cells were pulsed with 1 .mu.Ci [3H]thymidine (Amersham, Arlington, Ill.). The cells were harvested onto filter paper and [3H]thymidine incorporation was measured with a .beta.-plate scintillation counter (PerkinElmer, Wellesley, Mass.).

[0167] Immunization Procedures

[0168] The OVA protein concentration was adjusted using endotoxin-free sterile saline (<0.1 EU/mL, 1 EU has .about.0.1 of endotoxin (Sigma) to 2.5 .mu.g OVA in 20 .mu.g of vault nanoparticles or liposomes using a Typhoon 9410 Variable Mode Scanner of Coomassie blue stained SDS-PAGE gels. The immunogens were injected into C57BL/6 mice (5-6 wk old) by subcutaneous injections at the base of the neck in 100 .mu.l sterile saline. The mice were immunized 3 times at 2 wk intervals. The spleen and blood was obtained 2 wk after the last immunization. The splenocytes were immediately used for FACS analysis and serum samples were stored frozen at -80.degree. C. until assayed.

[0169] Measurement of Anti-OVA Antibody from Serum

[0170] An ELISA was used to determine the level of anti-OVA antibody isotypes in the serum. Briefly 96-well microtitre plates (Nunc, Roskilde, Denmark) were coated with 75 .mu.l per well of OVA (1 .mu.g/75 .mu.l) in PBS and incubated over night at 4.degree. C. After being washed in buffer (phosphate buffered saline containing 0.05% Tween-20 (v/v) (PBS/T20) the plates were blocked with 150 .mu.l of PBS supplemented with 5% non-fat dry milk for 2 h at room temperature. After washing, 7 .mu.l of serum diluted from 1:40 to 1:5120 in PBS was added and incubated at 4.degree. C. overnight. Unbound antibody was then washed away and 75 .mu.l of goat anti-mouse IgG1-IgG2c-biotin (Southern Biotechnology Associates, Inc., Birmingham, Ala.), diluted 1/10,000 in PBS, was added and the plates incubated for 4 h at room temperature. The plates were then washed and 75 .mu.l of NeutraAvidin horse radish peroxidase diluted in PBS at 1:1000 was added for 20 min. After a final wash step, 100 mL of TetraMethylBenzidine (TMB) (Zymed Laboratories Inc., San Francisco, Calif.) substrate was added and incubated at room temperature, in the dark, for 20 min. The reaction was stopped with 50 .mu.L of 2 N sulphuric acid and the plates were read at 450 nm in a microplate reader (Model 550, Bio-Rad Laboratories, Hercules, Calif.).

[0171] Measurement of IL-2 Production

[0172] Spleens were removed and placed in RPMI media (Gibco, Grand Island, N.Y.) supplemented with 10% heat inactivated FCS. They were macerated to release the lymphocytes which were then washed by centrifugation. The cell pellet was resuspended in fresh media at a concentration of 2.times.10.sup.6 cells/mL and 1 mL of cells placed in each well of a 24-well plate (Nunc, Roskilde, Demark). They were restimulated with media (negative control) or OVA (100 .mu.g/mL) for 72 h at 37.degree. C. in a humidified atmosphere with 5% CO.sub.2. The plate was frozen until required. One hundred microlitres of the supernatants were tested for IL-2 in a sandwich ELISA following the manufacturer's instructions (PharMingen, San Diego, USA). In brief, 96-well, flat-bottomed plates were coated with 50 .mu.L of a 2 .mu.g/mL concentration of capture antibody (PharMingen). Plates were washed and blocked with 200 .mu.L/well of PBS/FCS. Doubling dilutions of standards and supernatants were added and incubated at 4.degree. C. overnight. The plates were washed and 100 .mu.L of a biotin-conjugated detecting mAb (PharMingen) was added at a concentration of 1 mg/mL. The enzyme and substrate were then added and analyzed as per the serum antibody ELISA. The amount of each cytokine in the supernatant was extrapolated from the standard curve derived using recombinant IL-2 (PharMingen) standards.

[0173] Characterization of T Cell Populations by Flow Cytometry

[0174] Lymphocytes were isolated from spleens by mechanical disruption through a cell strainer. RBCs were lysed using ammonium chloride-potassium buffer. The cells were stimulated @ 37.degree. C. with OVA peptide 265-280:TEWTSSNVMEERKIKV (2 .mu.g) to identify CD4 cells or OVA peptide: SIINFEKL (2 .mu.g) to identify CD8 cells for 5 hr. For the last 4 h, cells were incubated in the presence of Brefeldin A (BioLegend) at 1 .mu.g/mL. At the end of culture, the cells were stained using fluorochrome-conjugated MAbs against CD3, CD8, CD4, CD44, CCR7 and CD62L (BioLegend, San Diego, Calif.) in staining buffer (PBS with 2% fetal bovine serum and 0.1% sodium azide) and then treated with Fix/Perm (BioLegend). After permeabilization, the cells were further stained with fluorochrome-conjugated antibodies against IFN-.gamma., IL-4, IL-17 and perforin. Data were collected on LSR II (BD Biosciences, San Jose, Calif.) and analyzed using FCS Express (De Novo Software, Los Angeles, Calif.). CD8.sup.+ and CD4.sup.+ T cells were determined by gating on lymphocytes (FSC vs SSC) and CD8.sup.+ or CD4.sup.+ memory, cytokine producing or perforin expressing T cells were determined by gating on either CD3.sup.+CD8.sup.+ or CD3.sup.+CD4.sup.+ T cells as shown in FIG. 51.

[0175] Statistical Analysis

[0176] Statistical analysis was performed using Prism 5 (GraphPad, San Diego, Calif.). Data are presented as mean for each group and statistical significance for IL-2 secretion, proliferation, flow cytometry and Ig titers were determined by one way analysis of variance (ANOVA) with Bonferroni's Multiple Comparison Test. The ratio of isotypes was compared by Kruskal-Walis and Dunn's post-test.

[0177] Discussion

[0178] The work presented here illustrates the potential of engineered vault nanocapsules to act as potent adjuvants for the induction of combined cellular and humoral immune responses. Overall, our results demonstrate that immunization of OVA encased in vault nanocapsules, was more effective at generating greater cellular immunity characterized by increased numbers of OVA responsive memory CD8.sup.+ and CD4.sup.+ T cells. Also, modification of the vault body, by addition of the "Z" domain, altered the level of anti-OVA Ig subclass as shown by an increased IgG1:IgG2C ratio. These findings show that immune responses against OVA induced by vault nanoparticles differ compared to those induced by liposomes.

[0179] An important feature of vault nanocapsules as adjuvants is the robust induction of CD8.sup.+ and CD4.sup.+ memory T cells. The delivery of antigens to antigen presenting cells, especially DC, is a critical step for initiating and regulating the adaptive immune responses and we have shown that DC efficiently internalize vault nanocapules [27,41]. We have also shown that vaults containing immunogenic proteins activate inflammasomes and escape into the cytoplasm [unpublished data, [27]. This may explain induction of an OVA-responsive CD8.sup.+ memory T cell response and cross-presentation. Vaults may also stimulate antigen-responsive CD8.sup.+ and CD4.sup.+ memory T cells by acting as intracellular depots or altering JAK/STAT signaling [47].

[0180] A potential vaccine should have the ability to induce and maintain antigen-responsive effector and/or memory T cells [7]. Our data show that immunization with vault nanocapsules was capable of inducing phenotypic markers of memory cells in CD8.sup.+ and CD4.sup.+ T cells. It will be interesting to extend these studies and examine memory responses in vivo using protection from infection or tumor models. In addition, we found enhanced production of OVA-responsive CD8.sup.+ T cells that could secrete IFN.gamma.. Surprisingly, there was not much difference between Liposome-OVA and OVA immunized groups and one questions the present of LPS. We did not measure LPS concentrations directly but all reagents used were endotoxin free and the purchased OVA was endotoxin free (see methods). However, there are differences in the amount of IFN.gamma. produced when splenocytes are stimulated with OVA protein, CD8 or CD4 OVA peptides and whether IFN.gamma. is measured in total splenocytes or CD8.sup.+ or CD4.sup.+ T cells [48].

[0181] The induction of effector CD4.sup.+ T cells occurs in the same manner and with similar dynamics as is seen with the induction of effector memory CD8.sup.+ T cells [43]. However, the increased CD4.sup.+ memory T cells appear to be dominated by helper cells in mice immunized with CPZ-OVA vaults. Our data shows that the addition of the "Z" domain modifies antibody isotypes and supports the increased ratio of anti-OVA IgG1 over IgG2c titers. Adjuvants enhance immunity to immunogens but also steer immunity toward specific immune responses. For instance, alum is a known to promote Th2 responses [49]. The ability of vault vaccines to alter antibody isotypes suggests that modification of the vault toward certain immune responses is possible [50]. Recently, we have modified the vault by the addition of a lytic peptide derived from the adenovirus pIV protein. This modification allows those vaults to rapidly escape phagocytic vesicles [51]. Future studies will examine the in vivo immune responses generated by these vaults.

[0182] These results plus our previous studies with chemokines (CCL21) [28] and a chlamydial protein (MOMP) [27], supports the hypothesis that vault nanocapsules can be potent antigen delivery vehicles. Vault nanocapsules act as "smart" adjuvants that are capable of directing immunity toward desired responses with little induction of inflammatory cytokines when delivered via a mucosal route [27]. Further studies comparing immunization routes will be needed to determine the most effective route for the desired immune response. Since vaults are ubiquitous and conserved across eukaryote species, the platform has a major advantage over other delivery systems which have safety concerns associated with attenuated bacteria or viruses. In addition, vault nanocapsules are uniform in size and are able to be produced in abundance. Combining adjuvant and carrier activity, engineered vaults enhance the response with a much lower dose of the antigen and circumvent the protein-purification requirements of traditional subunit vaccines and particulate antigen-delivery modalities. With possibilities of further engineering the surface of vaults to either target specific cells or by allowing the proteins to escape endosomes, vaults provide a uniquely tunable platform with ease of manufacture for the delivery of a wide spectrum of subunit antigens for vaccines against infectious disease or other therapeutic targets.

REFERENCES

[0183] 1. Reed S G, Bertholet S, Coler R N, Friede M (2009) New horizons in adjuvants for vaccine development. Trends Immunol 30: 23-32. [0184] 2. Walker B D, Burton D R (2008) Toward an AIDS vaccine. Science 320: 760-764. [0185] 3. Zhou F (2010) Perforin: More than Just a Pore-Forming Protein. Int Rev Immunol 29: 56-76. [0186] 4. Fritsche P J, Helbling A, Ballmer-Weber B K (2010) Vaccine hypersensitivity--update and overview. Swiss Med Wkly 140: 238-246. [0187] 5. Fulginiti V A, Eller J J, Sieber O F, Joyner J W, Minamitani M, et al. (1969) Respiratory virus immunization. I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol 89: 435-448. [0188] 6. Flatz L, Hegazy A N, Bergthaler A, Verschoor A, Claus C, et al. (2010) Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8(+) T cell immunity. Nat Med 16: 339-U142. [0189] 7. Haglund K, Leiner I, Kerksiek K, Buonocore L, Pamer E, et al. (2002) Robust recall and long-term memory T-cell responses induced by prime-boost regimens with heterologous live viral vectors expressing human immunodeficiency virus type I Gag and Env proteins. J Virol 76: 7506-7517. [0190] 8. Brave A, Ljungberg K, Wahren B, Liu M A (2007) Vaccine delivery methods using viral vectors. Mol Pharm 4: 18-32. [0191] 9. Hubbell J A, Thomas S N, Swartz M A (2009) Materials engineering for immunomodulation. Nature 462: 449-460. [0192] 10. Heath W R, Carbone F R (2001) Cross-presentation in viral immunity and self-tolerance. Nat Rev Immunol 1: 126-134. [0193] 11. Langridge W, Denes B, Fodor I (2010) Cholera toxin B subunit modulation of mucosal vaccines for infectious and autoimmune diseases. Curr Opin Investig Drugs 11: 919-928. [0194] 12. Harnack U, Johnen H, Pecher G (2010) IL-1 receptor antagonist anakinra enhances tumour growth inhibition in mice receiving peptide vaccination and beta-(1-3),(1-6)-D-glucan. Anticancer Res 30: 3959-3965. [0195] 13. Guy B (2007) The perfect mix: recent progress in adjuvant research. Nat Rev Microbiol 5: 505-517. [0196] 14. Perrie Y, Mohammed A R, Kirby D J, McNeil S E, Bramwell V W (2008) Vaccine adjuvant systems: Enhancing the efficacy of sub-unit protein antigens. Int J Pharm 364: 272-280. [0197] 15. Watts C (1997) Capture and processing of exogenous antigens for presentation on MHC molecules. Ann Rev Immuno 15: 821-850. [0198] 16. Regnault A, Lankar D, Lacabanne V, Rodriguez A, Thery C, et al. (1999) Fc gamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J Exp Med 189: 371-380. [0199] 17. Mitchell D A, Nair S K, Gilboa E (1998) Dendritic cell macrophage precursors capture exogenous antigen for MHC class I presentation by dendritic cells (vol 28, pg 1923, 1998). Eur J Immunol 28: 3891-3891. [0200] 18. Ingolotti M, Kawalekar 0, Shedlock D J, Muthumani K, Weiner D B (2010) DNA vaccines for targeting bacterial infections. Expert Rev Vaccines 9: 747-763. [0201] 19. Ohlschlager P, Spies E, Alvarez G, Quetting M, Groettrup M (2011) The combination of TLR-9 adjuvantation and electroporation-mediated delivery enhances in vivo antitumor responses after vaccination with HPV-16 E7 encoding DNA. Int J Cancer 128: 473-481. [0202] 20. McNeela E, Mills K (2001) Manipulating the immune system: humoral versus cell-mediated immunity. Adv Drug Deliv Rev 51: 43-54. [0203] 21. Pathak Y, Thassu D, editors (2009) Drug delivery nanoparticles formulations and characterization. New York: Informa healthcare. p. 1-391. [0204] 22. Bolhassani A, Safaiyan S, Rafati S (2011) Improvement of different vaccine delivery systems for cancer therapy. Mol Cancer 10:3. [0205] 23. Chou L Y, Ming K, Chan W C (2011) Strategies for the intracellular delivery of nanoparticles. Chem Soc Rev 40: 233-245. [0206] 24. Izquierdo M A, Scheffer G L, Flens M J, Giaccone G, Broxterman H J, et al. (1996) Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors. Am J Pathol 148: 877-887. [0207] 25. Suprenant K (2002) Vault ribonucleoprotein particles: sarcophagi, gondolas, or safety deposit boxes? Biochemistry 41: 14447-14454. [0208] 26. Berger W, Steiner E, Grusch M, Elbling L, Micksche M (2009) Vaults and the major vault protein: Novel roles in signal pathway regulation and immunity. Cellular and Molecular Life Sciences 66: 43-61. [0209] 27. Champion C I, Kickhoefer V A, Liu G C, Moniz R J, Freed A S, et al. (2009) A Vault Nanoparticle Vaccine Induces Protective Mucosal Immunity. Plos One 4: e5409. [0210] 28. Kar U K, Srivastava M K, Andersson A, Baratelli F, Huang M, et al. (2011) Novel CCL21-Vault Nanocapsule Intratumoral Delivery Inhibits Lung Cancer Growth. Plos One 6: e18758. [0211] 29. Carstens M G, Camps M G, Henriksen-Lacey M, Franken K, Ottenhoff T H, et al. (2011) Effect of vesicle size on tissue localization and immunogenicity of liposomal DNA vaccines. Vaccine 29: 4761-4770. [0212] 30. Assudani D, Cho H I, DeVito N, Bradley N, Celis E (2008) In vivo Expansion, Persistence, and Function of Peptide Vaccine-Induced CD8 T Cells Occur Independently of CD4 T Cells. Cancer Res 68: 9892-9899. [0213] 31. Mikyas Y, Makabi M, Raval-Fernandes S, Harrington L, Kickhoefer V A, et al. (2004) Cryoelectron microscopy imaging of recombinant and tissue derived vaults: localization of the MVP N termini and VPARP. J Mol Biol 344: 91-105. [0214] 32. Kickhoefer V A, Han M, Raval-Fernandes S, Poderycki M J, Moniz R J, et al. (2009) Targeting vault nanoparticles to specific cell surface receptors. ACS Nano 3: 27-36. [0215] 33. Stephen A G, Raval-Fernandes S, Huynh T, Torres M, Kickhoefer V A, et al. (2001) Assembly of vault-like particles in insect cells expressing only the major vault protein. J Biol Chem 276: 23217-23220. [0216] 34. Poderycki M J, Kickhoefer V A, Kaddis C S, Raval-Fernandes S, Johansson E, et al. (2006) The vault exterior shell is a dynamic structure that allows incorporation of vault-associated proteins into its interior. Biochemistry 45: 12184-12193. [0217] 35. Burgdorf S, Scholz C, Kautz A, Tampe R, Kurts C (2008) Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation. Nat Immunol 9: 558-566. [0218] 36. Ferrari C, Pilli M, Penna A, Bertoletti A, Valli A, et al. (1992) Autopresentation of hepatitis B virus envelope antigens by T cells. J Virol 66: 2536-2540. [0219] 37. Tiwari S, Agrawal G P, Vyas S P (2010) Molecular basis of the mucosal immune system: from fundamental concepts to advances in liposome-based vaccines. Nanomedicine (Lond) 5: 1617-1640. [0220] 38. Moon J J, Suh H, Bershteyn A, Stephan M T, Liu H, et al. (2011) Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nat Mater 10: 243-251. [0221] 39. Kim C, Williams M A (2010) Nature and nurture: T-cell receptor-dependent and T-cell receptor-independent differentiation cues in the selection of the memory T-cell pool. Immunology 131: 310-317. [0222] 40. Moser M (2001) Regulation of Th1/Th2 development by antigen-presenting cells in vivo. Immunobiology 204: 551-557. [0223] 41. Joffre O, Nolte M A, Sporri R, Sousa C R E (2009) Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol Rev 227: 234-247. [0224] 42. Nembrini C, Stano A, Dane K Y, Ballester M, van der Vlies A J, et al. (2011) Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination. Proc Natl Acad Sci USA 108:E989-97. [0225] 43. Ahlers J D, Belyakov I M (2010) Molecular pathways regulating CD4(+) T cell differentiation, anergy and memory with implications for vaccines. Trends Mol Med 16: 478-491. [0226] 44. Henriques A M, Madeira C, Fevereiro M, Prazeres D M, Aires-Barros M R, et al. (2009) Effect of cationic liposomes/DNA charge ratio on gene expression and antibody response of a candidate DNA vaccine against Maedi Visna virus. Int J Pharm 377: 92-98. [0227] 45. Mohanan D, Sliitter B, Henriksen-Lacey M, Jiskoot W, Bouwstra J A, et al. (2010) Administration routes affect the quality of immune responses: A cross-sectional evaluation of particulate antigen-delivery systems. J Control Release 147: 342-349. [0228] 46. Zhong Z, Wei X, Qi B, Xiao W, Yang L, et al. (2010) A novel liposomal vaccine improves humoral immunity and prevents tumor pulmonary metastasis in mice. Int J Pharm 399: 156-162. [0229] 47. Steiner E, Holzmann K, Pirker C, Elbling L, Micksche M, et al. (2006) The major vault protein is responsive to and interferes with interferon-gamma-mediated STAT 1 signals. J Cell Sci 119: 459-469. [0230] 48. Andrews C D, Huh M-S, Patton K, Higgins D, Van Nest G, et al. (2012) Encapsulating Immunostimulatory CpG Oligonucleotides in Listeriolysin O-Liposomes Promotes a Th1-Type Response and CTL Activity. Molecular Pharmaceutics April 6. [Epub ahead of print] [0231] 49. Marrack P, McKee A S, Munks M W (2009) Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol 9: 287-293. [0232] 50. Huber V C, McKeon R M, Brackin M N, Miller L A, Keating R, et al. (2006) Distinct contributions of vaccine-induced immunoglobulin G1 (IgG1) and IgG2a antibodies to protective immunity against influenza. Clin Vaccine Immunol 13: 981-990. [0233] 51. Han M, Kickhoefer V A, Nemerow G R, Rome L H (2011) Targeted vault nanoparticles engineered with an endosomolytic peptide deliver biomolecules to the cytoplasm. ACS Nano 5: 6128-6137. [0234] 52. Kickhoefer V A, Siva A C, Kedersha N L, Inman E M, Ruland C, et al. (1999) The 193-Kd Vault Protein, Vparp, Is a Novel Poly(Adp-Ribose) Polymerase. J Cell Biol 146: 917-928. [0235] 53. Kickhoefer V A, Garcia Y, Mikyas Y, Johansson E, Zhou J C, et al. (2005) Engineering of vault nanocapsules with enzymatic and fluorescent properties. Proc Natl Acad Sci USA 102: 4348-4352.

[0236] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0237] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

TABLE-US-00001 TABLE 1 Sequences SEQ ID NO: 1 INT DNA sequence TGC ACA CAA CAC TGG CAG GAT GCT GTG CCT TGG ACA GAA CTC CTC AGT CTA CAG ACA GAG GAT GGC TTC TGG AAA CTT ACA CCA GAA CTG GGA CTT ATA TTA AAT CTT AAT ACA AAT GGT TTG CAC AGC TTT CTT AAA CAA AAA GGC ATT CAA TCT CTA GGT GTA AAA GGA AGA GAA TGT CTC CTG GAC CTA ATT GCC ACA ATG CTG GTA CTA CAG TTT ATT CGC ACC AGG TTG GAA AAA GAG GGA ATA GTG TTC AAA TCA CTG ATG AAA ATG GAT GAC CCT TCT ATT TCC AGG AAT ATT CCC TGG GCT TTT GAG GCA ATA AAG CAA GCA AGT GAA TGG GTA AGA AGA ACT GAA GGA CAG TAC CCA TCT ATC TGC CCA CGG CTT GAA CTG GGG AAC GAC TGG GAC TCT GCC ACC AAG CAG TTG CTG GGA CTC CAG CCC ATA AGC ACT GTG TCC CCT CTT CAT AGA GTC CTC CAT TAC AGT CAA GGC TAA SEQ ID NO: 2 INT protein sequence (residues 1563-1724 of the humanVPARP protein sequence) CTQHWQDAVPWTELLSLQTEDGFWKLTPELGLILNLNTNGLHSFLKQKGIQSLGVKGRECLLDLIA TMLVLQFIRTRLEKEGIVFKSLMKMDDPSISRNIPWAFEAIKQASEWVRRTEGQYPSICPRLELGN DWDSATKQLLGLQPISTVSPLHRVLHYSQG SEQ ID NO: 3 VPARP protein sequence (Genbank #AAD47250) Met Val Met Gly Ile Phe Ala Asn Cys Ile Phe Cys Leu Lys Val Lys Tyr Leu Pro Gln Gln Gln Lys Lys Lys Leu Gln Thr Asp Ile Lys Glu Asn Gly Gly Lys Phe Ser Phe Ser Leu Asn Pro Gln Cys Thr His Ile Ile Leu Asp Asn Ala Asp Val Leu Ser Gln Tyr Gln Leu Asn Ser Ile Gln Lys Asn His Val His Ile Ala Asn Pro Asp Phe Ile Trp Lys Ser Ile Arg Glu Lys Arg Leu Leu Asp Val Lys Asn Tyr Asp Pro Tyr Lys Pro Leu Asp Ile Thr Pro Pro Pro Asp Gln Lys Ala Ser Ser Ser Glu Val Lys Thr Glu Gly Leu Cys Pro Asp Ser Ala Thr Glu Glu Glu Asp Thr Val Glu Leu Thr Glu Phe Gly Met Gln Asn Val Glu Ile Pro His Leu Pro Gln Asp Phe Glu Val Ala Lys Tyr Asn Thr Leu Glu Lys Val Gly Met Glu Gly Gly Gln Glu Ala Val Val Val Glu Leu Gln Cys Ser Arg Asp Ser Arg Asp Cys Pro Phe Leu Ile Ser Ser His Phe Leu Leu Asp Asp Gly Met Glu Thr Arg Arg Gln Phe Ala Ile Lys Lys Thr Ser Glu Asp Ala Ser Glu Tyr Phe Glu Asn Tyr Ile Glu Glu Leu Lys Lys Gln Gly Phe Leu Leu Arg Glu His Phe Thr Pro Glu Ala Thr Gln Leu Ala Ser Glu Gln Leu Gln Ala Leu Leu Leu Glu Glu Val Met Asn Ser Ser Thr Leu Ser Gln Glu Val Ser Asp Leu Val Glu Met Ile Trp Ala Glu Ala Leu Gly His Leu Glu His Met Leu Leu Lys Pro Val Asn Arg Ile Ser Leu Asn Asp Val Ser Lys Ala Glu Gly Ile Leu Leu Leu Val Lys Ala Ala Leu Lys Asn Gly Glu Thr Ala Glu Gln Leu Gln Lys Met Met Thr Glu Phe Tyr Arg Leu Ile Pro His Lys Gly Thr Met Pro Lys Glu Val Asn Leu Gly Leu Leu Ala Lys Lys Ala Asp Leu Cys Gln Leu Ile Arg Asp Met Val Asn Val Cys Glu Thr Asn Leu Ser Lys Pro Asn Pro Pro Ser Leu Ala Lys Tyr Arg Ala Leu Arg Cys Lys Ile Glu His Val Glu Gln Asn Thr Glu Glu Phe Leu Arg Val Arg Lys Glu Val Leu Gln Asn His His Ser Lys Ser Pro Val Asp Val Leu Gln Ile Phe Arg Val Gly Arg Val Asn Glu Thr Thr Glu Phe Leu Ser Lys Leu Gly Asn Val Arg Pro Leu Leu His Gly Ser Pro Val Gln Asn Ile Val Gly Ile Leu Cys Arg Gly Leu Leu Leu Pro Lys Val Val Glu Asp Arg Gly Val Gln Arg Thr Asp Val Gly Asn Leu Gly Ser Gly Ile Tyr Phe Ser Asp Ser Leu Ser Thr Ser Ile Lys Tyr Ser His Pro Gly Glu Thr Asp Gly Thr Arg Leu Leu Leu Ile Cys Asp Val Ala Leu Gly Lys Cys Met Asp Leu His Glu Lys Asp Phe Pro Leu Thr Glu Ala Pro Pro Gly Tyr Asp Ser Val His Gly Val Ser Gln Thr Ala Ser Val Thr Thr Asp Phe Glu Asp Asp Glu Phe Val Val Tyr Lys Thr Asn Gln Val Lys Met Lys Tyr Ile Ile Lys Phe Ser Met Pro Gly Asp Gln Ile Lys Asp Phe His Pro Ser Asp His Thr Glu Leu Glu Glu Tyr Arg Pro Glu Phe Ser Asn Phe Ser Lys Val Glu Asp Tyr Gln Leu Pro Asp Ala Lys Thr Ser Ser Ser Thr Lys Ala Gly Leu Gln Asp Ala Ser Gly Asn Leu Val Pro Leu Glu Asp Val His Ile Lys Gly Arg Ile Ile Asp Thr Val Ala Gln Val Ile Val Phe Gln Thr Tyr Thr Asn Lys Ser His Val Pro Ile Glu Ala Lys Tyr Ile Phe Pro Leu Asp Asp Lys Ala Ala Val Cys Gly Phe Glu Ala Phe Ile Asn Gly Lys His Ile Val Gly Glu Ile Lys Glu Lys Glu Glu Ala Gln Gln Glu Tyr Leu Glu Ala Val Thr Gln Gly His Gly Ala Tyr Leu Met Ser Gln Asp Ala Pro Asp Val Phe Thr Val Ser Val Gly Asn Leu Pro Pro Lys Ala Lys Val Leu Ile Lys Ile Thr Tyr Ile Thr Glu Leu Ser Ile Leu Gly Thr Val Gly Val Phe Phe Met Pro Ala Thr Val Ala Pro Trp Gln Gln Asp Lys Ala Leu Asn Glu Asn Leu Gln Asp Thr Val Glu Lys Ile Cys Ile Lys Glu Ile Gly Thr Lys Gln Ser Phe Ser Leu Thr Met Ser Ile Glu Met Pro Tyr Val Ile Glu Phe Ile Phe Ser Asp Thr His Glu Leu Lys Gln Lys Arg Thr Asp Cys Lys Ala Val Ile Ser Thr Met Glu Gly Ser Ser Leu Asp Ser Ser Gly Phe Ser Leu His Ile Gly Leu Ser Ala Ala Tyr Leu Pro Arg Met Trp Val Glu Lys His Pro Glu Lys Glu Ser Glu Ala Cys Met Leu Val Phe Gln Pro Asp Leu Asp Val Asp Leu Pro Asp Leu Ala Ser Glu Ser Glu Val Ile Ile Cys Leu Asp Cys Ser Ser Ser Met Glu Gly Val Thr Phe Leu Gln Ala Lys Gln Ile Thr Leu His Ala Leu Ser Leu Val Gly Glu Lys Gln Lys Val Asn Ile Ile Gln Phe Gly Thr Gly Tyr Lys Glu Leu Phe Ser Tyr Pro Lys His Ile Thr Ser Asn Thr Thr Ala Ala Glu Phe Ile Met Ser Ala Thr Pro Thr Met Gly Asn Thr Asp Phe Trp Lys Thr Leu Arg Tyr Leu Ser Leu Leu Tyr Pro Ala Arg Gly Ser Arg Asn Ile Leu Leu Val Ser Asp Gly His Leu Gln Asp Glu Ser Leu Thr Leu Gln Leu Val Lys Arg Ser Arg Pro His Thr Arg Leu Phe Ala Cys Gly Ile Gly Ser Thr Ala Asn Arg His Val Leu Arg Ile Leu Ser Gln Cys Gly Ala Gly Val Phe Glu Tyr Phe Asn Ala Lys Ser Lys His Ser Trp Arg Lys Gln Ile Glu Asp Gln Met Thr Arg Leu Cys Ser Pro Ser Cys His Ser Val Ser Val Lys Trp Gln Gln Leu Asn Pro Asp Ala Pro Glu Ala Leu Gln Ala Pro Ala Gln Val Pro Ser Leu Phe Arg Asn Asp Arg Leu Leu Val Tyr Gly Phe Ile Pro His Cys Thr Gln Ala Thr Leu Cys Ala Leu Ile Gln Glu Lys Glu Phe Cys Thr Met Val Ser Thr Thr Glu Leu Gln Lys Thr Thr Gly Thr Met Ile His Lys Leu Ala Ala Arg Ala Leu Ile Arg Asp Tyr Glu Asp Gly Ile Leu His Glu Asn Glu Thr Ser His Glu Met Lys Lys Gln Thr Leu Lys Ser Leu Ile Ile Lys Leu Ser Lys Glu Asn Ser Leu Ile Thr Gln Phe Thr Ser Phe Val Ala Val Glu Lys Arg Asp Glu Asn Glu Ser Pro Phe Pro Asp Ile Pro Lys Val Ser Glu Leu Ile Ala Lys Glu Asp Val Asp Phe Leu Pro Tyr Met Ser Trp Gln Gly Glu Pro Gln Glu Ala Val Arg Asn Gln Ser Leu Leu Ala Ser Ser Glu Trp Pro Glu Leu Arg Leu Ser Lys Arg Lys His Arg Lys Ile Pro Phe Ser Lys Arg Lys Met Glu Leu Ser Gln Pro Glu Val Ser Glu Asp Phe Glu Glu Asp Gly Leu Gly Val Leu Pro Ala Phe Thr Ser Asn Leu Glu Arg Gly Gly Val Glu Lys Leu Leu Asp Leu Ser Trp Thr Glu Ser Cys Lys Pro Thr Ala Thr Glu Pro Leu Phe Lys Lys Val Ser Pro Trp Glu Thr Ser Thr Ser Ser Phe Phe Pro Ile Leu Ala Pro Ala Val Gly Ser Tyr Leu Thr Pro Thr Thr Arg Ala His Ser Pro Ala Ser Leu Ser Phe Ala Ser Tyr Arg Gln Val Ala Ser Phe Gly Ser Ala Ala Pro Pro Arg Gln Phe Asp Ala Ser Gln Phe Ser Gln Gly Pro Val Pro Gly Thr Cys Ala Asp Trp Ile Pro Gln Ser Ala Ser Cys Pro Thr Gly Pro Pro Gln Asn Pro Pro Ser Ala Pro Tyr Cys Gly Ile Val Phe Ser Gly Ser Ser Leu Ser Ser Ala Gln Ser Ala Pro Leu Gln His Pro Gly Gly Phe Thr Thr Arg Pro Ser Ala Gly Thr Phe Pro Glu Leu Asp Ser Pro Gln Leu His Phe Ser Leu Pro Thr Asp Pro Asp Pro Ile Arg Gly Phe Gly Ser Tyr His Pro Ser Ala Tyr Ser Pro Phe His Phe Gln Pro Ser Ala Ala Ser Leu Thr Ala Asn Leu Arg Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys Ser Gln Ser Arg Thr Thr Pro Val Asp Leu Cys Leu Leu Glu Glu Ser Val Gly Ser Leu Glu Gly Ser Arg Cys Pro Val Phe Ala Phe Gln Ser Ser Asp Thr Glu Ser Asp Glu Leu Ser Glu Val Leu Gln Asp Ser Cys Phe Leu Gln Ile Lys Cys Asp Thr Lys Asp Asp Ser Ile Pro Cys Phe Leu Glu Leu Lys Glu Glu Asp Glu Ile Val Cys Thr Gln His Trp Gln Asp Ala Val Pro Trp Thr Glu Leu Leu Ser Leu Gln Thr Glu Asp Gly Phe Trp Lys Leu Thr Pro Glu Leu Gly Leu Ile Leu Asn Leu Asn Thr Asn Gly Leu His Ser Phe Leu Lys Gln Lys Gly Ile Gln Ser Leu Gly Val Lys Gly Arg Glu Cys Leu Leu Asp Leu Ile Ala Thr Met Leu Val Leu Gln Phe Ile Arg Thr Arg Leu Glu Lys Glu Gly Ile Val Phe Lys Ser Leu Met Lys Met Asp Asp Pro Ser Ile Ser Arg Asn Ile Pro Trp Ala Phe Glu Ala Ile Lys Gln Ala Ser Glu Trp Val Arg Arg Thr Glu Gly Gln Tyr Pro Ser Ile Cys Pro Arg Leu Glu Leu Gly Asn Asp Trp Asp Ser Ala Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser Thr Val Ser Pro Leu His Arg Val Leu His Tyr Ser Gln Gly SEQ ID NO: 5 VPARP cDNA, Genbank #AF158255 atggtgatgg gaatctttgc aaattgtatc ttctgtttga aagtgaagta cttacctcag cagcagaaga aaaagctaca aactgacatt aaggaaaatg gcggaaagtt ttccttttcg ttaaatcctc agtgcacaca tataatctta gataatgctg atgttctgag tcagtaccaa ctgaattcta tccaaaagaa ccacgttcat attgcaaacc cagattttat atggaaatct atcagagaaa agagactctt ggatgtaaag aattatgatc cttataagcc cctggacatc acaccacctc ctgatcagaa ggcgagcagt tctgaagtga aaacagaagg tctatgcccg gacagtgcca cagaggagga agacactgtg gaactcactg agtttggtat gcagaatgtt gaaattcctc atcttcctca agattttgaa gttgcaaaat ataacacctt ggagaaagtg ggaatggagg gaggccagga agctgtggtg gtggagcttc agtgttcgcg ggactccagg gactgtcctt tcctgatatc ctcacacttc ctcctggatg atggcatgga gactagaaga cagtttgcta taaagaaaac ctctgaagat gcaagtgaat actttgaaaa ttacattgaa gaactgaaga aacaaggatt tctactaaga gaacatttca cacctgaagc aacccaatta gcatctgaac aattgcaagc attgcttttg gaggaagtca tgaattcaag cactctgagc caagaggtga gcgatttagt agagatgatt tgggcagagg ccctgggcca cctggaacac atgcttctca agccagtgaa caggattagc ctcaacgatg tgagcaaggc agaggggatt ctccttctag taaaggcagc actgaaaaat ggagaaacag cagagcaatt gcaaaagatg atgacagagt tttacagact gatacctcac aaaggcacaa tgcccaaaga agtgaacctg ggactattgg ctaagaaagc agacctctgc cagctaataa gagacatggt taatgtctgt gaaactaatt tgtccaaacc caacccacca tccctggcca aataccgagc tttgaggtgc aaaattgagc atgttgaaca gaatactgaa gaatttctca gggttagaaa agaggttttg cagaatcatc acagtaagag cccagtggat gtcttgcaga tatttagagt tggcagagtg aatgaaacca cagagttttt gagcaaactt ggtaatgtga ggcccttgtt gcatggttct cctgtacaaa acatcgtggg aatcttgtgt cgagggttgc ttttacccaa agtagtggaa gatcgtggtg tgcaaagaac agacgtcgga aaccttggaa gtgggattta tttcagtgat tcgctcagta caagtatcaa gtactcacac ccgggagaga cagatggcac cagactcctg ctcatttgtg acgtagccct cggaaagtgt atggacttac atgagaagga ctttccctta actgaagcac caccaggcta cgacagtgtg catggagttt cacaaacagc ctctgtcacc acagactttg aggatgatga atttgttgtc tataaaacca atcaggttaa aatgaaatat attattaaat tttccatgcc tggagatcag ataaaggact ttcatcctag tgatcatact gaattagagg aatacagacc tgagttttca aatttttcaa aggttgaaga ttaccagtta ccagatgcca aaacttccag cagcaccaag gccggcctcc aggatgcctc tgggaacttg gttcctctgg aggatgtcca catcaaaggg agaatcatag acactgtagc ccaggtcatt gtttttcaga catacacaaa taaaagtcac gtgcccattg aggcaaaata tatctttcct ttggatgaca aggccgctgt gtgtggcttc gaagccttca tcaatgggaa gcacatagtt ggagagatta aagagaagga agaagcccag caagagtacc tagaagccgt gacccagggc catggcgctt acctgatgag tcaggatgct ccggacgttt ttactgtaag tgttggaaac ttacccccta aggctaaggt tcttataaaa attacctaca tcacagaact cagcatcctg ggcactgttg gtgtcttttt catgcccgcc accgtagcac cctggcaaca ggacaaggct ttgaatgaaa accttcagga tacagtagag aagatttgta taaaagaaat aggaacaaag caaagcttct ctttgactat gtctattgag atgccgtatg tgattgaatt cattttcagt gatacacatg aactgaaaca aaagcgcaca gactgcaaag ctgtcattag caccatggaa ggcagctcct tagacagcag tggattttct ctccacatcg gtttgtctgc tgcctatctc ccaagaatgt gggttgaaaa acatccagaa aaagaaagcg aggcttgcat gcttgtcttt caacccgatc tcgatgtcga cctccctgac ctagccagtg agagcgaagt gattatttgt cttgactgct ccagttccat ggagggtgtg acattcttgc aagccaagca aatcaccttg catgcgctgt ccttggtggg tgagaagcag aaagtaaata ttatccagtt cggcacaggt tacaaggagc tattttcgta tcctaagcat atcacaagca ataccacggc agcagagttc atcatgtctg ccacacctac catggggaac acagacttct ggaaaacact ccgatatctt agcttattgt accctgctcg agggtcacgg aacatcctcc tggtgtctga tgggcacctc caggatgaga gcctgacatt acagctcgtg aagaggagcc gcccgcacac caggttattc gcctgcggta tcggttctac agcaaatcgt cacgtcttaa ggattttgtc ccagtgtggt gccggagtat ttgaatattt taatgcaaaa tccaagcata gttggagaaa acagatagaa gaccaaatga ccaggctatg ttctccgagt tgccactctg tctccgtcaa atggcagcaa ctcaatccag atgcgcccga ggccctgcag gccccagccc aggtgccatc cttgtttcgc aatgatcgac tccttgtcta tggattcatt cctcactgca cacaagcaac tctgtgtgca ctaattcaag agaaagaatt ttgtacaatg gtgtcgacta ctgagcttca gaagacaact ggaactatga tccacaagct ggcagcccga gctctaatca gagattatga agatggcatt cttcacgaaa atgaaaccag tcatgagatg aaaaaacaaa ccttgaaatc tctgattatt aaactcagta aagaaaactc tctcataaca caatttacaa gctttgtggc agttgagaaa agggatgaga atgagtcgcc ttttcctgat attccaaaag tttctgaact tattgccaaa gaagatgtag acttcctgcc ctacatgagc tggcaggggg agccccaaga agccgtcagg aaccagtctc ttttagcatc ctctgagtgg ccagaattac gtttatccaa acgaaaacat aggaaaattc cattttccaa aagaaaaatg gaattatctc agccagaagt ttctgaagat tttgaagagg atggcttagg tgtactacca gctttcacat caaatttgga acgtggaggt gtggaaaagc tattggattt aagttggaca gagtcatgta aaccaacagc aactgaacca ctatttaaga aagtcagtcc atgggaaaca tctacttcta gcttttttcc tattttggct ccggccgttg gttcctatct taccccgact acccgcgctc acagtcctgc ttccttgtct tttgcctcat atcgtcaggt agctagtttc ggttcagctg ctcctcccag acagtttgat gcatctcaat tcagccaagg ccctgtgcct ggcacttgtg ctgactggat cccacagtcg gcgtcttgtc ccacaggacc tccccagaac ccaccttctg caccctattg tggcattgtt ttttcaggga gctcattaag ctctgcacag tctgctccac tgcaacatcc tggaggcttt actaccaggc cttctgctgg caccttccct gagctggatt ctccccagct tcatttctct cttcctacag accctgatcc catcagaggt tttgggtctt atcatccctc tgcttactct ccttttcatt ttcaaccttc cgcagcctct ttgactgcca accttaggct gccaatggcc tctgctttac ctgaggctct ttgcagtcag tcccggacta ccccagtaga tctctgtctt ctagaagaat cagtaggcag tctcgaagga agtcgatgtc ctgtctttgc ttttcaaagt tctgacacag aaagtgatga gctatcagaa gtacttcaag acagctgctt tttacaaata aagtgtgata caaaagatga cagtatcccg tgctttctgg aattaaaaga agaggatgaa atagtgtgca cacaacactg gcaggatgct gtgccttgga cagaactcct cagtctacag acagaggatg gcttctggaa acttacacca gaactgggac ttatattaaa tcttaataca aatggtttgc acagctttct taaacaaaaa ggcattcaat ctctaggtgt aaaaggaaga gaatgtctcc tggacctaat tgccacaatg ctggtactac agtttattcg caccaggttg gaaaaagagg gaatagtgtt caaatcactg atgaaaatgg atgacccttc tatttccagg aatattccct gggcttttga ggcaataaag caagcaagtg aatgggtaag aagaactgaa ggacagtacc catctatctg cccacggctt gaactgggga acgactggga ctctgccacc aagcagttgc tgggactcca gcccataagc actgtgtccc ctcttcatag agtcctccat tacagtcaag gctaa SEQ ID NO: 6 MVP (Genbank #CAA56256) Met Ala Thr Glu Glu Phe Ile Ile Arg Ile Pro Pro Tyr His Tyr Ile His Val Leu Asp Gln Asn Ser Asn Val Ser Arg Val Glu Val Gly Pro Lys Thr Tyr Ile Arg Gln Asp Asn Glu Arg Val Leu Phe Ala Pro Met Arg Met Val Thr Val Pro Pro Arg His Tyr Cys Thr Val Ala Asn Pro Val Ser Arg Asp Ala Gln Gly Leu Val Leu Phe Asp Val Thr Gly Gln Val Arg Leu Arg His Ala Asp Leu Glu Ile Arg Leu Ala Gln Asp Pro Phe Pro Leu Tyr Pro Gly Glu Val Leu Glu Lys Asp Ile Thr Pro Leu Gln Val Val Leu Pro Asn Thr Ala Leu His Leu Lys Ala Leu Leu Asp Phe Glu Asp Lys Asp Gly Asp Lys Val Val Ala Gly Asp Glu Trp Leu Phe Glu Gly Pro Gly Thr Tyr Ile Pro Arg Lys Glu Val Glu Val Val Glu Ile Ile Gln Ala Thr Ile Ile Arg Gln Asn Gln Ala Leu Arg Leu Arg Ala Arg Lys Glu Cys Trp Asp Arg Asp Gly Lys Glu Arg Val Thr Gly Glu Glu Trp Leu Val Thr Thr Val Gly Ala Tyr Leu Pro Ala Val Phe Glu Glu Val Leu Asp Leu Val Asp Ala Val Ile Leu Thr Glu Lys Thr Ala Leu His Leu Arg Ala Arg Arg Asn Phe Arg Asp Phe Arg Gly Val Ser Arg Arg Thr Gly Glu Glu Trp Leu Val Thr Val Gln Asp Thr Glu Ala His Val Pro Asp Val His Glu Glu Val Leu Gly Val Val Pro Ile Thr Thr Leu Gly Pro His Asn Tyr Cys Val Ile Leu Asp Pro Val Gly Pro Asp Gly Lys Asn Gln Leu Gly Gln Lys Arg Val Val Lys Gly Glu Lys Ser Phe Phe Leu Gln Pro Gly Glu Gln Leu Glu Gln Gly Ile Gln Asp Val Tyr Val Leu Ser Glu Gln Gln Gly Leu Leu Leu Arg Ala Leu Gln Pro Leu Glu Glu Gly Glu Asp Glu Glu Lys Val Ser His Gln Ala Gly Asp His Trp Leu Ile Arg Gly Pro Leu Glu Tyr Val Pro Ser Ala Lys Val Glu Val Val Glu Glu Arg Gln Ala Ile Pro Leu Asp Glu Asn Glu Gly Ile Tyr Val Gln Asp Val Lys Thr Gly Lys Val Arg Ala Val Ile Gly Ser Thr Tyr Met Leu Thr Gln Asp Glu Val Leu Trp Glu Lys Glu Leu Pro Pro Gly Val Glu Glu Leu Leu Asn Lys Gly Gln Asp Pro Leu Ala Asp Arg Gly Glu Lys Asp Thr Ala Lys Ser Leu Gln Pro Leu Ala Pro Arg Asn Lys Thr Arg Val Val Ser Tyr Arg Val Pro His Asn Ala Ala Val Gln Val Tyr Asp Tyr Arg Glu Lys Arg Ala Arg Val Val Phe Gly Pro Glu Leu Val Ser Leu Gly Pro Glu Glu Gln Phe Thr Val Leu Ser Leu Ser Ala Gly Arg Pro Lys Arg Pro His Ala Arg Arg Ala Leu Cys Leu Leu Leu Gly Pro Asp Phe Phe Thr Asp Val Ile Thr Ile Glu Thr Ala Asp His Ala Arg Leu Gln Leu Gln Leu Ala Tyr Asn Trp His Phe Glu Val Asn Asp Arg Lys Asp Pro Gln Glu Thr Ala Lys Leu Phe Ser Val Pro Asp Phe Val Gly Asp Ala Cys Lys Ala Ile Ala Ser Arg Val Arg Gly Ala Val Ala Ser Val Thr Phe Asp Asp Phe His Lys Asn Ser Ala Arg Ile Ile Arg Thr Ala Val Phe Gly Phe Glu Thr Ser Glu Ala Lys Gly Pro Asp Gly Met Ala Leu Pro Arg Pro Arg Asp Gln Ala Val Phe Pro Gln Asn Gly Leu Val Val Ser Ser Val Asp Val Gln Ser Val Glu Pro Val Asp Gln Arg Thr Arg Asp Ala Leu Gln Arg Ser Val Gln Leu Ala Ile Glu Ile Thr Thr Asn Ser Gln Glu Ala Ala Ala Lys His Glu Ala Gln Arg Leu Glu Gln Glu Ala

Arg Gly Arg Leu Glu Arg Gln Lys Ile Leu Asp Gln Ser Glu Ala Glu Lys Ala Arg Lys Glu Leu Leu Glu Leu Glu Ala Leu Ser Met Ala Val Glu Ser Thr Gly Thr Ala Lys Ala Glu Ala Glu Ser Arg Ala Glu Ala Ala Arg Ile Glu Gly Glu Gly Ser Val Leu Gln A;a Lys Leu Lys Ala Gln Ala Leu Ala Ile Glu Thr Glu Ala Glu Leu Gln Arg Val Gln Lys Val Arg Glu Leu Glu Leu Leu Val Ala Arg Ala Gln Leu Glu Leu Glu Val Ser Lys Ala Gln Gln Leu Ala Glu Val Glu Val Lys Lys Phe Lys Gln Met Thr Glu Ala Ile Gly Pro Ser Thr Ile Arg Asp Leu Ala Val Ala Gly Pro Glu Met Gln Val Lys Leu Leu Gln Ser Leu Gly Leu Lys Ser Thr Leu Ile Thr Asp Gly Ser Thr Pro Ile Asn Leu Phe Asn Thr Ala Phe Gly Leu Leu Gly Met Gly Pro Glu Gly Gln Pro Leu Gly Arg Arg Val Ala Ser Gly Pro Ser Pro Gly Glu Gly Ile Ser Pro Gln Ser Ala Gln Ala Pro Gln Ala Pro Gly Asp Asn His Val Val Pro Val Leu Arg SEQ ID NO: 7 MVP cDNA, Genbank #X79882 atggcaactg aagagttcat catccgcatc cccccatacc actatatcca tgtgctggac cagaacagca acgtgtcccg tgtggaggtc gggccaaaga cctacatccg gcaggacaat gagagggtac tgtttgcccc catgcgcatg gtgaccgtcc ccccacgtca ctactgcaca gtggccaacc ctgtgtctcg ggatgcccag ggcttggtgc tgtttgatgt cacagggcaa gttcggcttc gccacgctga cctcgagatc cggctggccc aggacccctt ccccctgtac ccaggggagg tgctggaaaa ggacatcaca cccctgcagg tggttctgcc caacactgcc ctccatctaa aggcgctgct tgattttgag gataaagatg gagacaaggt ggtggcagga gatgagtggc ttttcgaggg acctggcacg tacatccccc ggaaggaagt ggaggtcgtg gagatcattc aggccaccat catcaggcag aaccaggctc tgcggctcag ggcccgcaag gagtgctggg accgggacgg caaggagagg gtgacagggg aagaatggct ggtcaccaca gtaggggcgt acctcccagc ggtgtttgag gaggttctgg atttggtgga cgccgtcatc cttacggaaa agacagccct gcacctccgg gctcggcgga acttccggga cttcagggga gtgtcccgcc gcactgggga ggagtggctg gtaacagtgc aggacacaga ggcccacgtg ccagatgtcc acgaggaggt gctgggggtt gtgcccatca ccaccctggg cccccacaac tactgcgtga ttctcgaccc tgtcggaccg gatggcaaga atcagctggg gcagaagcgc gtggtcaagg gagagaagtc ttttttcctc cagccaggag agcagctgga acaaggcatc caggatgtgt atgtgctgtc ggagcagcag gggctgctgc tgagggccct gcagcccctg gaggaggggg aggatgagga gaaggtctca caccaggctg gggaccactg gctcatccgc ggacccctgg agtatgtgcc atctgccaaa gtggaggtgg tggaggagcg ccaggccatc cctctagacg agaacgaggg catctatgtg caggatgtca agaccggaaa ggtgcgcgct gtgattggaa gcacctacat gctgacccag gacgaagtcc tgtgggagaa agagctgcct cccggggtgg aggagctgct gaacaagggg caggaccctc tggcagacag gggtgagaag gacacagcta agagcctcca gcccttggcg ccccggaaca agacccgtgt ggtcagctac cgcgtgcccc acaacgctgc ggtgcaggtg tacgactacc gagagaagcg agcccgcgtg gtcttcgggc ctgagctggt gtcgctgggt cctgaggagc agttcacagt gttgtccctc tcagctgggc ggcccaagcg tccccatgcc cgccgtgcgc tctgcctgct gctggggcct gacttcttca cagacgtcat caccatcgga acggcggatc atgccaggct gcaactgcag ctggcctaca actggcactt tgaggtgaat gaccggaagg acccccaaga gacggccaag ctcttttcag tgccagactt tgtaggtgat gcctgcaaag ccatcgcatc ccgggtgcgg ggggccgtgg cctctgtcac tttcgatgac ttccataaga actcagcccg catcattcgc actgctgtct ttggctttga gacctcggaa gcgaagggcc ccgatggcat ggccctgccc aggccccggg accaggctgt cttcccccaa aacgggctgg tggtcagcag tgtggacgtg cagtcagtgg agcctgtgga tcagaggacc cgggacgccc tgcaacgcag cgtccagctg gccatcgaga tcaccaccaa ctcccaggaa gcggcggcca agcatgaggc tcagagactg gagcaggaag cccgcggccg gcttgagcgg cagaagatcc tggaccagtc agaagccgag aaagctcgca aggaactttt ggagctggag gctctgagca tggccgtgga gagcaccggg actgccaagg cggaggccga gtcccgtgcg gaggcagccc ggattgaggg agaagggtcc gtgctgcagg ccaagctaaa agcacaggcc ttggccattg aaacggaggc tgagctccag agggtccaga aggtccgaga gctggaactg gtctatgccc gggcccagct ggagctggag gtgagcaagg ctcagcagct ggctgaggtg gaggtgaaga agttcaagca gatgacagag gccataggcc ccagcaccat cagggacctt gctgtggctg ggcctgagat gcaggtaaaa ctgctccagt ccctgggcct gaaatcaacc ctcatcaccg atggctccac tcccatcaac ctcttcaaca cagcctttgg gctgctgggg atggggcccg agggtcagcc cctgggcaga agggtggcca gtgggcccag ccctggggag gggatatccc cccagtctgc tcaggcccct caagctcctg gagacaacca cgtggtgcct gtactgcgct aa SEQ ID NO: 8 CP Peptide Met Ala Gly Cys Gly Cys Pro Cys Gly Cys Gly Ala SEQ ID NO: 9 CP-MVP Met Ala Gly Cys Gly Cys Pro Cys Gly Cys Gly Ala Met Ala Thr Glu Glu Phe Ile Ile Arg Ile Pro Pro Tyr His Tyr Ile His Val Leu Asp Gln Asn Ser Asn Val Ser Arg Val Glu Val Gly Pro Lys Thr Tyr Ile Arg Gln Asp Asn Glu Arg Val Leu Phe Ala Pro Met Arg Met Val Thr Val Pro Pro Arg His Tyr Cys Thr Val Ala Asn Pro Val Ser Arg Asp Ala Gln Gly Leu Val Leu Phe Asp Val Thr Gly Gln Val Arg Leu Arg His Ala Asp Leu Glu Ile Arg Leu Ala Gln Asp Pro Phe Pro Leu Tyr Pro Gly Glu Val Leu Glu Lys Asp Ile Thr Pro Leu Gln Val Val Leu Pro Asn Thr Ala Leu His Leu Lys Ala Leu Leu Asp Phe Glu Asp Lys Asp Gly Asp Lys Val Val Ala Gly Asp Glu Trp Leu Phe Glu Gly Pro Gly Thr Tyr Ile Pro Arg Lys Glu Val Glu Val Val Glu Ile Ile Gln Ala Thr Ile Ile Arg Gln Asn Gln Ala Leu Arg Leu Arg Ala Arg Lys Glu Cys Trp Asp Arg Asp Gly Lys Glu Arg Val Thr Gly Glu Glu Trp Leu Val Thr Thr Val Gly Ala Tyr Leu Pro Ala Val Phe Glu Glu Val Leu Asp Leu Val Asp Ala Val Ile Leu Thr Glu Lys Thr Ala Leu His Leu Arg Ala Arg Arg Asn Phe Arg Asp Phe Arg Gly Val Ser Arg Arg Thr Gly Glu Glu Trp Leu Val Thr Val Gln Asp Thr Glu Ala His Val Pro Asp Val His Glu Glu Val Leu Gly Val Val Pro Ile Thr Thr Leu Gly Pro His Asn Tyr Cys Val Ile Leu Asp Pro Val Gly Pro Asp Gly Lys Asn Gln Leu Gly Gln Lys Arg Val Val Lys Gly Glu Lys Ser Phe Phe Leu Gln Pro Gly Glu Gln Leu Glu Gln Gly Ile Gln Asp Val Tyr Val Leu Ser Glu Gln Gln Gly Leu Leu Leu Arg Ala Leu Gln Pro Leu Glu Glu Gly Glu Asp Glu Glu Lys Val Ser His Gln Ala Gly Asp His Trp Leu Ile Arg Gly Pro Leu Glu Tyr Val Pro Ser Ala Lys Val Glu Val Val Glu Glu Arg Gln Ala Ile Pro Leu Asp Glu Asn Glu Gly Ile Tyr Val Gln Asp Val Lys Thr Gly Lys Val Arg Ala Val Ile Gly Ser Thr Tyr Met Leu Thr Gln Asp Glu Val Leu Trp Glu Lys Glu Leu Pro Pro Gly Val Glu Glu Leu Leu Asn Lys Gly Gln Asp Pro Leu Ala Asp Arg Gly Glu Lys Asp Thr Ala Lys Ser Leu Gln Pro Leu Ala Pro Arg Asn Lys Thr Arg Val Val Ser Tyr Arg Val Pro His Asn Ala Ala Val Gln Val Tyr Asp Tyr Arg Glu Lys Arg Ala Arg Val Val Phe Gly Pro Glu Leu Val Ser Leu Gly Pro Glu Glu Gln Phe Thr Val Leu Ser Leu Ser Ala Gly Arg Pro Lys Arg Pro His Ala Arg Arg Ala Leu Cys Leu Leu Leu Gly Pro Asp Phe Phe Thr Asp Val Ile Thr Ile Glu Thr Ala Asp His Ala Arg Leu Gln Leu Gln Leu Ala Tyr Asn Trp His Phe Glu Val Asn Asp Arg Lys Asp Pro Gln Glu Thr Ala Lys Leu Phe Ser Val Pro Asp Phe Val Gly Asp Ala Cys Lys Ala Ile Ala Ser Arg Val Arg Gly Ala Val Ala Ser Val Thr Phe Asp Asp Phe His Lys Asn Ser Ala Arg Ile Ile Arg Thr Ala Val Phe Gly Phe Glu Thr Ser Glu Ala Lys Gly Pro Asp Gly Met Ala Leu Pro Arg Pro Arg Asp Gln Ala Val Phe Pro Gln Asn Gly Leu Val Val Ser Ser Val Asp Val Gln Ser Val Glu Pro Val Asp Gln Arg Thr Arg Asp Ala Leu Gln Arg Ser Val Gln Leu Ala Ile Glu Ile Thr Thr Asn Ser Gln Glu Ala Ala Ala Lys His Glu Ala Gln Arg Leu Glu Gln Glu Ala Arg Gly Arg Leu Glu Arg Gln Lys Ile Leu Asp Gln Ser Glu Ala Glu Lys Ala Arg Lys Glu Leu Leu Glu Leu Glu Ala Leu Ser Met Ala Val Glu Ser Thr Gly Thr Ala Lys Ala Glu Ala Glu Ser Arg Ala Glu Ala Ala Arg Ile Glu Gly Glu Gly Ser Val Leu Gln Ala Lys Leu Lys Ala Gln Ala Leu Ala Ile Glu Thr Glu Ala Glu Leu Gln Arg Val Gln Lys Val Arg Glu Leu Glu Leu Val Tyr Ala Arg Ala Gln Leu Glu Leu Glu Val Ser Lys Ala Gln Gln Leu Ala Glu Val Glu Val Lys Lys Phe Lys Gln Met Thr Glu Ala Ile Gly Pro Ser Thr Ile Arg Asp Leu Ala Val Ala Gly Pro Glu Met Gln Val Lys Leu Leu Gln Ser Leu Gly Leu Lys Ser Thr Leu Ile Thr Asp Gly Ser Thr Pro Ile Asn Leu Phe Asn Thr Ala Phe Gly Leu Leu Gly Met Gly Pro Glu Gly Gln Pro Leu Gly Arg Arg Val Ala Ser Gly Pro Ser Pro Gly Glu Gly Ile Ser Pro Gln Ser Ala Gln Ala Pro Gln Ala Pro Gly Asp Asn His Val Val Pro Val Leu Arg SEQ ID NO: 10 CP-MVP cDNA atggcaggct gcggttgtcc atgcggttgt ggcgccatgg caactgaaga gttcatcatc cgcatccccc cataccacta tatccatgtg ctggaccaga acagcaacgt gtcccgtgtg gaggtcgggc caaagaccta catccggcag gacaatgaga gggtactgtt tgcccccatg cgcatggtga ccgtcccccc acgtcactac tgcacagtgg ccaaccctgt gtctcgggat gcccagggct tggtgctggt tgatgtcaca gggcaagttc ggcttcgcca cgctgacctc gagatccggc tggcccagga ccccttcccc ctgtacccag gggaggtgct ggaaaaggac atcacacccc tgcaggtggt tctgcccaac actgccctcc atctaaaggc gctgcttgat tttgaggata aagatggaga caaggtggtg gcaggagatg agtggctttt cgagggacct ggcacgtaca tcccccggaa ggaagtggag gtcgtggaga tcattcaggc caccatcatc aggcagaacc aggctctgcg gctcagggcc cgcaaggagt gctgggaccg ggacggcaag gagagggtga caggggaaga atggctggtc accacagtag gggcgtacct cccagcggtg tttgaggagg ttctggattt ggtggacgcc gtcatcctta cggaaaagac agccctgcac ctccgggctc ggcggaactt ccgggacttc aggggagtgt cccgccgcac tggggaggag tggctggtaa cagtgcagga cacagaggcc cacgtgccag atgtccacga ggaggtgctg ggggttgtgc ccatcaccac cctgggcccc cacaactact gcgtgattct cgaccctgtc ggaccggatg gcaagaatca gctggggcag aagcgcgtgg tcaagggaga gaagtctttt ttcctccagc caggagagca gctggaacaa ggcatccagg atgtgtatgt gctgtcggag cagcaggggc tgctgctgag ggccctgcag cccctggagg agggggagga tgaggagaag gtctcacacc aggctgggga ccactggctc atccgcggac ccctggagta tgtgccatct gccaaagtgg agttggtgga ggagcgccag gccatccctc tagacgagaa cgagggcatc tatgtgcagg atgtcaagac cggaaaggtg cgcgctgtga ttggaagcac ctacatgctg acccaggacg aagtcctgtg ggagaaagag ctgcctcccg gggtggagga gctgctgaac aaggggcagg accctctggc agacaggggt gagaaggaca cagctaagag cctccagccc ttggcgcccc ggaacaagac ccgtgtggtc agctaccgcg tgccccacaa cgctgcggtg caggtgtacg actaccgaga gaagcgagcc cgcgtggtct tcgggcctga gctggtgtcg ctgggtcctg aggagcagtt cacagtgttg tccctctcag ctgggcggcc caagcgtccc catgcccgcc gtgcgctctg cctgctgctg gggcctgact tcttcacaga cgtcatcacc atcgaaacgg cggatcatgc caggctgca ctgcagcctgg cctacaactg gcactttgag gtgaatgacc ggaaggaccc ccaagagacg gccaagctct tttcagtgcc agactttgta ggtgatgcct gcaaagccat cgcatcccgg gtgcgggggg ccgtggcctc tgtcactttc gatgacttcc ataagaactc agcccgcatc attcgcactg ctgtctttgg ctttgagacc tcggaagcga agggccccga tggcatggcc ctgcccaggc cccgggacca ggctgtcttc ccccaaaacg ggctggtggt cagcagtgtg gacgtgcagt cagtggagcc tgtggatcag aggacccggg acgccctgca acgcagcgtc cagctggcca tcgagatcac caccaactcc caggaagcgg cggccaagca tgaggctcag agactggagc aggaagcccg cggccggctt gagcggcaga agatcctgga ccagtcagaa gccgagaaag ctcgcaagga acttttggag ctggaggctc tgagcatggc cgtggagagc accgggactg ccaaggcgga ggccgagtcc cgtgcggagg cagcccggat tgagggagaa gggtccgtgc tgcaggccaa gctaaaagca caggccttgg ccattgaaac ggaggctgag ctccagaggg tccagaaggt ccgagagctg gaactggtct atgcccgggc ccagctggag ctggaggtga gcaaggctca gcagctggct gaggtggagg tgaagaagtt caagcagatg acagaggcca taggccccag caccatcagg gaccttgctg tggctgggcc tgagatgcag gtaaaactgc tccagtccct gggcctgaaa tcaaccctca tcaccgatgg ctccactccc atcaacctct tcaacacagc ctttgggctg ctggggatgg ggcccgaggg tcagcccctg ggcagaaggg tggccagtgg gcccagccct ggggagggga tatcccccca gtctgctcag gcccctcaag ctcctggaga caaccacgtg gtgcctgtac tgcgctaa SEQ ID NO: 11 TEP1, Genbank #AAC51107 Met Glu Lys Leu His Gly His Val Ser Ala His Pro Asp Ile Leu Ser Leu Glu Asn Arg Cys Leu Ala Net Leu Pro Asp Leu Gln Pro Leu Glu Lys Leu His Gln His Val Ser Thr His Ser Asp Ile Leu Ser Leu Lys Asn Gln Cys Leu Ala Thr Leu Pro Asp Leu Lys Thr Met Glu Lys Pro His Gly Tyr Val Ser Ala His Pro Asp Ile Leu Ser Leu Glu Asn Gln Cys Leu ala Thr Leu Ser Asp Leu Lys Thr Met Glu Lys Pro His Gly His Val Ser Ala His Pro Asp Ile Leu Ser Leu Glu Asn arg Cys Leu Ala Thr Leu Pro Ser Leu Lys Ser Thr Val Ser Ala Ser Pro Leu Phe Gln Ser Leu Gln Ile ser His Met Thr Gln Ala Asp Leu Tyr Arg Val Asn Asn Ser Asn Cys Leu Leu Ser Glu Pro Pro Ser Trp Arg Ala Gln His Phe Ser Lys Gly Leu Asp Leu Ser Thr Cys Pro Ile Ala Leu Lys Ser Ile Ser Ala Thr Glu Thr Ala Gln Glu Ala Thr Leu Gly Arg Trp Phe Asp Ser Glu Glu Lys Lys Gly Ala Glu Thr Gln Met Pro Ser Tys Ser Leu Ser Leu Gly Glu Glu Glu Glu Val Glu Asp Leu Ala Val Lys leu Thr Ser Gly asp Ser Glu Ser His Pro Glu Pro Thr Asp His Val Leu Gln Glu Lys Lys Met Ala Leu Leu Ser Leu Leu Cys Ser Thr Leu Val Ser Glu Val Asn Met Asn Asn Thr Ser Asp Pro Thr Leu Ala Ala Ile Phe Glu Ile Cys Arg Glu Leu Ala Leu Leu Glu Pro Glu Phe Ile Leu Lys Ala Ser Leu Tyr Ala Arg Gln Gln Leu Asn Val Arg Asn Val Ala Asn Asn Ile Leu Ala Ile Ala Ala Phe Leu pro Ala Cys Arg Pro His Leu Arg Arg Tyr Phe Cys Ala Ile Val Gln Leu Pro Ser ASp Trp Ile Gln Val Ala Glu Leu Tyr Gln Ser Leu Ala Glu Gly Asp Lys Asn Lys Leu Val Pro Leu Pro Ala Cys Leu Arg Thr Ala Met Thr Asp Lys Phe Ala Gln Phe Asp Glu Tyr Gln Leu Ala Lys Tyr Asn Pro Arg Lys His Arg Ala Lys Arg His Pro Arg Arg Pro Pro Arg Ser Pro Gly Met Glu Pro Pro Phe Ser His Arg Cys Phe Pro Arg Tyr Ile Gly Phe Leu Arg Glu Glu Gln Arg Lys Phe Glu Lys Ala Gly Asp Thr Val Ser Glu Lys Lys Asn Pro Pro Arg Phe Thr Leu Lys Lys Leu Val Gln Arg Leu His Ile His Lys Pro Ala Gln His Val Gln Ala Leu Leu Gly Tyr Arg Tyr Pro Ser Asn Leu Gln Leu Phe Ser Arg Ser Arg Leu Pro Gly Pro Trp Asp Ser Ser Arg Ala Gly Lys Arg Met Lys Leu Ser Arg Pro Glu Thr Trp Glu Arg Glu Leu Ser Leu Arg Gly Asn Lys Ala Ser Val Trp Glu Glu Leu Ile Glu Asn Gly Lys Leu Pro Phe Met Ala Met Leu Arg Asn Leu Cys Asn Leu Leu Arg Val Gly Ile Ser Ser Arg His His Glu Leu Ile Leu Gln Arg Leu Gln His Gly Lys Ser Val Ile His Ser Arg Gln Phe Pro Phe Arg Phe Leu Asn Ala His Asp Ala Ile Asp Ala Leu Glu Ala Gln Leu Arg Asn Gln Ala Leu Pro Phe Pro Ser Asn Ile Thr Leu Met Arg Arg Ile Leu Thr Arg Asn Glu Lys Asn Arg Pro Arg Arg Arg Phe Leu Cys His Leu Ser Arg Gln Gln Leu Arg Met Ala Met Arg Ile Pro Val Leu Tyr Glu Gln Leu Lys Arg Glu Lys Leu Arg Val His Lys Ala Arg Gln Trp Lys Tyr Asp Gly Glu Met Leu Asn Arg Tyr Arg Gln Ala Leu Glu Thr Ala Val Asn Leu Ser Val Lys His Ser Leu Pro Leu Leu Pro Gly Arg Thr Val Leu Val Tyr Leu Thr Asp Ala Asn Ala Asp Arg Leu Cys Pro Lys Ser Asn Pro Gln Gly Pro Pro Leu Asn Tyr Ala Leu Leu Leu Ile Gly Met Met Ile Thr Arg Ala Glu Gln Val Asp Val Val Leu Cys Gly Gly Asp Thr Leu Lys Thr Ala Val Leu Lys Ala Glu Glu Gly Ile Leu Lys Thr Ala Ile Lys Leu Gln Ala Gln Val Gln Glu Phe Asp Glu Asn Asp Gly Trp Ser Leu Asn Thr Phe Gly Lys Tyr Leu Leu Ser Leu Ala Gly Gln Arg Val Pro Val Asp Arg Val Ile Leu Leu Gly Gln Ser Met Asp Asp Gly Met Ile Asn Val Ala Lys Gln Leu Tyr Trp Gln Arg Val Asn Ser Lys Cys Leu Phe Val Gly Ile Leu Leu Arg Arg Val Gln Tyr Leu Ser Thr Asp Leu Asn Pro Asn Asp Val Thr Leu Ser Gly Cys Thr Asp Ala Ile Leu Lys Phe Ile Ala Glu His Gly Ala Ser His Leu Leu Glu His Val Gly Gln Met Asp Lys Ile Phe Lys Ile Pro Pro Pro Pro Gly Lys Thr Gly Val Gln Ser Leu Arg Pro Leu Glu Glu Asp Thr Pro Ser Pro Leu Ala Pro Val Ser Gln Gln Gly Trp Arg Ser Ile Arg Leu Phe Ile Ser Ser Thr Phe Arg Asp Met His Gly Glu Arg Asp Leu Leu Leu Arg Ser Val Leu Pro Ala Leu Gln Ala Arg Ala Ala Pro His Arg Ile Ser Leu His Gly Ile Asp Leu Arg Trp Gly Val Thr Glu Glu Glu Thr Arg Arg Asn Arg Gln Leu Glu Val Cys Leu Gly Glu Val Glu Asn Ala Gln Leu Phe Val Gly Ile Leu Gly Ser Arg Tyr Gly Tyr Ile Pro Pro Ser Tyr Asn Leu Pro Asp His Pro His Phe His Trp Ala Gln Gln Tyr Pro Ser Gly Arg Ser Val Thr Glu Met Glu Val Met Gln Phe Leu Asn Arg Asn Gln Arg Leu Gln Pro Ser Ala Gln Ala Leu Ile Tyr Phe Arg Asp Ser Ser Phe Leu Ser Ser Val Pro Asp Ala Trp Lys Ser Asp Phe Val Ser Glu Ser Glu Glu Ala Ala Cys Arg Ile Ser Glu Leu Lys Ser Tyr Leu Ser Arg Gln Lys Gly Ile Thr Cys Arg Arg Tyr Pro Cys Glu Trp Gly Gly Val Ala Ala Gly Arg Pro Tyr Val Gly Gly Leu Glu Glu Phe Gly Gln Leu Val Leu Gln Asp Val Trp Asn Met Ile Gln Lys Leu Tyr Leu Gln Pro Gly Ala Leu Leu Glu Gln Pro Val Ser Ile Pro Asp Asp Asp Leu Val Gln Ala Thr Phe Gln Gln Leu Gln Lys Pro Pro Ser Pro Ala Arg Pro Arg Leu Leu Gln Asp Thr Val Gln Gln Leu Met Leu Pro His Gly Arg Leu Ser Leu Val Thr Gly Gln Ser Gly Gln Gly Lys Thr Ala Phe Leu Ala Ser Leu Val Ser Ala Leu Gln Ala Pro Asp Gly Ala Lys Val Ala Pro Leu Val Phe Phe His Phe Ser Gly Ala Arg Pro Asp Gln Gly Leu Ala Leu Thr Leu Leu Arg Arg Leu Cys Thr Tyr Leu Arg Gly Gln Leu Lys Glu Pro Gly Ala Leu Pro Ser Thr Tyr Arg Ser Leu Val Trp Glu Leu Gln Gln Arg Leu Leu Pro Lys Ser Ala Glu Ser Leu His Pro Gly Gln Thr Gln Val Leu Ile Ile Asp Gly Ala Asp Arg Leu Val Asp Gln Asn Gly Gln Leu Ile Ser Asp Trp Ile Pro Lys Lys Leu Pro Arg Cys Val His Leu Val Leu Ser Val Ser Ser Asp Ala Gly Leu Gly Glu Thr Leu Glu Gln Ser Gln Gly Ala His Val Leu Ala Leu Gly Pro Leu Glu Ala Ser Ala Arg Ala Arg Leu Val Arg Glu Glu Leu Ala Leu Tyr Gly Lys Arg Leu Glu Glu Ser Pro Phe Asn Asn Gln Met Arg Leu Leu Leu Val Lys Arg Glu Ser Gly Arg Pro Leu Tyr Leu Arg Leu Val Thr Asp His Leu Arg Leu Phe Thr Leu Tyr Gle Gln Val Ser Glu Arg Leu Arg Thr Leu Pro Ala Thr Val Pro Leu Leu Leu Gln His Ile Leu Ser Thr Leu Glu Lys Glu His Gly Pro Asp Val Leu Pro Gln Ala Leu Thr Ala Leu Glu Val Thr Arg Ser Gly Leu Thr Val Asp Gln Leu His Gly Val Leu Ser Val Trp Arg Thr Leu Pro Lys Gly Thr Lys Ser Trp Glu Glu Ala Val Ala Ala Gly Asn Ser Gly Asp Pro Tyr Pro Met Gly Pro Phe Ala Cys Leu Val Gln Ser Leu Arg Ser Leu Leu Gly glu Gly Pro Leu Glu arg Pro Gly Ala Arg Leu Cys Leu Pro Asp Gly Pro Leu Arg Thr Ala Ala Lys Arg Cys Tyr Gly Lys Arg Pro Gly Leu Glu Asp Thr Ala His Ile Leu Ile Ala Ala Gln Leu Trp Lys Thr Cys Asp Ala Asp Ala Ser Gly Thr Phe Arg Ser Cys Pro Pro Glu Ala Leu Gly Asp Leu Pro Tyr His

Leu Leu Gln Ser Gly Asn Arg Gly Leu Leu Ser Lys Phe Leu Thr Asn Leu His Val Val Ala Ala His Leu Glu Leu Gly Leu Val Ser Arg Leu Leu Glu Ala His Ala Leu Tyr Ala Ser Ser Val Pro Lys Glu Glu Gln Lys Leu Pro Glu Ala Asp Val Ala Val Phe Arg Thr Phe Leu Arg Gln Gln Ala Ser Ile Leu Ser Gln Tyr Pro Arg Leu Leu Pro Gln Gln Ala Ala Asn Gln Pro Leu Asp Ser Pro Leu Cys His Gln Ala Ser Leu Leu Ser Arg Arg Trp His Leu Gln His Thr Leu Arg Trp Leu Asn Lys Pro Arg Thr Met Lys Asn Gln Gln Ser Ser Ser Leu Ser Leu Ala Val Ser Ser Ser Pro Thr Ala Val Ala Phe Ser Thr Asn Gly Gln Arg Ala Ala Val Gly Thr Ala Asn Gly Thr Val Tyr Leu Leu Asp Leu Arg Thr Trp Gln Glu Glu Lys Ser Val Val Ser Gly Cys Asp Gly Ile Ser Ala Cys Leu Phe Leu Ser Asp Asp Thr Leu Phe Leu Thr Ala Phe Asp Gly Leu Leu Glu Leu Trp Asp Leu Gln His Gly Cys Arg Val Leu Gln Thr Lys Ala His Gln Tyr Gln Ile Thr Gly Cys Cys Leu Ser Pro Asp Cys Arg Leu Leu Ala Thr Val Cys Leu Gly Gly Cys Leu Lys Leu Trp Asp Thr Val Arg Gly Gln Leu Ala Phe Gln His Thr Tyr Pro Lys Ser Leu Asn Cys Val Ala Phe His Pro Glu Gly Gln Val Ile Ala Thr Gly Ser Trp Ala Gly Ser Ile Ser Phe Phe Gln Val Asp Gly Leu Lys Val Thr Lys Asp Leu Gly Ala Pro Gly Ala Ser Ile Arg Thr Leu Ala Phe Asn Val Pro Gly Gly Val Val Ala Val Gly Arg Leu Asp Ser Met Val Glu Leu Trp Ala Trp Arg Glu Gly Ala Arg Leu Ala Ala Phe Pro Ala His His Gly Phe Val Ala Ala Ala Leu Phe Leu His Ala Gly Cys Gln Leu Leu Thr Ala Gly Glu Asp Gly Lys Val Gln Val Trp Ser Gly Ser Leu Gly Arg Pro Arg Gly His Leu Gly Ser Leu Ser Leu Ser Pro Ala Leu Ser Val Ala Leu Ser Pro Asp Gly Asp Arg Val Ala Val Gly Tyr Arg Ala Asp Gly Ile Arg Ile Tyr Lys Ile Ser Ser Gly Ser Gln Gly Ala Gln Gly Gln Ala Leu Asp Val Ala Val Ser Ala Leu Ala Trp Leu Ser Pro Lys Val Leu Val Ser Gly Ala Glu Asp Gly Ser Leu Gln Gly Trp Ala Leu Lys Glu Cys Ser Leu Gln Ser Leu Trp Leu Leu Ser Arg Phe Gln Lys Pro Val Leu Gly Leu Ala Thr Ser Gln Glu Leu Leu Ala Ser Ala Ser Glu Asp Phe Thr Val Gln Leu Trp Pro Arg Gln Leu Leu Thr Arg Pro His Lys Ala Glu Asp Phe Pro Cys Gly Thr Glu Leu Arg Gly His Glu Gly Pro Val Ser Cys Cys Ser Phe Ser Thr Asp Gly Gly Ser Leu Ala Thr Gly Gly Arg Asp Arg Ser Leu Leu Cys Trp Asp Val Arg Thr Pro Lys Thr Pro Val Leu Ile His Ser Phe Pro Ala Cys His Arg Asp Trp Val Thr Gly Cys Ala Trp Thr Lys Asp Asn Leu Leu Ile Ser Cys Ser Ser Asp Gly Ser Val Gly Leu Trp Asp Pro Glu Ser Gly Gln Arg Leu Gly Gln Phe Leu Gly His Gln Ser Ala Val Ser Ala Val Ala Ala Val Glu Glu His Val Val Ser Val Ser Arg Asp Gly Thr Leu Lys Val Trp Asp His Gln Gly Val Glu Leu Thr Ser Ile Pro Ala His Ser Gly Pro Ile Ser His Cys Ala Ala Ala Met Glu Pro Arg Ala Ala Gly Gln Pro Gly Ser Glu Leu Leu Val Val Thr Val Gly Leu Asp Gly Ala Thr Arg Leu Trp His Pro Leu Leu Val Cys Gln Thr His Thr Leu Leu Gly His Ser Gly Pro Val Arg Ala Ala Ala Val Ser Glu Thr Ser Gly Leu Met Leu Thr Ala Ser Glu Asp Gly Ser Val Arg Leu Trp Gln Val Pro Lys Glu Ala Asp Asp Thr Cys Ile Pro Arg Ser Ser Ala Ala Val Thr Ala Val Ala Trp Ala Pro Asp Gly Ser Met Ala Val Ser Gly Asn Gln Ala Gly Glu Leu Ile Leu Trp Gln Glu Ala Lys Ala Val Ala Thr Ala Gln Ala Pro Gly His Ile Gly Ala Leu Ile Trp Ser Ser Ala His Thr Phe Phe Val Leu Ser Ala Asp Glu Lys Ile Ser Glu Trp Gln Val Lys Leu Arg Lys Gly Ser Ala Pro Gly Asn Leu Ser Leu His Leu Asn Arg Ile Leu Gln Glu Asp Leu Gly Val Leu Thr Ser Leu Asp Trp Ala Pro Asp Gly His Phe Leu Ile Leu Ala Lys Ala Asp Leu Lys Leu Leu Cys Met Lys Pro Gly Asp Ala Pro Ser Glu Ile Trp Ser Ser Tyr Thr Glu Asn Pro Met Ile Leu Ser Thr His Lys Glu Tyr Gly Ile Phe Val Leu Gln Pro Lys Asp Pro Gly Val Leu Ser Phe Leu Arg Gln Lys Glu Ser Gly Glu Phe Glu Glu Arg Leu Asn Phe Asp Ile Asn Leu Glu Asn Pro Ser Arg Thr Leu Ile Ser Ile Thr Gln Ala Lys Pro Glu Ser Glu Ser Ser Phe Leu Cys Ala Ser Ser Asp Gly Ile Leu Trp Asn Leu Ala Lys Cys Ser Pro Glu Gly Glu Trp Thr Thr Gly Asn Met Trp Gln Lys Lys Ala Asn Thr Pro Glu Thr Gln Thr Pro Gly Thr Asp Pro Ser Thr Cys Arg glu Ser Asp Ala Ser Met Asp Ser Asp Ala Ser Met Asp ser Glu Pro Thr Pro His Leu Lys Thr Arg Gln Arg Arg Lys Ile His Ser Gly Ser Val Thr Ala Leu His Val Leu Pro Glu Leu Leu Val Thr Ala Ser Lys Asp Arg Asp Val Lys Leu Trp Glu Arg Pro Ser Met Gln Leu Leu Gly Leu Phe Arg Cys Glu Gly Ser Val Ser Cys Leu Glu Pro Trp Glu Gly ala Asn Ser Thr Leu Gln Leu Ala Val Gly Asp Val Gln Gly Asn Val Tyr Phe Leu Asn Trp Glu SEQ ID NO: 12 TEN cDNA, Genbank #U86136 atggaaaaac tccatgggca tgtgtctgcc catccagaca tcctctcctt ggagaaccgg tgcctggcta tgctccctga cttacagccc ttggagaaac tacatcagca tgtatctacc cactcagata tcctctcctt gaagaaccag tgcctagcca cgcttcctga cctgaagacc atggaaaaac cacatggata tgtgtctgcc cacccagaca tcctctcctt ggagaaccag tgcctggcca cactttctga cctgaagacc atggagaaac cacatggaca tgtttctgcc cacccagaca tcctctcctt ggagaaccgg tgcctggcca ccctccctag tctaaagagc actgtgtctg ccagcccctt gttccagagt ctacagatat ctcacatgac gcaagctgat ttgtaccgtg tgaacaacag caattgcctg ctctctgagc ctccaagttg gagggctcag catttctcta agggactaga cctttcaacc tgccctatag ccctgaaatc catctctgcc acagagacag ctcaggaagc aactttgggt cgttggtttg attcagaaga gaagaaaggg gcagagaccc aaatgccttc ttatagtctg agcttgggag aggaggagga ggtggaggat ctggccgtga agctcacctc tggagactct gaatctcatc cagagcctac tgaccatgtc cttcaggaaa agaagatggc tctactgagc ttgctgtgct ctactctggt ctcagaagta aacatgaaca atacatctga ccccaccctg gctgccattt ttgaaatctg tcgtgaactt gccctcctgg agcctgagtt tatcctcaag gcatctttgt atgccaggca gcagctgaac gtccggaatg tggccaataa catcttggcc attgctgctt tcttgccggc gtgtcgcccc cacctgcgac gatatttctg tgccattgtc cagctgcctt ctgactggat ccaggtggct gagctttacc agagcctggc tgagggagat aagaataagc tggtgcccct gcccgcctgt ctccgtactg ccatgacgga caaatttgcc cagtttgacg agtaccagct ggctaagtac aaccctcgga agcaccgggc caagagacac ccccgccggc caccccgctc tccagggatg gagcctccat tttctcacag atgttttcca aggtacatag ggtttctcag agaagagcag agaaagtttg agaaggccgg tgatacagtg tcagagaaaa agaatcctcc aaggttcacc ctgaagaagc tggttcagcg actgcacatc cacaagcctg cccagcacgt tcaagccctg ctgggttaca gatacccctc caacctacag ctcttttctc gaagtcgcct tcctgggcct tgggattcta gcagagctgg gaagaggatg aagctgtcta ggccagagac ctgggagcgg gagctgagcc tacgggggaa caaagcgtcg gtctgggagg aactcattga aaatgggaag cttcccttca tggccatgct tcggaacctg tgcaacctgc tgcgggttgg aatcagttcc cgccaccatg agctcattct ccagagactc cagcatggga agtcggtgat ccacagtcgg cagtttccat tcagatttct taacgcccat gatgccattg atgccctcga ggctcaactc agaaatcaag cattgccctt tccttcgaat ataacactga tgaggcggat actaactaga aatgaaaaga accgtcccag gcggaggttt ctttgccacc taagccgtca gcagcttcgt atggcaatga ggatacctgt gttgtatgag cagctcaaga gggagaagct gagagtacac aaggccagac agtggaaata tgatggtgag atgctgaaca ggtaccgaca ggccctagag acagctgtga acctctctgt gaagcacagc ctgcccctgc tgccaggccg cactgtcttg gtctatctga cagatgctaa tgcagacagg ctctgtccaa agagcaaccc acaagggccc ccgctgaact atgcactgct gttgattggg atgatgatca cgagggcgga gcaggtggac gtcgtgctgt gtggaggtga cactctgaag actgcagtgc ttaaggcaga agaaggcatc ctgaagactg ccatcaagct ccaggctcaa gtccaggagt ttgatgaaaa tgatggatgg tccctgaata cttttgggaa atacctgctg tctctggctg gccaaagggt tcctgtggac agggtcatcc tccttggcca aagcatggat gatggaatga taaatgtggc caaacagctt tactggcagc gtgtgaattc caagtgcctc tttgttggta tcctcctaag aagggtacaa tacctgtcaa cagatttgaa tcccaatgat gtgacactct caggctgtac tgatgcgata ctgaagttca ttgcagagca tggggcctcc catcttctgg aacatgtggg ccaaatggac aaaatattca agattccacc acccccagga aagacagggg tccagtctct ccggccactg gaagaggaca ctccaagccc cttggctcct gtttcccagc aaggatggcg cagcatccgg cttttcattt catccacttt ccgagacatg cacggggagc gggacctgct gctgaggtct gtgctgccag cactgcaggc ccgagcggcc cctcaccgta tcagccttca cggaatcgac ctccgctggg gcgtcactga ggaggagacc cgtaggaaca gacaactgga agtgtgcctt ggggaggtgg agaacgcaca gctgtttgtg gggattctgg gctcccgtta tggatacatt ccccccagct acaaccttcc tgaccatcca cacttccact gggcccagca gtacccttca gggcgctctg tgacagagat ggaggtgatg cagttcctga accggaacca acgtctgcag ccctctgccc aagctctcat ctacttccgg gattccagct tcctcagctc tgtgccagat gcctggaaat ctgactttgt ttctgagtct gaagaggccg catgtcggat ctcagaactg aagagctacc taagcagaca gaaagggata acctgccgca gatacccctg tgagtggggg ggtgtggcag ctggccggcc ctatgttggc gggctggagg agtttgggca gttggttctg caggatgtat ggaatatgat ccagaagctc tacctgcagc ctggggccct gctggagcag ccagtgtcca tcccagacga tgacttggtc caggccacct tccagcagct gcagaagcca ccgagtcctg cccggccacg ccttcttcag gacacagtgc aacagctgat gctgccccac ggaaggctga gcctggtgac ggggcagtca ggacagggca agacagcctt cctggcatct cttgtgtcag ccctgcaggc tcctgatggg gccaaggtgg caccattagt cttcttccac ttttctgggg ctcgtcctga ccagggtctt gccctcactc tgctcagacg cctctgtacc tatctgcgtg gccaactaaa agagccaggt gccctcccca gcacctaccg aagcctggtg tgggagctgc agcagaggct gctgcccaag tctgctgagt ccctgcatcc tggccagacc caggtcctga tcatcgatgg ggctgatagg ttagtggacc agaatgggca gctgatttca gactggatcc caaagaagct tccccggtgt gtacacctgg tgctgagtgt gtctagtgat gcaggcctag gggagaccct tgagcagagc cagggtgccc acgtgctggc cttggggcct ctggaggcct ctgctcgggc ccggctggtg agagaggagc tggccctgta cgggaagcgg ctggaggagt caccatttaa caaccagatg cgactgctgc tggtgaagcg ggaatcaggc cggccgctct acctgcgctt ggtcaccgat cacctgaggc tcttcacgct gtatgagcag gtgtctgaga gactccggac cctgcctgcc actgtccccc tgctgctgca gcacatcctg agcacactgg agaaggagca cgggcctgat gtccttcccc aggccttgac tgccctagaa gtcacacgga gtggtttgac tgtggaccag ctgcacggag tgctgagtgt gtggcggaca ctaccgaagg ggactaagag ctgggaagaa gcagtggctg ctggtaacag tggagacccc taccccatgg gcccgtttgc ctgcctcgtc cagagtctgc gcagtttgct aggggagggc cctctggagc gccctggtgc ccggctgtgc ctccctgatg ggcccctgag aacagcagct aaacgttgct atgggaagag gccagggcta gaggacacgg cacacatcct cattgcagct cagctctgga agacatgtga cgctgatgcc tcaggcacct tccgaagttg ccctcctgag gctctgggag acctgcctta ccacctgctc cagagcggga accgtggact tctttcgaag ttccttacca acctccatgt ggtggctgca cacttggaat tgggtctggt ctctcggctc ttggaggccc atgccctcta tgcttcttca gtccccaaag aggaacaaaa gctccccgag gctgacgttg cagtgtttcg caccttcctg aggcagcagg cttcaatcct cagccagtac ccccggctcc tgccccagca ggcagccaac cagcccctgg actcacctct ttgccaccaa gcctcgctgc tctcccggag atggcacctc caacacacac tacgatggct taataaaccc cggaccatga aaaatcagca aagctccagc ctgtctctgg cagtttcctc atcccctact gctgtggcct tctccaccaa tgggcaaaga gcagctgtgg gcactgccaa tgggacagtt tacctgttgg acctgagaac ttggcaggag gagaagtctg tggtgagtgg ctgtgatgga atctctgctt gtttgttcct ctccgatgat acactctttc ttactgcctt cgacgggctc ctggagctct gggacctgca gcatggttgt cgggtgctgc agactaaggc tcaccagtac caaatcactg gctgctgcct gagcccagac tgccggctgc tagccaccgt gtgcttggga ggatgcctaa agctgtggga cacagtccgt gggcagctgg ccttccagca cacctacccc aagtccctga actgtgttgc cttccaccca gaggggcagg taatagccac aggcagctgg gctggcagca tcagcttctt ccaggtggat gggctcaaag tcaccaagga cctgggggca cccggagcct ctatccgtac cttggccttc aatgtgcctg ggggggttgt ggctgtgggc cggctggaca gtatggtgga gctgtgggcc tggcgagaag gggcacggct ggctgccttc cctgcccacc atggctttgt tgctgctgcg cttttcctgc atgcgggttg ccagttactg acggctggag aggatggcaa ggttcaggtg tggtcagggt ctctgggtcg gccccgtggg cacctgggtt ccctttctct ctctcctgcc ctctctgtgg cactcagccc agatggtgat cgggtggctg ttggatatcg agcggatggc attaggatct acaaaatctc ttcaggttcc cagggggctc agggtcaggc actggatgtg gcagtgtccg ccctggcctg gctaagcccc aaggtattgg tgagtggtgc agaagatggg tccttgcagg gctgggcact caaggaatgc tcccttcagt ccctctggct cctgtccaga ttccagaagc ctgtgctagg actggccact tcccaggagc tcttggcttc tgcctcagag gatttcacag tgcagctgtg gccaaggcag ctgctgacgc ggccacacaa ggcagaagac tttccctgtg gcactgagct gcggggacat gagggccctg tgagctgctg tagtttcagc actgatggag gcagcctggc caccgggggc cgggatcgga gtctcctctg ctgggacgtg aggacaccca aaacccctgt tttgatccac tccttccctg cctgtcaccg tgactgggtc actggctgtg cctggaccaa agataaccta ctgatatcct gctccagtga tggctctgtg gggctctggg acccagagtc aggacagcgg cttggtcagt tcctgggtca tcagagtgct gtgagcgctg tggcagctgt ggaggagcac gtggtgtctg tgagccggga tgggaccttg aaagtgtggg accatcaagg cgtggagctg accagcatcc ctgctcactc aggacccatt agccactgtg cagctgccat ggagccccgt gcagctggac agcctgggtc agagcttctg gtggtaaccg tcgggctaga tggggccaca cggttatggc atccactctt ggtgtgccaa acccacaccc tcctgggaca cagcggccca gtccgtgctg ctgctgtttc agaaacctca ggcctcatgc tgaccgcctc tgaggatggt tctgtacggc tctggcaggt tcctaaggaa gcagatgaca catgtatacc aaggagttct gcagccgtca ctgctgtggc ttgggcacca gatggttcca tggcagtatc tggaaatcaa gctggggaac taatcttgtg gcaggaagct aaggctgtgg ccacagcaca ggctccaggc cacattggtg ctctgatctg gtcctcggca cacacctttt ttgtcctcag tgctgatgag aaaatcagcg agtggcaagt gaaactgcgg aagggttcgg cacccggaaa tttgagtctt cacctgaacc gaattctaca ggaggactta ggggtgctga caagtctgga ttgggctcct gatggtcact ttctcatctt ggccaaagca gatttgaagt tactttgcat gaagccaggg gatgctccat ctgaaatctg gagcagctat acagaaaatc ctatgatatt gtccacccac aaggagtatg gcatatttgt cctgcagccc aaggatcctg gagttctttc tttcttgagg caaaaggaat caggagagtt tgaagagagg ctgaactttg atataaactt agagaatcct agtaggaccc taatatcgat aactcaagcc aaacctgaat ctgagtcctc atttttgtgt gccagctctg atgggatcct atggaacctg gccaaatgca gcccagaagg agaatggacc acaggtaaca tgtggcagaa aaaagcaaac actccagaaa cccaaactcc agggacagac ccatctacct gcagggaatc tgatgccagc atggatagtg atgccagcat ggatagtgag ccaacaccac atctaaagac acggcagcgt agaaagattc actcgggctc tgtcacagcc ctccatgtgc tacctgagtt gctggtgaca gcttcgaagg acagagatgt taagctatgg gagagaccca gtatgcagct gctgggcctg ttccgatgcg aagggtcagt gagctgcctg gaaccttggc tgggcgctaa ctccaccctg cagcttgccg tgggagacgt gcagggcaat gtgtactttc tgaattggga atga SEQ ID NO: 13 vRNA, Genbank #AF045143 ggcuggcuuu agcucagcgg uuacuucgac aguucuuuaa uugaaacaag caaccugucu ggguuguucg agacccgcgg gcgcucucca guccuuuu SEQ ID NO:14 vRNA, Genbank #AF045144 ggcuggcuuu agcucagcgg uuacuucgag uacauuguaa ccaccucucu gggugguucg agacccgcgg gugcuuucca gcucuuuu SEQ ID NO: 15 vRNA, Genbank #AF045145 ggcuggcuuu agcucagcgg uuacuucgcg ugucaucaaa ccaccucucu ggguuguucg agacccgcgg gcgcucucca gcccucuu SEQ ID NO: 16 INT protein sequence (residues 1473-1724 of human VPARP protein sequence) Ala Asn Leu Arg Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys Ser Gln Ser Arg Thr Thr Pro Val Asp Leu Cys Leu Leu Glu Glu Ser Val Gly Ser Leu Glu Gly Ser Arg Cys Pro Val Phe Ala Phe Gln Ser Ser Asp Thr Glu Ser Asp Glu Leu Ser Glu Val Leu Gln Asp Ser Cys Phe Leu Gln Ile Lys Cys Asp Thr Lys Asp Asp Ser Ile Pro Cys Phe Leu Glu Leu Lys Glu Glu Asp Glu Ile Val Cys Thr Gln His Trp Gln Asp Ala Val Pro Trp Thr Glu Leu Leu Ser Leu Gln Thr Glu Asp Gly Phe Trp Lys Leu Thr Pro Glu Leu Gly Leu Ile Leu Asn Leu Asn Thr Asn Gly Leu His Ser Phe Leu Lys Gln Lys Gly Ile Gln Ser Leu Gly Val Lys Gly Arg Glu Cys Leu Leu Asp Leu Ile Ala Thr Met Leu Val Leu Gln Phe Ile Arg Thr Arg Leu Glu Lys Glu Gly Ile Val Phe Lys Ser Leu Met Lys Met Asp Asp Pro Ser Ile Ser Arg Asn Ile Pro Trp Ala Phe Glu Ala Ile Lys Gln Ala Ser Glu Trp Val Arg Arg Thr Glu Gly Gln Tyr Pro Ser Ile Cys Pro Arg Leu Glu Leu Gly Asn Asp Trp Asp Ser Ala Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser Thr Val Ser Pro Leu His Arg Val Leu His Tyr Ser Gln Gly

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 22 <210> SEQ ID NO 1 <211> LENGTH: 489 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 tgcacacaac actggcagga tgctgtgcct tggacagaac tcctcagtct acagacagag 60 gatggcttct ggaaacttac accagaactg ggacttatat taaatcttaa tacaaatggt 120 ttgcacagct ttcttaaaca aaaaggcatt caatctctag gtgtaaaagg aagagaatgt 180 ctcctggacc taattgccac aatgctggta ctacagttta ttcgcaccag gttggaaaaa 240 gagggaatag tgttcaaatc actgatgaaa atggatgacc cttctatttc caggaatatt 300 ccctgggctt ttgaggcaat aaagcaagca agtgaatggg taagaagaac tgaaggacag 360 tacccatcta tctgcccacg gcttgaactg gggaacgact gggactctgc caccaagcag 420 ttgctgggac tccagcccat aagcactgtg tcccctcttc atagagtcct ccattacagt 480 caaggctaa 489 <210> SEQ ID NO 2 <211> LENGTH: 162 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Cys Thr Gln His Trp Gln Asp Ala Val Pro Trp Thr Glu Leu Leu Ser 1 5 10 15 Leu Gln Thr Glu Asp Gly Phe Trp Lys Leu Thr Pro Glu Leu Gly Leu 20 25 30 Ile Leu Asn Leu Asn Thr Asn Gly Leu His Ser Phe Leu Lys Gln Lys 35 40 45 Gly Ile Gln Ser Leu Gly Val Lys Gly Arg Glu Cys Leu Leu Asp Leu 50 55 60 Ile Ala Thr Met Leu Val Leu Gln Phe Ile Arg Thr Arg Leu Glu Lys 65 70 75 80 Glu Gly Ile Val Phe Lys Ser Leu Met Lys Met Asp Asp Pro Ser Ile 85 90 95 Ser Arg Asn Ile Pro Trp Ala Phe Glu Ala Ile Lys Gln Ala Ser Glu 100 105 110 Trp Val Arg Arg Thr Glu Gly Gln Tyr Pro Ser Ile Cys Pro Arg Leu 115 120 125 Glu Leu Gly Asn Asp Trp Asp Ser Ala Thr Lys Gln Leu Leu Gly Leu 130 135 140 Gln Pro Ile Ser Thr Val Ser Pro Leu His Arg Val Leu His Tyr Ser 145 150 155 160 Gln Gly <210> SEQ ID NO 3 <211> LENGTH: 1724 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 Met Val Met Gly Ile Phe Ala Asn Cys Ile Phe Cys Leu Lys Val Lys 1 5 10 15 Tyr Leu Pro Gln Gln Gln Lys Lys Lys Leu Gln Thr Asp Ile Lys Glu 20 25 30 Asn Gly Gly Lys Phe Ser Phe Ser Leu Asn Pro Gln Cys Thr His Ile 35 40 45 Ile Leu Asp Asn Ala Asp Val Leu Ser Gln Tyr Gln Leu Asn Ser Ile 50 55 60 Gln Lys Asn His Val His Ile Ala Asn Pro Asp Phe Ile Trp Lys Ser 65 70 75 80 Ile Arg Glu Lys Arg Leu Leu Asp Val Lys Asn Tyr Asp Pro Tyr Lys 85 90 95 Pro Leu Asp Ile Thr Pro Pro Pro Asp Gln Lys Ala Ser Ser Ser Glu 100 105 110 Val Lys Thr Glu Gly Leu Cys Pro Asp Ser Ala Thr Glu Glu Glu Asp 115 120 125 Thr Val Glu Leu Thr Glu Phe Gly Met Gln Asn Val Glu Ile Pro His 130 135 140 Leu Pro Gln Asp Phe Glu Val Ala Lys Tyr Asn Thr Leu Glu Lys Val 145 150 155 160 Gly Met Glu Gly Gly Gln Glu Ala Val Val Val Glu Leu Gln Cys Ser 165 170 175 Arg Asp Ser Arg Asp Cys Pro Phe Leu Ile Ser Ser His Phe Leu Leu 180 185 190 Asp Asp Gly Met Glu Thr Arg Arg Gln Phe Ala Ile Lys Lys Thr Ser 195 200 205 Glu Asp Ala Ser Glu Tyr Phe Glu Asn Tyr Ile Glu Glu Leu Lys Lys 210 215 220 Gln Gly Phe Leu Leu Arg Glu His Phe Thr Pro Glu Ala Thr Gln Leu 225 230 235 240 Ala Ser Glu Gln Leu Gln Ala Leu Leu Leu Glu Glu Val Met Asn Ser 245 250 255 Ser Thr Leu Ser Gln Glu Val Ser Asp Leu Val Glu Met Ile Trp Ala 260 265 270 Glu Ala Leu Gly His Leu Glu His Met Leu Leu Lys Pro Val Asn Arg 275 280 285 Ile Ser Leu Asn Asp Val Ser Lys Ala Glu Gly Ile Leu Leu Leu Val 290 295 300 Lys Ala Ala Leu Lys Asn Gly Glu Thr Ala Glu Gln Leu Gln Lys Met 305 310 315 320 Met Thr Glu Phe Tyr Arg Leu Ile Pro His Lys Gly Thr Met Pro Lys 325 330 335 Glu Val Asn Leu Gly Leu Leu Ala Lys Lys Ala Asp Leu Cys Gln Leu 340 345 350 Ile Arg Asp Met Val Asn Val Cys Glu Thr Asn Leu Ser Lys Pro Asn 355 360 365 Pro Pro Ser Leu Ala Lys Tyr Arg Ala Leu Arg Cys Lys Ile Glu His 370 375 380 Val Glu Gln Asn Thr Glu Glu Phe Leu Arg Val Arg Lys Glu Val Leu 385 390 395 400 Gln Asn His His Ser Lys Ser Pro Val Asp Val Leu Gln Ile Phe Arg 405 410 415 Val Gly Arg Val Asn Glu Thr Thr Glu Phe Leu Ser Lys Leu Gly Asn 420 425 430 Val Arg Pro Leu Leu His Gly Ser Pro Val Gln Asn Ile Val Gly Ile 435 440 445 Leu Cys Arg Gly Leu Leu Leu Pro Lys Val Val Glu Asp Arg Gly Val 450 455 460 Gln Arg Thr Asp Val Gly Asn Leu Gly Ser Gly Ile Tyr Phe Ser Asp 465 470 475 480 Ser Leu Ser Thr Ser Ile Lys Tyr Ser His Pro Gly Glu Thr Asp Gly 485 490 495 Thr Arg Leu Leu Leu Ile Cys Asp Val Ala Leu Gly Lys Cys Met Asp 500 505 510 Leu His Glu Lys Asp Phe Pro Leu Thr Glu Ala Pro Pro Gly Tyr Asp 515 520 525 Ser Val His Gly Val Ser Gln Thr Ala Ser Val Thr Thr Asp Phe Glu 530 535 540 Asp Asp Glu Phe Val Val Tyr Lys Thr Asn Gln Val Lys Met Lys Tyr 545 550 555 560 Ile Ile Lys Phe Ser Met Pro Gly Asp Gln Ile Lys Asp Phe His Pro 565 570 575 Ser Asp His Thr Glu Leu Glu Glu Tyr Arg Pro Glu Phe Ser Asn Phe 580 585 590 Ser Lys Val Glu Asp Tyr Gln Leu Pro Asp Ala Lys Thr Ser Ser Ser 595 600 605 Thr Lys Ala Gly Leu Gln Asp Ala Ser Gly Asn Leu Val Pro Leu Glu 610 615 620 Asp Val His Ile Lys Gly Arg Ile Ile Asp Thr Val Ala Gln Val Ile 625 630 635 640 Val Phe Gln Thr Tyr Thr Asn Lys Ser His Val Pro Ile Glu Ala Lys 645 650 655 Tyr Ile Phe Pro Leu Asp Asp Lys Ala Ala Val Cys Gly Phe Glu Ala 660 665 670 Phe Ile Asn Gly Lys His Ile Val Gly Glu Ile Lys Glu Lys Glu Glu 675 680 685 Ala Gln Gln Glu Tyr Leu Glu Ala Val Thr Gln Gly His Gly Ala Tyr 690 695 700 Leu Met Ser Gln Asp Ala Pro Asp Val Phe Thr Val Ser Val Gly Asn 705 710 715 720 Leu Pro Pro Lys Ala Lys Val Leu Ile Lys Ile Thr Tyr Ile Thr Glu 725 730 735 Leu Ser Ile Leu Gly Thr Val Gly Val Phe Phe Met Pro Ala Thr Val 740 745 750 Ala Pro Trp Gln Gln Asp Lys Ala Leu Asn Glu Asn Leu Gln Asp Thr 755 760 765 Val Glu Lys Ile Cys Ile Lys Glu Ile Gly Thr Lys Gln Ser Phe Ser 770 775 780 Leu Thr Met Ser Ile Glu Met Pro Tyr Val Ile Glu Phe Ile Phe Ser 785 790 795 800 Asp Thr His Glu Leu Lys Gln Lys Arg Thr Asp Cys Lys Ala Val Ile 805 810 815 Ser Thr Met Glu Gly Ser Ser Leu Asp Ser Ser Gly Phe Ser Leu His 820 825 830 Ile Gly Leu Ser Ala Ala Tyr Leu Pro Arg Met Trp Val Glu Lys His 835 840 845 Pro Glu Lys Glu Ser Glu Ala Cys Met Leu Val Phe Gln Pro Asp Leu 850 855 860 Asp Val Asp Leu Pro Asp Leu Ala Ser Glu Ser Glu Val Ile Ile Cys 865 870 875 880 Leu Asp Cys Ser Ser Ser Met Glu Gly Val Thr Phe Leu Gln Ala Lys 885 890 895 Gln Ile Thr Leu His Ala Leu Ser Leu Val Gly Glu Lys Gln Lys Val 900 905 910 Asn Ile Ile Gln Phe Gly Thr Gly Tyr Lys Glu Leu Phe Ser Tyr Pro 915 920 925 Lys His Ile Thr Ser Asn Thr Thr Ala Ala Glu Phe Ile Met Ser Ala 930 935 940 Thr Pro Thr Met Gly Asn Thr Asp Phe Trp Lys Thr Leu Arg Tyr Leu 945 950 955 960 Ser Leu Leu Tyr Pro Ala Arg Gly Ser Arg Asn Ile Leu Leu Val Ser 965 970 975 Asp Gly His Leu Gln Asp Glu Ser Leu Thr Leu Gln Leu Val Lys Arg 980 985 990 Ser Arg Pro His Thr Arg Leu Phe Ala Cys Gly Ile Gly Ser Thr Ala 995 1000 1005 Asn Arg His Val Leu Arg Ile Leu Ser Gln Cys Gly Ala Gly Val 1010 1015 1020 Phe Glu Tyr Phe Asn Ala Lys Ser Lys His Ser Trp Arg Lys Gln 1025 1030 1035 Ile Glu Asp Gln Met Thr Arg Leu Cys Ser Pro Ser Cys His Ser 1040 1045 1050 Val Ser Val Lys Trp Gln Gln Leu Asn Pro Asp Ala Pro Glu Ala 1055 1060 1065 Leu Gln Ala Pro Ala Gln Val Pro Ser Leu Phe Arg Asn Asp Arg 1070 1075 1080 Leu Leu Val Tyr Gly Phe Ile Pro His Cys Thr Gln Ala Thr Leu 1085 1090 1095 Cys Ala Leu Ile Gln Glu Lys Glu Phe Cys Thr Met Val Ser Thr 1100 1105 1110 Thr Glu Leu Gln Lys Thr Thr Gly Thr Met Ile His Lys Leu Ala 1115 1120 1125 Ala Arg Ala Leu Ile Arg Asp Tyr Glu Asp Gly Ile Leu His Glu 1130 1135 1140 Asn Glu Thr Ser His Glu Met Lys Lys Gln Thr Leu Lys Ser Leu 1145 1150 1155 Ile Ile Lys Leu Ser Lys Glu Asn Ser Leu Ile Thr Gln Phe Thr 1160 1165 1170 Ser Phe Val Ala Val Glu Lys Arg Asp Glu Asn Glu Ser Pro Phe 1175 1180 1185 Pro Asp Ile Pro Lys Val Ser Glu Leu Ile Ala Lys Glu Asp Val 1190 1195 1200 Asp Phe Leu Pro Tyr Met Ser Trp Gln Gly Glu Pro Gln Glu Ala 1205 1210 1215 Val Arg Asn Gln Ser Leu Leu Ala Ser Ser Glu Trp Pro Glu Leu 1220 1225 1230 Arg Leu Ser Lys Arg Lys His Arg Lys Ile Pro Phe Ser Lys Arg 1235 1240 1245 Lys Met Glu Leu Ser Gln Pro Glu Val Ser Glu Asp Phe Glu Glu 1250 1255 1260 Asp Gly Leu Gly Val Leu Pro Ala Phe Thr Ser Asn Leu Glu Arg 1265 1270 1275 Gly Gly Val Glu Lys Leu Leu Asp Leu Ser Trp Thr Glu Ser Cys 1280 1285 1290 Lys Pro Thr Ala Thr Glu Pro Leu Phe Lys Lys Val Ser Pro Trp 1295 1300 1305 Glu Thr Ser Thr Ser Ser Phe Phe Pro Ile Leu Ala Pro Ala Val 1310 1315 1320 Gly Ser Tyr Leu Thr Pro Thr Thr Arg Ala His Ser Pro Ala Ser 1325 1330 1335 Leu Ser Phe Ala Ser Tyr Arg Gln Val Ala Ser Phe Gly Ser Ala 1340 1345 1350 Ala Pro Pro Arg Gln Phe Asp Ala Ser Gln Phe Ser Gln Gly Pro 1355 1360 1365 Val Pro Gly Thr Cys Ala Asp Trp Ile Pro Gln Ser Ala Ser Cys 1370 1375 1380 Pro Thr Gly Pro Pro Gln Asn Pro Pro Ser Ala Pro Tyr Cys Gly 1385 1390 1395 Ile Val Phe Ser Gly Ser Ser Leu Ser Ser Ala Gln Ser Ala Pro 1400 1405 1410 Leu Gln His Pro Gly Gly Phe Thr Thr Arg Pro Ser Ala Gly Thr 1415 1420 1425 Phe Pro Glu Leu Asp Ser Pro Gln Leu His Phe Ser Leu Pro Thr 1430 1435 1440 Asp Pro Asp Pro Ile Arg Gly Phe Gly Ser Tyr His Pro Ser Ala 1445 1450 1455 Tyr Ser Pro Phe His Phe Gln Pro Ser Ala Ala Ser Leu Thr Ala 1460 1465 1470 Asn Leu Arg Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys 1475 1480 1485 Ser Gln Ser Arg Thr Thr Pro Val Asp Leu Cys Leu Leu Glu Glu 1490 1495 1500 Ser Val Gly Ser Leu Glu Gly Ser Arg Cys Pro Val Phe Ala Phe 1505 1510 1515 Gln Ser Ser Asp Thr Glu Ser Asp Glu Leu Ser Glu Val Leu Gln 1520 1525 1530 Asp Ser Cys Phe Leu Gln Ile Lys Cys Asp Thr Lys Asp Asp Ser 1535 1540 1545 Ile Pro Cys Phe Leu Glu Leu Lys Glu Glu Asp Glu Ile Val Cys 1550 1555 1560 Thr Gln His Trp Gln Asp Ala Val Pro Trp Thr Glu Leu Leu Ser 1565 1570 1575 Leu Gln Thr Glu Asp Gly Phe Trp Lys Leu Thr Pro Glu Leu Gly 1580 1585 1590 Leu Ile Leu Asn Leu Asn Thr Asn Gly Leu His Ser Phe Leu Lys 1595 1600 1605 Gln Lys Gly Ile Gln Ser Leu Gly Val Lys Gly Arg Glu Cys Leu 1610 1615 1620 Leu Asp Leu Ile Ala Thr Met Leu Val Leu Gln Phe Ile Arg Thr 1625 1630 1635 Arg Leu Glu Lys Glu Gly Ile Val Phe Lys Ser Leu Met Lys Met 1640 1645 1650 Asp Asp Pro Ser Ile Ser Arg Asn Ile Pro Trp Ala Phe Glu Ala 1655 1660 1665 Ile Lys Gln Ala Ser Glu Trp Val Arg Arg Thr Glu Gly Gln Tyr 1670 1675 1680 Pro Ser Ile Cys Pro Arg Leu Glu Leu Gly Asn Asp Trp Asp Ser 1685 1690 1695 Ala Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser Thr Val Ser 1700 1705 1710 Pro Leu His Arg Val Leu His Tyr Ser Gln Gly 1715 1720 <210> SEQ ID NO 4 <400> SEQUENCE: 4 000 <210> SEQ ID NO 5 <211> LENGTH: 5175 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5 atggtgatgg gaatctttgc aaattgtatc ttctgtttga aagtgaagta cttacctcag 60 cagcagaaga aaaagctaca aactgacatt aaggaaaatg gcggaaagtt ttccttttcg 120 ttaaatcctc agtgcacaca tataatctta gataatgctg atgttctgag tcagtaccaa 180 ctgaattcta tccaaaagaa ccacgttcat attgcaaacc cagattttat atggaaatct 240 atcagagaaa agagactctt ggatgtaaag aattatgatc cttataagcc cctggacatc 300 acaccacctc ctgatcagaa ggcgagcagt tctgaagtga aaacagaagg tctatgcccg 360 gacagtgcca cagaggagga agacactgtg gaactcactg agtttggtat gcagaatgtt 420 gaaattcctc atcttcctca agattttgaa gttgcaaaat ataacacctt ggagaaagtg 480 ggaatggagg gaggccagga agctgtggtg gtggagcttc agtgttcgcg ggactccagg 540 gactgtcctt tcctgatatc ctcacacttc ctcctggatg atggcatgga gactagaaga 600 cagtttgcta taaagaaaac ctctgaagat gcaagtgaat actttgaaaa ttacattgaa 660 gaactgaaga aacaaggatt tctactaaga gaacatttca cacctgaagc aacccaatta 720 gcatctgaac aattgcaagc attgcttttg gaggaagtca tgaattcaag cactctgagc 780 caagaggtga gcgatttagt agagatgatt tgggcagagg ccctgggcca cctggaacac 840 atgcttctca agccagtgaa caggattagc ctcaacgatg tgagcaaggc agaggggatt 900 ctccttctag taaaggcagc actgaaaaat ggagaaacag cagagcaatt gcaaaagatg 960 atgacagagt tttacagact gatacctcac aaaggcacaa tgcccaaaga agtgaacctg 1020 ggactattgg ctaagaaagc agacctctgc cagctaataa gagacatggt taatgtctgt 1080 gaaactaatt tgtccaaacc caacccacca tccctggcca aataccgagc tttgaggtgc 1140 aaaattgagc atgttgaaca gaatactgaa gaatttctca gggttagaaa agaggttttg 1200 cagaatcatc acagtaagag cccagtggat gtcttgcaga tatttagagt tggcagagtg 1260 aatgaaacca cagagttttt gagcaaactt ggtaatgtga ggcccttgtt gcatggttct 1320 cctgtacaaa acatcgtggg aatcttgtgt cgagggttgc ttttacccaa agtagtggaa 1380 gatcgtggtg tgcaaagaac agacgtcgga aaccttggaa gtgggattta tttcagtgat 1440 tcgctcagta caagtatcaa gtactcacac ccgggagaga cagatggcac cagactcctg 1500 ctcatttgtg acgtagccct cggaaagtgt atggacttac atgagaagga ctttccctta 1560 actgaagcac caccaggcta cgacagtgtg catggagttt cacaaacagc ctctgtcacc 1620 acagactttg aggatgatga atttgttgtc tataaaacca atcaggttaa aatgaaatat 1680 attattaaat tttccatgcc tggagatcag ataaaggact ttcatcctag tgatcatact 1740 gaattagagg aatacagacc tgagttttca aatttttcaa aggttgaaga ttaccagtta 1800 ccagatgcca aaacttccag cagcaccaag gccggcctcc aggatgcctc tgggaacttg 1860 gttcctctgg aggatgtcca catcaaaggg agaatcatag acactgtagc ccaggtcatt 1920 gtttttcaga catacacaaa taaaagtcac gtgcccattg aggcaaaata tatctttcct 1980 ttggatgaca aggccgctgt gtgtggcttc gaagccttca tcaatgggaa gcacatagtt 2040 ggagagatta aagagaagga agaagcccag caagagtacc tagaagccgt gacccagggc 2100 catggcgctt acctgatgag tcaggatgct ccggacgttt ttactgtaag tgttggaaac 2160 ttacccccta aggctaaggt tcttataaaa attacctaca tcacagaact cagcatcctg 2220 ggcactgttg gtgtcttttt catgcccgcc accgtagcac cctggcaaca ggacaaggct 2280 ttgaatgaaa accttcagga tacagtagag aagatttgta taaaagaaat aggaacaaag 2340 caaagcttct ctttgactat gtctattgag atgccgtatg tgattgaatt cattttcagt 2400 gatacacatg aactgaaaca aaagcgcaca gactgcaaag ctgtcattag caccatggaa 2460 ggcagctcct tagacagcag tggattttct ctccacatcg gtttgtctgc tgcctatctc 2520 ccaagaatgt gggttgaaaa acatccagaa aaagaaagcg aggcttgcat gcttgtcttt 2580 caacccgatc tcgatgtcga cctccctgac ctagccagtg agagcgaagt gattatttgt 2640 cttgactgct ccagttccat ggagggtgtg acattcttgc aagccaagca aatcaccttg 2700 catgcgctgt ccttggtggg tgagaagcag aaagtaaata ttatccagtt cggcacaggt 2760 tacaaggagc tattttcgta tcctaagcat atcacaagca ataccacggc agcagagttc 2820 atcatgtctg ccacacctac catggggaac acagacttct ggaaaacact ccgatatctt 2880 agcttattgt accctgctcg agggtcacgg aacatcctcc tggtgtctga tgggcacctc 2940 caggatgaga gcctgacatt acagctcgtg aagaggagcc gcccgcacac caggttattc 3000 gcctgcggta tcggttctac agcaaatcgt cacgtcttaa ggattttgtc ccagtgtggt 3060 gccggagtat ttgaatattt taatgcaaaa tccaagcata gttggagaaa acagatagaa 3120 gaccaaatga ccaggctatg ttctccgagt tgccactctg tctccgtcaa atggcagcaa 3180 ctcaatccag atgcgcccga ggccctgcag gccccagccc aggtgccatc cttgtttcgc 3240 aatgatcgac tccttgtcta tggattcatt cctcactgca cacaagcaac tctgtgtgca 3300 ctaattcaag agaaagaatt ttgtacaatg gtgtcgacta ctgagcttca gaagacaact 3360 ggaactatga tccacaagct ggcagcccga gctctaatca gagattatga agatggcatt 3420 cttcacgaaa atgaaaccag tcatgagatg aaaaaacaaa ccttgaaatc tctgattatt 3480 aaactcagta aagaaaactc tctcataaca caatttacaa gctttgtggc agttgagaaa 3540 agggatgaga atgagtcgcc ttttcctgat attccaaaag tttctgaact tattgccaaa 3600 gaagatgtag acttcctgcc ctacatgagc tggcaggggg agccccaaga agccgtcagg 3660 aaccagtctc ttttagcatc ctctgagtgg ccagaattac gtttatccaa acgaaaacat 3720 aggaaaattc cattttccaa aagaaaaatg gaattatctc agccagaagt ttctgaagat 3780 tttgaagagg atggcttagg tgtactacca gctttcacat caaatttgga acgtggaggt 3840 gtggaaaagc tattggattt aagttggaca gagtcatgta aaccaacagc aactgaacca 3900 ctatttaaga aagtcagtcc atgggaaaca tctacttcta gcttttttcc tattttggct 3960 ccggccgttg gttcctatct taccccgact acccgcgctc acagtcctgc ttccttgtct 4020 tttgcctcat atcgtcaggt agctagtttc ggttcagctg ctcctcccag acagtttgat 4080 gcatctcaat tcagccaagg ccctgtgcct ggcacttgtg ctgactggat cccacagtcg 4140 gcgtcttgtc ccacaggacc tccccagaac ccaccttctg caccctattg tggcattgtt 4200 ttttcaggga gctcattaag ctctgcacag tctgctccac tgcaacatcc tggaggcttt 4260 actaccaggc cttctgctgg caccttccct gagctggatt ctccccagct tcatttctct 4320 cttcctacag accctgatcc catcagaggt tttgggtctt atcatccctc tgcttactct 4380 ccttttcatt ttcaaccttc cgcagcctct ttgactgcca accttaggct gccaatggcc 4440 tctgctttac ctgaggctct ttgcagtcag tcccggacta ccccagtaga tctctgtctt 4500 ctagaagaat cagtaggcag tctcgaagga agtcgatgtc ctgtctttgc ttttcaaagt 4560 tctgacacag aaagtgatga gctatcagaa gtacttcaag acagctgctt tttacaaata 4620 aagtgtgata caaaagatga cagtatcccg tgctttctgg aattaaaaga agaggatgaa 4680 atagtgtgca cacaacactg gcaggatgct gtgccttgga cagaactcct cagtctacag 4740 acagaggatg gcttctggaa acttacacca gaactgggac ttatattaaa tcttaataca 4800 aatggtttgc acagctttct taaacaaaaa ggcattcaat ctctaggtgt aaaaggaaga 4860 gaatgtctcc tggacctaat tgccacaatg ctggtactac agtttattcg caccaggttg 4920 gaaaaagagg gaatagtgtt caaatcactg atgaaaatgg atgacccttc tatttccagg 4980 aatattccct gggcttttga ggcaataaag caagcaagtg aatgggtaag aagaactgaa 5040 ggacagtacc catctatctg cccacggctt gaactgggga acgactggga ctctgccacc 5100 aagcagttgc tgggactcca gcccataagc actgtgtccc ctcttcatag agtcctccat 5160 tacagtcaag gctaa 5175 <210> SEQ ID NO 6 <211> LENGTH: 893 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Met Ala Thr Glu Glu Phe Ile Ile Arg Ile Pro Pro Tyr His Tyr Ile 1 5 10 15 His Val Leu Asp Gln Asn Ser Asn Val Ser Arg Val Glu Val Gly Pro 20 25 30 Lys Thr Tyr Ile Arg Gln Asp Asn Glu Arg Val Leu Phe Ala Pro Met 35 40 45 Arg Met Val Thr Val Pro Pro Arg His Tyr Cys Thr Val Ala Asn Pro 50 55 60 Val Ser Arg Asp Ala Gln Gly Leu Val Leu Phe Asp Val Thr Gly Gln 65 70 75 80 Val Arg Leu Arg His Ala Asp Leu Glu Ile Arg Leu Ala Gln Asp Pro 85 90 95 Phe Pro Leu Tyr Pro Gly Glu Val Leu Glu Lys Asp Ile Thr Pro Leu 100 105 110 Gln Val Val Leu Pro Asn Thr Ala Leu His Leu Lys Ala Leu Leu Asp 115 120 125 Phe Glu Asp Lys Asp Gly Asp Lys Val Val Ala Gly Asp Glu Trp Leu 130 135 140 Phe Glu Gly Pro Gly Thr Tyr Ile Pro Arg Lys Glu Val Glu Val Val 145 150 155 160 Glu Ile Ile Gln Ala Thr Ile Ile Arg Gln Asn Gln Ala Leu Arg Leu 165 170 175 Arg Ala Arg Lys Glu Cys Trp Asp Arg Asp Gly Lys Glu Arg Val Thr 180 185 190 Gly Glu Glu Trp Leu Val Thr Thr Val Gly Ala Tyr Leu Pro Ala Val 195 200 205 Phe Glu Glu Val Leu Asp Leu Val Asp Ala Val Ile Leu Thr Glu Lys 210 215 220 Thr Ala Leu His Leu Arg Ala Arg Arg Asn Phe Arg Asp Phe Arg Gly 225 230 235 240 Val Ser Arg Arg Thr Gly Glu Glu Trp Leu Val Thr Val Gln Asp Thr 245 250 255 Glu Ala His Val Pro Asp Val His Glu Glu Val Leu Gly Val Val Pro 260 265 270 Ile Thr Thr Leu Gly Pro His Asn Tyr Cys Val Ile Leu Asp Pro Val 275 280 285 Gly Pro Asp Gly Lys Asn Gln Leu Gly Gln Lys Arg Val Val Lys Gly 290 295 300 Glu Lys Ser Phe Phe Leu Gln Pro Gly Glu Gln Leu Glu Gln Gly Ile 305 310 315 320 Gln Asp Val Tyr Val Leu Ser Glu Gln Gln Gly Leu Leu Leu Arg Ala 325 330 335 Leu Gln Pro Leu Glu Glu Gly Glu Asp Glu Glu Lys Val Ser His Gln 340 345 350 Ala Gly Asp His Trp Leu Ile Arg Gly Pro Leu Glu Tyr Val Pro Ser 355 360 365 Ala Lys Val Glu Val Val Glu Glu Arg Gln Ala Ile Pro Leu Asp Glu 370 375 380 Asn Glu Gly Ile Tyr Val Gln Asp Val Lys Thr Gly Lys Val Arg Ala 385 390 395 400 Val Ile Gly Ser Thr Tyr Met Leu Thr Gln Asp Glu Val Leu Trp Glu 405 410 415 Lys Glu Leu Pro Pro Gly Val Glu Glu Leu Leu Asn Lys Gly Gln Asp 420 425 430 Pro Leu Ala Asp Arg Gly Glu Lys Asp Thr Ala Lys Ser Leu Gln Pro 435 440 445 Leu Ala Pro Arg Asn Lys Thr Arg Val Val Ser Tyr Arg Val Pro His 450 455 460 Asn Ala Ala Val Gln Val Tyr Asp Tyr Arg Glu Lys Arg Ala Arg Val 465 470 475 480 Val Phe Gly Pro Glu Leu Val Ser Leu Gly Pro Glu Glu Gln Phe Thr 485 490 495 Val Leu Ser Leu Ser Ala Gly Arg Pro Lys Arg Pro His Ala Arg Arg 500 505 510 Ala Leu Cys Leu Leu Leu Gly Pro Asp Phe Phe Thr Asp Val Ile Thr 515 520 525 Ile Glu Thr Ala Asp His Ala Arg Leu Gln Leu Gln Leu Ala Tyr Asn 530 535 540 Trp His Phe Glu Val Asn Asp Arg Lys Asp Pro Gln Glu Thr Ala Lys 545 550 555 560 Leu Phe Ser Val Pro Asp Phe Val Gly Asp Ala Cys Lys Ala Ile Ala 565 570 575 Ser Arg Val Arg Gly Ala Val Ala Ser Val Thr Phe Asp Asp Phe His 580 585 590 Lys Asn Ser Ala Arg Ile Ile Arg Thr Ala Val Phe Gly Phe Glu Thr 595 600 605 Ser Glu Ala Lys Gly Pro Asp Gly Met Ala Leu Pro Arg Pro Arg Asp 610 615 620 Gln Ala Val Phe Pro Gln Asn Gly Leu Val Val Ser Ser Val Asp Val 625 630 635 640 Gln Ser Val Glu Pro Val Asp Gln Arg Thr Arg Asp Ala Leu Gln Arg 645 650 655 Ser Val Gln Leu Ala Ile Glu Ile Thr Thr Asn Ser Gln Glu Ala Ala 660 665 670 Ala Lys His Glu Ala Gln Arg Leu Glu Gln Glu Ala Arg Gly Arg Leu 675 680 685 Glu Arg Gln Lys Ile Leu Asp Gln Ser Glu Ala Glu Lys Ala Arg Lys 690 695 700 Glu Leu Leu Glu Leu Glu Ala Leu Ser Met Ala Val Glu Ser Thr Gly 705 710 715 720 Thr Ala Lys Ala Glu Ala Glu Ser Arg Ala Glu Ala Ala Arg Ile Glu 725 730 735 Gly Glu Gly Ser Val Leu Gln Ala Lys Leu Lys Ala Gln Ala Leu Ala 740 745 750 Ile Glu Thr Glu Ala Glu Leu Gln Arg Val Gln Lys Val Arg Glu Leu 755 760 765 Glu Leu Val Tyr Ala Arg Ala Gln Leu Glu Leu Glu Val Ser Lys Ala 770 775 780 Gln Gln Leu Ala Glu Val Glu Val Lys Lys Phe Lys Gln Met Thr Glu 785 790 795 800 Ala Ile Gly Pro Ser Thr Ile Arg Asp Leu Ala Val Ala Gly Pro Glu 805 810 815 Met Gln Val Lys Leu Leu Gln Ser Leu Gly Leu Lys Ser Thr Leu Ile 820 825 830 Thr Asp Gly Ser Thr Pro Ile Asn Leu Phe Asn Thr Ala Phe Gly Leu 835 840 845 Leu Gly Met Gly Pro Glu Gly Gln Pro Leu Gly Arg Arg Val Ala Ser 850 855 860 Gly Pro Ser Pro Gly Glu Gly Ile Ser Pro Gln Ser Ala Gln Ala Pro 865 870 875 880 Gln Ala Pro Gly Asp Asn His Val Val Pro Val Leu Arg 885 890 <210> SEQ ID NO 7 <211> LENGTH: 2682 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 atggcaactg aagagttcat catccgcatc cccccatacc actatatcca tgtgctggac 60 cagaacagca acgtgtcccg tgtggaggtc gggccaaaga cctacatccg gcaggacaat 120 gagagggtac tgtttgcccc catgcgcatg gtgaccgtcc ccccacgtca ctactgcaca 180 gtggccaacc ctgtgtctcg ggatgcccag ggcttggtgc tgtttgatgt cacagggcaa 240 gttcggcttc gccacgctga cctcgagatc cggctggccc aggacccctt ccccctgtac 300 ccaggggagg tgctggaaaa ggacatcaca cccctgcagg tggttctgcc caacactgcc 360 ctccatctaa aggcgctgct tgattttgag gataaagatg gagacaaggt ggtggcagga 420 gatgagtggc ttttcgaggg acctggcacg tacatccccc ggaaggaagt ggaggtcgtg 480 gagatcattc aggccaccat catcaggcag aaccaggctc tgcggctcag ggcccgcaag 540 gagtgctggg accgggacgg caaggagagg gtgacagggg aagaatggct ggtcaccaca 600 gtaggggcgt acctcccagc ggtgtttgag gaggttctgg atttggtgga cgccgtcatc 660 cttacggaaa agacagccct gcacctccgg gctcggcgga acttccggga cttcagggga 720 gtgtcccgcc gcactgggga ggagtggctg gtaacagtgc aggacacaga ggcccacgtg 780 ccagatgtcc acgaggaggt gctgggggtt gtgcccatca ccaccctggg cccccacaac 840 tactgcgtga ttctcgaccc tgtcggaccg gatggcaaga atcagctggg gcagaagcgc 900 gtggtcaagg gagagaagtc ttttttcctc cagccaggag agcagctgga acaaggcatc 960 caggatgtgt atgtgctgtc ggagcagcag gggctgctgc tgagggccct gcagcccctg 1020 gaggaggggg aggatgagga gaaggtctca caccaggctg gggaccactg gctcatccgc 1080 ggacccctgg agtatgtgcc atctgccaaa gtggaggtgg tggaggagcg ccaggccatc 1140 cctctagacg agaacgaggg catctatgtg caggatgtca agaccggaaa ggtgcgcgct 1200 gtgattggaa gcacctacat gctgacccag gacgaagtcc tgtgggagaa agagctgcct 1260 cccggggtgg aggagctgct gaacaagggg caggaccctc tggcagacag gggtgagaag 1320 gacacagcta agagcctcca gcccttggcg ccccggaaca agacccgtgt ggtcagctac 1380 cgcgtgcccc acaacgctgc ggtgcaggtg tacgactacc gagagaagcg agcccgcgtg 1440 gtcttcgggc ctgagctggt gtcgctgggt cctgaggagc agttcacagt gttgtccctc 1500 tcagctgggc ggcccaagcg tccccatgcc cgccgtgcgc tctgcctgct gctggggcct 1560 gacttcttca cagacgtcat caccatcgaa acggcggatc atgccaggct gcaactgcag 1620 ctggcctaca actggcactt tgaggtgaat gaccggaagg acccccaaga gacggccaag 1680 ctcttttcag tgccagactt tgtaggtgat gcctgcaaag ccatcgcatc ccgggtgcgg 1740 ggggccgtgg cctctgtcac tttcgatgac ttccataaga actcagcccg catcattcgc 1800 actgctgtct ttggctttga gacctcggaa gcgaagggcc ccgatggcat ggccctgccc 1860 aggccccggg accaggctgt cttcccccaa aacgggctgg tggtcagcag tgtggacgtg 1920 cagtcagtgg agcctgtgga tcagaggacc cgggacgccc tgcaacgcag cgtccagctg 1980 gccatcgaga tcaccaccaa ctcccaggaa gcggcggcca agcatgaggc tcagagactg 2040 gagcaggaag cccgcggccg gcttgagcgg cagaagatcc tggaccagtc agaagccgag 2100 aaagctcgca aggaactttt ggagctggag gctctgagca tggccgtgga gagcaccggg 2160 actgccaagg cggaggccga gtcccgtgcg gaggcagccc ggattgaggg agaagggtcc 2220 gtgctgcagg ccaagctaaa agcacaggcc ttggccattg aaacggaggc tgagctccag 2280 agggtccaga aggtccgaga gctggaactg gtctatgccc gggcccagct ggagctggag 2340 gtgagcaagg ctcagcagct ggctgaggtg gaggtgaaga agttcaagca gatgacagag 2400 gccataggcc ccagcaccat cagggacctt gctgtggctg ggcctgagat gcaggtaaaa 2460 ctgctccagt ccctgggcct gaaatcaacc ctcatcaccg atggctccac tcccatcaac 2520 ctcttcaaca cagcctttgg gctgctgggg atggggcccg agggtcagcc cctgggcaga 2580 agggtggcca gtgggcccag ccctggggag gggatatccc cccagtctgc tcaggcccct 2640 caagctcctg gagacaacca cgtggtgcct gtactgcgct aa 2682 <210> SEQ ID NO 8 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 8 Met Ala Gly Cys Gly Cys Pro Cys Gly Cys Gly Ala 1 5 10 <210> SEQ ID NO 9 <211> LENGTH: 905 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 9 Met Ala Gly Cys Gly Cys Pro Cys Gly Cys Gly Ala Met Ala Thr Glu 1 5 10 15 Glu Phe Ile Ile Arg Ile Pro Pro Tyr His Tyr Ile His Val Leu Asp 20 25 30 Gln Asn Ser Asn Val Ser Arg Val Glu Val Gly Pro Lys Thr Tyr Ile 35 40 45 Arg Gln Asp Asn Glu Arg Val Leu Phe Ala Pro Met Arg Met Val Thr 50 55 60 Val Pro Pro Arg His Tyr Cys Thr Val Ala Asn Pro Val Ser Arg Asp 65 70 75 80 Ala Gln Gly Leu Val Leu Phe Asp Val Thr Gly Gln Val Arg Leu Arg 85 90 95 His Ala Asp Leu Glu Ile Arg Leu Ala Gln Asp Pro Phe Pro Leu Tyr 100 105 110 Pro Gly Glu Val Leu Glu Lys Asp Ile Thr Pro Leu Gln Val Val Leu 115 120 125 Pro Asn Thr Ala Leu His Leu Lys Ala Leu Leu Asp Phe Glu Asp Lys 130 135 140 Asp Gly Asp Lys Val Val Ala Gly Asp Glu Trp Leu Phe Glu Gly Pro 145 150 155 160 Gly Thr Tyr Ile Pro Arg Lys Glu Val Glu Val Val Glu Ile Ile Gln 165 170 175 Ala Thr Ile Ile Arg Gln Asn Gln Ala Leu Arg Leu Arg Ala Arg Lys 180 185 190 Glu Cys Trp Asp Arg Asp Gly Lys Glu Arg Val Thr Gly Glu Glu Trp 195 200 205 Leu Val Thr Thr Val Gly Ala Tyr Leu Pro Ala Val Phe Glu Glu Val 210 215 220 Leu Asp Leu Val Asp Ala Val Ile Leu Thr Glu Lys Thr Ala Leu His 225 230 235 240 Leu Arg Ala Arg Arg Asn Phe Arg Asp Phe Arg Gly Val Ser Arg Arg 245 250 255 Thr Gly Glu Glu Trp Leu Val Thr Val Gln Asp Thr Glu Ala His Val 260 265 270 Pro Asp Val His Glu Glu Val Leu Gly Val Val Pro Ile Thr Thr Leu 275 280 285 Gly Pro His Asn Tyr Cys Val Ile Leu Asp Pro Val Gly Pro Asp Gly 290 295 300 Lys Asn Gln Leu Gly Gln Lys Arg Val Val Lys Gly Glu Lys Ser Phe 305 310 315 320 Phe Leu Gln Pro Gly Glu Gln Leu Glu Gln Gly Ile Gln Asp Val Tyr 325 330 335 Val Leu Ser Glu Gln Gln Gly Leu Leu Leu Arg Ala Leu Gln Pro Leu 340 345 350 Glu Glu Gly Glu Asp Glu Glu Lys Val Ser His Gln Ala Gly Asp His 355 360 365 Trp Leu Ile Arg Gly Pro Leu Glu Tyr Val Pro Ser Ala Lys Val Glu 370 375 380 Val Val Glu Glu Arg Gln Ala Ile Pro Leu Asp Glu Asn Glu Gly Ile 385 390 395 400 Tyr Val Gln Asp Val Lys Thr Gly Lys Val Arg Ala Val Ile Gly Ser 405 410 415 Thr Tyr Met Leu Thr Gln Asp Glu Val Leu Trp Glu Lys Glu Leu Pro 420 425 430 Pro Gly Val Glu Glu Leu Leu Asn Lys Gly Gln Asp Pro Leu Ala Asp 435 440 445 Arg Gly Glu Lys Asp Thr Ala Lys Ser Leu Gln Pro Leu Ala Pro Arg 450 455 460 Asn Lys Thr Arg Val Val Ser Tyr Arg Val Pro His Asn Ala Ala Val 465 470 475 480 Gln Val Tyr Asp Tyr Arg Glu Lys Arg Ala Arg Val Val Phe Gly Pro 485 490 495 Glu Leu Val Ser Leu Gly Pro Glu Glu Gln Phe Thr Val Leu Ser Leu 500 505 510 Ser Ala Gly Arg Pro Lys Arg Pro His Ala Arg Arg Ala Leu Cys Leu 515 520 525 Leu Leu Gly Pro Asp Phe Phe Thr Asp Val Ile Thr Ile Glu Thr Ala 530 535 540 Asp His Ala Arg Leu Gln Leu Gln Leu Ala Tyr Asn Trp His Phe Glu 545 550 555 560 Val Asn Asp Arg Lys Asp Pro Gln Glu Thr Ala Lys Leu Phe Ser Val 565 570 575 Pro Asp Phe Val Gly Asp Ala Cys Lys Ala Ile Ala Ser Arg Val Arg 580 585 590 Gly Ala Val Ala Ser Val Thr Phe Asp Asp Phe His Lys Asn Ser Ala 595 600 605 Arg Ile Ile Arg Thr Ala Val Phe Gly Phe Glu Thr Ser Glu Ala Lys 610 615 620 Gly Pro Asp Gly Met Ala Leu Pro Arg Pro Arg Asp Gln Ala Val Phe 625 630 635 640 Pro Gln Asn Gly Leu Val Val Ser Ser Val Asp Val Gln Ser Val Glu 645 650 655 Pro Val Asp Gln Arg Thr Arg Asp Ala Leu Gln Arg Ser Val Gln Leu 660 665 670 Ala Ile Glu Ile Thr Thr Asn Ser Gln Glu Ala Ala Ala Lys His Glu 675 680 685 Ala Gln Arg Leu Glu Gln Glu Ala Arg Gly Arg Leu Glu Arg Gln Lys 690 695 700 Ile Leu Asp Gln Ser Glu Ala Glu Lys Ala Arg Lys Glu Leu Leu Glu 705 710 715 720 Leu Glu Ala Leu Ser Met Ala Val Glu Ser Thr Gly Thr Ala Lys Ala 725 730 735 Glu Ala Glu Ser Arg Ala Glu Ala Ala Arg Ile Glu Gly Glu Gly Ser 740 745 750 Val Leu Gln Ala Lys Leu Lys Ala Gln Ala Leu Ala Ile Glu Thr Glu 755 760 765 Ala Glu Leu Gln Arg Val Gln Lys Val Arg Glu Leu Glu Leu Val Tyr 770 775 780 Ala Arg Ala Gln Leu Glu Leu Glu Val Ser Lys Ala Gln Gln Leu Ala 785 790 795 800 Glu Val Glu Val Lys Lys Phe Lys Gln Met Thr Glu Ala Ile Gly Pro 805 810 815 Ser Thr Ile Arg Asp Leu Ala Val Ala Gly Pro Glu Met Gln Val Lys 820 825 830 Leu Leu Gln Ser Leu Gly Leu Lys Ser Thr Leu Ile Thr Asp Gly Ser 835 840 845 Thr Pro Ile Asn Leu Phe Asn Thr Ala Phe Gly Leu Leu Gly Met Gly 850 855 860 Pro Glu Gly Gln Pro Leu Gly Arg Arg Val Ala Ser Gly Pro Ser Pro 865 870 875 880 Gly Glu Gly Ile Ser Pro Gln Ser Ala Gln Ala Pro Gln Ala Pro Gly 885 890 895 Asp Asn His Val Val Pro Val Leu Arg 900 905 <210> SEQ ID NO 10 <211> LENGTH: 2718 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 10 atggcaggct gcggttgtcc atgcggttgt ggcgccatgg caactgaaga gttcatcatc 60 cgcatccccc cataccacta tatccatgtg ctggaccaga acagcaacgt gtcccgtgtg 120 gaggtcgggc caaagaccta catccggcag gacaatgaga gggtactgtt tgcccccatg 180 cgcatggtga ccgtcccccc acgtcactac tgcacagtgg ccaaccctgt gtctcgggat 240 gcccagggct tggtgctgtt tgatgtcaca gggcaagttc ggcttcgcca cgctgacctc 300 gagatccggc tggcccagga ccccttcccc ctgtacccag gggaggtgct ggaaaaggac 360 atcacacccc tgcaggtggt tctgcccaac actgccctcc atctaaaggc gctgcttgat 420 tttgaggata aagatggaga caaggtggtg gcaggagatg agtggctttt cgagggacct 480 ggcacgtaca tcccccggaa ggaagtggag gtcgtggaga tcattcaggc caccatcatc 540 aggcagaacc aggctctgcg gctcagggcc cgcaaggagt gctgggaccg ggacggcaag 600 gagagggtga caggggaaga atggctggtc accacagtag gggcgtacct cccagcggtg 660 tttgaggagg ttctggattt ggtggacgcc gtcatcctta cggaaaagac agccctgcac 720 ctccgggctc ggcggaactt ccgggacttc aggggagtgt cccgccgcac tggggaggag 780 tggctggtaa cagtgcagga cacagaggcc cacgtgccag atgtccacga ggaggtgctg 840 ggggttgtgc ccatcaccac cctgggcccc cacaactact gcgtgattct cgaccctgtc 900 ggaccggatg gcaagaatca gctggggcag aagcgcgtgg tcaagggaga gaagtctttt 960 ttcctccagc caggagagca gctggaacaa ggcatccagg atgtgtatgt gctgtcggag 1020 cagcaggggc tgctgctgag ggccctgcag cccctggagg agggggagga tgaggagaag 1080 gtctcacacc aggctgggga ccactggctc atccgcggac ccctggagta tgtgccatct 1140 gccaaagtgg aggtggtgga ggagcgccag gccatccctc tagacgagaa cgagggcatc 1200 tatgtgcagg atgtcaagac cggaaaggtg cgcgctgtga ttggaagcac ctacatgctg 1260 acccaggacg aagtcctgtg ggagaaagag ctgcctcccg gggtggagga gctgctgaac 1320 aaggggcagg accctctggc agacaggggt gagaaggaca cagctaagag cctccagccc 1380 ttggcgcccc ggaacaagac ccgtgtggtc agctaccgcg tgccccacaa cgctgcggtg 1440 caggtgtacg actaccgaga gaagcgagcc cgcgtggtct tcgggcctga gctggtgtcg 1500 ctgggtcctg aggagcagtt cacagtgttg tccctctcag ctgggcggcc caagcgtccc 1560 catgcccgcc gtgcgctctg cctgctgctg gggcctgact tcttcacaga cgtcatcacc 1620 atcgaaacgg cggatcatgc caggctgcaa ctgcagctgg cctacaactg gcactttgag 1680 gtgaatgacc ggaaggaccc ccaagagacg gccaagctct tttcagtgcc agactttgta 1740 ggtgatgcct gcaaagccat cgcatcccgg gtgcgggggg ccgtggcctc tgtcactttc 1800 gatgacttcc ataagaactc agcccgcatc attcgcactg ctgtctttgg ctttgagacc 1860 tcggaagcga agggccccga tggcatggcc ctgcccaggc cccgggacca ggctgtcttc 1920 ccccaaaacg ggctggtggt cagcagtgtg gacgtgcagt cagtggagcc tgtggatcag 1980 aggacccggg acgccctgca acgcagcgtc cagctggcca tcgagatcac caccaactcc 2040 caggaagcgg cggccaagca tgaggctcag agactggagc aggaagcccg cggccggctt 2100 gagcggcaga agatcctgga ccagtcagaa gccgagaaag ctcgcaagga acttttggag 2160 ctggaggctc tgagcatggc cgtggagagc accgggactg ccaaggcgga ggccgagtcc 2220 cgtgcggagg cagcccggat tgagggagaa gggtccgtgc tgcaggccaa gctaaaagca 2280 caggccttgg ccattgaaac ggaggctgag ctccagaggg tccagaaggt ccgagagctg 2340 gaactggtct atgcccgggc ccagctggag ctggaggtga gcaaggctca gcagctggct 2400 gaggtggagg tgaagaagtt caagcagatg acagaggcca taggccccag caccatcagg 2460 gaccttgctg tggctgggcc tgagatgcag gtaaaactgc tccagtccct gggcctgaaa 2520 tcaaccctca tcaccgatgg ctccactccc atcaacctct tcaacacagc ctttgggctg 2580 ctggggatgg ggcccgaggg tcagcccctg ggcagaaggg tggccagtgg gcccagccct 2640 ggggagggga tatcccccca gtctgctcag gcccctcaag ctcctggaga caaccacgtg 2700 gtgcctgtac tgcgctaa 2718 <210> SEQ ID NO 11 <211> LENGTH: 2627 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 Met Glu Lys Leu His Gly His Val Ser Ala His Pro Asp Ile Leu Ser 1 5 10 15 Leu Glu Asn Arg Cys Leu Ala Met Leu Pro Asp Leu Gln Pro Leu Glu 20 25 30 Lys Leu His Gln His Val Ser Thr His Ser Asp Ile Leu Ser Leu Lys 35 40 45 Asn Gln Cys Leu Ala Thr Leu Pro Asp Leu Lys Thr Met Glu Lys Pro 50 55 60 His Gly Tyr Val Ser Ala His Pro Asp Ile Leu Ser Leu Glu Asn Gln 65 70 75 80 Cys Leu Ala Thr Leu Ser Asp Leu Lys Thr Met Glu Lys Pro His Gly 85 90 95 His Val Ser Ala His Pro Asp Ile Leu Ser Leu Glu Asn Arg Cys Leu 100 105 110 Ala Thr Leu Pro Ser Leu Lys Ser Thr Val Ser Ala Ser Pro Leu Phe 115 120 125 Gln Ser Leu Gln Ile Ser His Met Thr Gln Ala Asp Leu Tyr Arg Val 130 135 140 Asn Asn Ser Asn Cys Leu Leu Ser Glu Pro Pro Ser Trp Arg Ala Gln 145 150 155 160 His Phe Ser Lys Gly Leu Asp Leu Ser Thr Cys Pro Ile Ala Leu Lys 165 170 175 Ser Ile Ser Ala Thr Glu Thr Ala Gln Glu Ala Thr Leu Gly Arg Trp 180 185 190 Phe Asp Ser Glu Glu Lys Lys Gly Ala Glu Thr Gln Met Pro Ser Tyr 195 200 205 Ser Leu Ser Leu Gly Glu Glu Glu Glu Val Glu Asp Leu Ala Val Lys 210 215 220 Leu Thr Ser Gly Asp Ser Glu Ser His Pro Glu Pro Thr Asp His Val 225 230 235 240 Leu Gln Glu Lys Lys Met Ala Leu Leu Ser Leu Leu Cys Ser Thr Leu 245 250 255 Val Ser Glu Val Asn Met Asn Asn Thr Ser Asp Pro Thr Leu Ala Ala 260 265 270 Ile Phe Glu Ile Cys Arg Glu Leu Ala Leu Leu Glu Pro Glu Phe Ile 275 280 285 Leu Lys Ala Ser Leu Tyr Ala Arg Gln Gln Leu Asn Val Arg Asn Val 290 295 300 Ala Asn Asn Ile Leu Ala Ile Ala Ala Phe Leu Pro Ala Cys Arg Pro 305 310 315 320 His Leu Arg Arg Tyr Phe Cys Ala Ile Val Gln Leu Pro Ser Asp Trp 325 330 335 Ile Gln Val Ala Glu Leu Tyr Gln Ser Leu Ala Glu Gly Asp Lys Asn 340 345 350 Lys Leu Val Pro Leu Pro Ala Cys Leu Arg Thr Ala Met Thr Asp Lys 355 360 365 Phe Ala Gln Phe Asp Glu Tyr Gln Leu Ala Lys Tyr Asn Pro Arg Lys 370 375 380 His Arg Ala Lys Arg His Pro Arg Arg Pro Pro Arg Ser Pro Gly Met 385 390 395 400 Glu Pro Pro Phe Ser His Arg Cys Phe Pro Arg Tyr Ile Gly Phe Leu 405 410 415 Arg Glu Glu Gln Arg Lys Phe Glu Lys Ala Gly Asp Thr Val Ser Glu 420 425 430 Lys Lys Asn Pro Pro Arg Phe Thr Leu Lys Lys Leu Val Gln Arg Leu 435 440 445 His Ile His Lys Pro Ala Gln His Val Gln Ala Leu Leu Gly Tyr Arg 450 455 460 Tyr Pro Ser Asn Leu Gln Leu Phe Ser Arg Ser Arg Leu Pro Gly Pro 465 470 475 480 Trp Asp Ser Ser Arg Ala Gly Lys Arg Met Lys Leu Ser Arg Pro Glu 485 490 495 Thr Trp Glu Arg Glu Leu Ser Leu Arg Gly Asn Lys Ala Ser Val Trp 500 505 510 Glu Glu Leu Ile Glu Asn Gly Lys Leu Pro Phe Met Ala Met Leu Arg 515 520 525 Asn Leu Cys Asn Leu Leu Arg Val Gly Ile Ser Ser Arg His His Glu 530 535 540 Leu Ile Leu Gln Arg Leu Gln His Gly Lys Ser Val Ile His Ser Arg 545 550 555 560 Gln Phe Pro Phe Arg Phe Leu Asn Ala His Asp Ala Ile Asp Ala Leu 565 570 575 Glu Ala Gln Leu Arg Asn Gln Ala Leu Pro Phe Pro Ser Asn Ile Thr 580 585 590 Leu Met Arg Arg Ile Leu Thr Arg Asn Glu Lys Asn Arg Pro Arg Arg 595 600 605 Arg Phe Leu Cys His Leu Ser Arg Gln Gln Leu Arg Met Ala Met Arg 610 615 620 Ile Pro Val Leu Tyr Glu Gln Leu Lys Arg Glu Lys Leu Arg Val His 625 630 635 640 Lys Ala Arg Gln Trp Lys Tyr Asp Gly Glu Met Leu Asn Arg Tyr Arg 645 650 655 Gln Ala Leu Glu Thr Ala Val Asn Leu Ser Val Lys His Ser Leu Pro 660 665 670 Leu Leu Pro Gly Arg Thr Val Leu Val Tyr Leu Thr Asp Ala Asn Ala 675 680 685 Asp Arg Leu Cys Pro Lys Ser Asn Pro Gln Gly Pro Pro Leu Asn Tyr 690 695 700 Ala Leu Leu Leu Ile Gly Met Met Ile Thr Arg Ala Glu Gln Val Asp 705 710 715 720 Val Val Leu Cys Gly Gly Asp Thr Leu Lys Thr Ala Val Leu Lys Ala 725 730 735 Glu Glu Gly Ile Leu Lys Thr Ala Ile Lys Leu Gln Ala Gln Val Gln 740 745 750 Glu Phe Asp Glu Asn Asp Gly Trp Ser Leu Asn Thr Phe Gly Lys Tyr 755 760 765 Leu Leu Ser Leu Ala Gly Gln Arg Val Pro Val Asp Arg Val Ile Leu 770 775 780 Leu Gly Gln Ser Met Asp Asp Gly Met Ile Asn Val Ala Lys Gln Leu 785 790 795 800 Tyr Trp Gln Arg Val Asn Ser Lys Cys Leu Phe Val Gly Ile Leu Leu 805 810 815 Arg Arg Val Gln Tyr Leu Ser Thr Asp Leu Asn Pro Asn Asp Val Thr 820 825 830 Leu Ser Gly Cys Thr Asp Ala Ile Leu Lys Phe Ile Ala Glu His Gly 835 840 845 Ala Ser His Leu Leu Glu His Val Gly Gln Met Asp Lys Ile Phe Lys 850 855 860 Ile Pro Pro Pro Pro Gly Lys Thr Gly Val Gln Ser Leu Arg Pro Leu 865 870 875 880 Glu Glu Asp Thr Pro Ser Pro Leu Ala Pro Val Ser Gln Gln Gly Trp 885 890 895 Arg Ser Ile Arg Leu Phe Ile Ser Ser Thr Phe Arg Asp Met His Gly 900 905 910 Glu Arg Asp Leu Leu Leu Arg Ser Val Leu Pro Ala Leu Gln Ala Arg 915 920 925 Ala Ala Pro His Arg Ile Ser Leu His Gly Ile Asp Leu Arg Trp Gly 930 935 940 Val Thr Glu Glu Glu Thr Arg Arg Asn Arg Gln Leu Glu Val Cys Leu 945 950 955 960 Gly Glu Val Glu Asn Ala Gln Leu Phe Val Gly Ile Leu Gly Ser Arg 965 970 975 Tyr Gly Tyr Ile Pro Pro Ser Tyr Asn Leu Pro Asp His Pro His Phe 980 985 990 His Trp Ala Gln Gln Tyr Pro Ser Gly Arg Ser Val Thr Glu Met Glu 995 1000 1005 Val Met Gln Phe Leu Asn Arg Asn Gln Arg Leu Gln Pro Ser Ala 1010 1015 1020 Gln Ala Leu Ile Tyr Phe Arg Asp Ser Ser Phe Leu Ser Ser Val 1025 1030 1035 Pro Asp Ala Trp Lys Ser Asp Phe Val Ser Glu Ser Glu Glu Ala 1040 1045 1050 Ala Cys Arg Ile Ser Glu Leu Lys Ser Tyr Leu Ser Arg Gln Lys 1055 1060 1065 Gly Ile Thr Cys Arg Arg Tyr Pro Cys Glu Trp Gly Gly Val Ala 1070 1075 1080 Ala Gly Arg Pro Tyr Val Gly Gly Leu Glu Glu Phe Gly Gln Leu 1085 1090 1095 Val Leu Gln Asp Val Trp Asn Met Ile Gln Lys Leu Tyr Leu Gln 1100 1105 1110 Pro Gly Ala Leu Leu Glu Gln Pro Val Ser Ile Pro Asp Asp Asp 1115 1120 1125 Leu Val Gln Ala Thr Phe Gln Gln Leu Gln Lys Pro Pro Ser Pro 1130 1135 1140 Ala Arg Pro Arg Leu Leu Gln Asp Thr Val Gln Gln Leu Met Leu 1145 1150 1155 Pro His Gly Arg Leu Ser Leu Val Thr Gly Gln Ser Gly Gln Gly 1160 1165 1170 Lys Thr Ala Phe Leu Ala Ser Leu Val Ser Ala Leu Gln Ala Pro 1175 1180 1185 Asp Gly Ala Lys Val Ala Pro Leu Val Phe Phe His Phe Ser Gly 1190 1195 1200 Ala Arg Pro Asp Gln Gly Leu Ala Leu Thr Leu Leu Arg Arg Leu 1205 1210 1215 Cys Thr Tyr Leu Arg Gly Gln Leu Lys Glu Pro Gly Ala Leu Pro 1220 1225 1230 Ser Thr Tyr Arg Ser Leu Val Trp Glu Leu Gln Gln Arg Leu Leu 1235 1240 1245 Pro Lys Ser Ala Glu Ser Leu His Pro Gly Gln Thr Gln Val Leu 1250 1255 1260 Ile Ile Asp Gly Ala Asp Arg Leu Val Asp Gln Asn Gly Gln Leu 1265 1270 1275 Ile Ser Asp Trp Ile Pro Lys Lys Leu Pro Arg Cys Val His Leu 1280 1285 1290 Val Leu Ser Val Ser Ser Asp Ala Gly Leu Gly Glu Thr Leu Glu 1295 1300 1305 Gln Ser Gln Gly Ala His Val Leu Ala Leu Gly Pro Leu Glu Ala 1310 1315 1320 Ser Ala Arg Ala Arg Leu Val Arg Glu Glu Leu Ala Leu Tyr Gly 1325 1330 1335 Lys Arg Leu Glu Glu Ser Pro Phe Asn Asn Gln Met Arg Leu Leu 1340 1345 1350 Leu Val Lys Arg Glu Ser Gly Arg Pro Leu Tyr Leu Arg Leu Val 1355 1360 1365 Thr Asp His Leu Arg Leu Phe Thr Leu Tyr Glu Gln Val Ser Glu 1370 1375 1380 Arg Leu Arg Thr Leu Pro Ala Thr Val Pro Leu Leu Leu Gln His 1385 1390 1395 Ile Leu Ser Thr Leu Glu Lys Glu His Gly Pro Asp Val Leu Pro 1400 1405 1410 Gln Ala Leu Thr Ala Leu Glu Val Thr Arg Ser Gly Leu Thr Val 1415 1420 1425 Asp Gln Leu His Gly Val Leu Ser Val Trp Arg Thr Leu Pro Lys 1430 1435 1440 Gly Thr Lys Ser Trp Glu Glu Ala Val Ala Ala Gly Asn Ser Gly 1445 1450 1455 Asp Pro Tyr Pro Met Gly Pro Phe Ala Cys Leu Val Gln Ser Leu 1460 1465 1470 Arg Ser Leu Leu Gly Glu Gly Pro Leu Glu Arg Pro Gly Ala Arg 1475 1480 1485 Leu Cys Leu Pro Asp Gly Pro Leu Arg Thr Ala Ala Lys Arg Cys 1490 1495 1500 Tyr Gly Lys Arg Pro Gly Leu Glu Asp Thr Ala His Ile Leu Ile 1505 1510 1515 Ala Ala Gln Leu Trp Lys Thr Cys Asp Ala Asp Ala Ser Gly Thr 1520 1525 1530 Phe Arg Ser Cys Pro Pro Glu Ala Leu Gly Asp Leu Pro Tyr His 1535 1540 1545 Leu Leu Gln Ser Gly Asn Arg Gly Leu Leu Ser Lys Phe Leu Thr 1550 1555 1560 Asn Leu His Val Val Ala Ala His Leu Glu Leu Gly Leu Val Ser 1565 1570 1575 Arg Leu Leu Glu Ala His Ala Leu Tyr Ala Ser Ser Val Pro Lys 1580 1585 1590 Glu Glu Gln Lys Leu Pro Glu Ala Asp Val Ala Val Phe Arg Thr 1595 1600 1605 Phe Leu Arg Gln Gln Ala Ser Ile Leu Ser Gln Tyr Pro Arg Leu 1610 1615 1620 Leu Pro Gln Gln Ala Ala Asn Gln Pro Leu Asp Ser Pro Leu Cys 1625 1630 1635 His Gln Ala Ser Leu Leu Ser Arg Arg Trp His Leu Gln His Thr 1640 1645 1650 Leu Arg Trp Leu Asn Lys Pro Arg Thr Met Lys Asn Gln Gln Ser 1655 1660 1665 Ser Ser Leu Ser Leu Ala Val Ser Ser Ser Pro Thr Ala Val Ala 1670 1675 1680 Phe Ser Thr Asn Gly Gln Arg Ala Ala Val Gly Thr Ala Asn Gly 1685 1690 1695 Thr Val Tyr Leu Leu Asp Leu Arg Thr Trp Gln Glu Glu Lys Ser 1700 1705 1710 Val Val Ser Gly Cys Asp Gly Ile Ser Ala Cys Leu Phe Leu Ser 1715 1720 1725 Asp Asp Thr Leu Phe Leu Thr Ala Phe Asp Gly Leu Leu Glu Leu 1730 1735 1740 Trp Asp Leu Gln His Gly Cys Arg Val Leu Gln Thr Lys Ala His 1745 1750 1755 Gln Tyr Gln Ile Thr Gly Cys Cys Leu Ser Pro Asp Cys Arg Leu 1760 1765 1770 Leu Ala Thr Val Cys Leu Gly Gly Cys Leu Lys Leu Trp Asp Thr 1775 1780 1785 Val Arg Gly Gln Leu Ala Phe Gln His Thr Tyr Pro Lys Ser Leu 1790 1795 1800 Asn Cys Val Ala Phe His Pro Glu Gly Gln Val Ile Ala Thr Gly 1805 1810 1815 Ser Trp Ala Gly Ser Ile Ser Phe Phe Gln Val Asp Gly Leu Lys 1820 1825 1830 Val Thr Lys Asp Leu Gly Ala Pro Gly Ala Ser Ile Arg Thr Leu 1835 1840 1845 Ala Phe Asn Val Pro Gly Gly Val Val Ala Val Gly Arg Leu Asp 1850 1855 1860 Ser Met Val Glu Leu Trp Ala Trp Arg Glu Gly Ala Arg Leu Ala 1865 1870 1875 Ala Phe Pro Ala His His Gly Phe Val Ala Ala Ala Leu Phe Leu 1880 1885 1890 His Ala Gly Cys Gln Leu Leu Thr Ala Gly Glu Asp Gly Lys Val 1895 1900 1905 Gln Val Trp Ser Gly Ser Leu Gly Arg Pro Arg Gly His Leu Gly 1910 1915 1920 Ser Leu Ser Leu Ser Pro Ala Leu Ser Val Ala Leu Ser Pro Asp 1925 1930 1935 Gly Asp Arg Val Ala Val Gly Tyr Arg Ala Asp Gly Ile Arg Ile 1940 1945 1950 Tyr Lys Ile Ser Ser Gly Ser Gln Gly Ala Gln Gly Gln Ala Leu 1955 1960 1965 Asp Val Ala Val Ser Ala Leu Ala Trp Leu Ser Pro Lys Val Leu 1970 1975 1980 Val Ser Gly Ala Glu Asp Gly Ser Leu Gln Gly Trp Ala Leu Lys 1985 1990 1995 Glu Cys Ser Leu Gln Ser Leu Trp Leu Leu Ser Arg Phe Gln Lys 2000 2005 2010 Pro Val Leu Gly Leu Ala Thr Ser Gln Glu Leu Leu Ala Ser Ala 2015 2020 2025 Ser Glu Asp Phe Thr Val Gln Leu Trp Pro Arg Gln Leu Leu Thr 2030 2035 2040 Arg Pro His Lys Ala Glu Asp Phe Pro Cys Gly Thr Glu Leu Arg 2045 2050 2055 Gly His Glu Gly Pro Val Ser Cys Cys Ser Phe Ser Thr Asp Gly 2060 2065 2070 Gly Ser Leu Ala Thr Gly Gly Arg Asp Arg Ser Leu Leu Cys Trp 2075 2080 2085 Asp Val Arg Thr Pro Lys Thr Pro Val Leu Ile His Ser Phe Pro 2090 2095 2100 Ala Cys His Arg Asp Trp Val Thr Gly Cys Ala Trp Thr Lys Asp 2105 2110 2115 Asn Leu Leu Ile Ser Cys Ser Ser Asp Gly Ser Val Gly Leu Trp 2120 2125 2130 Asp Pro Glu Ser Gly Gln Arg Leu Gly Gln Phe Leu Gly His Gln 2135 2140 2145 Ser Ala Val Ser Ala Val Ala Ala Val Glu Glu His Val Val Ser 2150 2155 2160 Val Ser Arg Asp Gly Thr Leu Lys Val Trp Asp His Gln Gly Val 2165 2170 2175 Glu Leu Thr Ser Ile Pro Ala His Ser Gly Pro Ile Ser His Cys 2180 2185 2190 Ala Ala Ala Met Glu Pro Arg Ala Ala Gly Gln Pro Gly Ser Glu 2195 2200 2205 Leu Leu Val Val Thr Val Gly Leu Asp Gly Ala Thr Arg Leu Trp 2210 2215 2220 His Pro Leu Leu Val Cys Gln Thr His Thr Leu Leu Gly His Ser 2225 2230 2235 Gly Pro Val Arg Ala Ala Ala Val Ser Glu Thr Ser Gly Leu Met 2240 2245 2250 Leu Thr Ala Ser Glu Asp Gly Ser Val Arg Leu Trp Gln Val Pro 2255 2260 2265 Lys Glu Ala Asp Asp Thr Cys Ile Pro Arg Ser Ser Ala Ala Val 2270 2275 2280 Thr Ala Val Ala Trp Ala Pro Asp Gly Ser Met Ala Val Ser Gly 2285 2290 2295 Asn Gln Ala Gly Glu Leu Ile Leu Trp Gln Glu Ala Lys Ala Val 2300 2305 2310 Ala Thr Ala Gln Ala Pro Gly His Ile Gly Ala Leu Ile Trp Ser 2315 2320 2325 Ser Ala His Thr Phe Phe Val Leu Ser Ala Asp Glu Lys Ile Ser 2330 2335 2340 Glu Trp Gln Val Lys Leu Arg Lys Gly Ser Ala Pro Gly Asn Leu 2345 2350 2355 Ser Leu His Leu Asn Arg Ile Leu Gln Glu Asp Leu Gly Val Leu 2360 2365 2370 Thr Ser Leu Asp Trp Ala Pro Asp Gly His Phe Leu Ile Leu Ala 2375 2380 2385 Lys Ala Asp Leu Lys Leu Leu Cys Met Lys Pro Gly Asp Ala Pro 2390 2395 2400 Ser Glu Ile Trp Ser Ser Tyr Thr Glu Asn Pro Met Ile Leu Ser 2405 2410 2415 Thr His Lys Glu Tyr Gly Ile Phe Val Leu Gln Pro Lys Asp Pro 2420 2425 2430 Gly Val Leu Ser Phe Leu Arg Gln Lys Glu Ser Gly Glu Phe Glu 2435 2440 2445 Glu Arg Leu Asn Phe Asp Ile Asn Leu Glu Asn Pro Ser Arg Thr 2450 2455 2460 Leu Ile Ser Ile Thr Gln Ala Lys Pro Glu Ser Glu Ser Ser Phe 2465 2470 2475 Leu Cys Ala Ser Ser Asp Gly Ile Leu Trp Asn Leu Ala Lys Cys 2480 2485 2490 Ser Pro Glu Gly Glu Trp Thr Thr Gly Asn Met Trp Gln Lys Lys 2495 2500 2505 Ala Asn Thr Pro Glu Thr Gln Thr Pro Gly Thr Asp Pro Ser Thr 2510 2515 2520 Cys Arg Glu Ser Asp Ala Ser Met Asp Ser Asp Ala Ser Met Asp 2525 2530 2535 Ser Glu Pro Thr Pro His Leu Lys Thr Arg Gln Arg Arg Lys Ile 2540 2545 2550 His Ser Gly Ser Val Thr Ala Leu His Val Leu Pro Glu Leu Leu 2555 2560 2565 Val Thr Ala Ser Lys Asp Arg Asp Val Lys Leu Trp Glu Arg Pro 2570 2575 2580 Ser Met Gln Leu Leu Gly Leu Phe Arg Cys Glu Gly Ser Val Ser 2585 2590 2595 Cys Leu Glu Pro Trp Leu Gly Ala Asn Ser Thr Leu Gln Leu Ala 2600 2605 2610 Val Gly Asp Val Gln Gly Asn Val Tyr Phe Leu Asn Trp Glu 2615 2620 2625 <210> SEQ ID NO 12 <211> LENGTH: 7884 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 atggaaaaac tccatgggca tgtgtctgcc catccagaca tcctctcctt ggagaaccgg 60 tgcctggcta tgctccctga cttacagccc ttggagaaac tacatcagca tgtatctacc 120 cactcagata tcctctcctt gaagaaccag tgcctagcca cgcttcctga cctgaagacc 180 atggaaaaac cacatggata tgtgtctgcc cacccagaca tcctctcctt ggagaaccag 240 tgcctggcca cactttctga cctgaagacc atggagaaac cacatggaca tgtttctgcc 300 cacccagaca tcctctcctt ggagaaccgg tgcctggcca ccctccctag tctaaagagc 360 actgtgtctg ccagcccctt gttccagagt ctacagatat ctcacatgac gcaagctgat 420 ttgtaccgtg tgaacaacag caattgcctg ctctctgagc ctccaagttg gagggctcag 480 catttctcta agggactaga cctttcaacc tgccctatag ccctgaaatc catctctgcc 540 acagagacag ctcaggaagc aactttgggt cgttggtttg attcagaaga gaagaaaggg 600 gcagagaccc aaatgccttc ttatagtctg agcttgggag aggaggagga ggtggaggat 660 ctggccgtga agctcacctc tggagactct gaatctcatc cagagcctac tgaccatgtc 720 cttcaggaaa agaagatggc tctactgagc ttgctgtgct ctactctggt ctcagaagta 780 aacatgaaca atacatctga ccccaccctg gctgccattt ttgaaatctg tcgtgaactt 840 gccctcctgg agcctgagtt tatcctcaag gcatctttgt atgccaggca gcagctgaac 900 gtccggaatg tggccaataa catcttggcc attgctgctt tcttgccggc gtgtcgcccc 960 cacctgcgac gatatttctg tgccattgtc cagctgcctt ctgactggat ccaggtggct 1020 gagctttacc agagcctggc tgagggagat aagaataagc tggtgcccct gcccgcctgt 1080 ctccgtactg ccatgacgga caaatttgcc cagtttgacg agtaccagct ggctaagtac 1140 aaccctcgga agcaccgggc caagagacac ccccgccggc caccccgctc tccagggatg 1200 gagcctccat tttctcacag atgttttcca aggtacatag ggtttctcag agaagagcag 1260 agaaagtttg agaaggccgg tgatacagtg tcagagaaaa agaatcctcc aaggttcacc 1320 ctgaagaagc tggttcagcg actgcacatc cacaagcctg cccagcacgt tcaagccctg 1380 ctgggttaca gatacccctc caacctacag ctcttttctc gaagtcgcct tcctgggcct 1440 tgggattcta gcagagctgg gaagaggatg aagctgtcta ggccagagac ctgggagcgg 1500 gagctgagcc tacgggggaa caaagcgtcg gtctgggagg aactcattga aaatgggaag 1560 cttcccttca tggccatgct tcggaacctg tgcaacctgc tgcgggttgg aatcagttcc 1620 cgccaccatg agctcattct ccagagactc cagcatggga agtcggtgat ccacagtcgg 1680 cagtttccat tcagatttct taacgcccat gatgccattg atgccctcga ggctcaactc 1740 agaaatcaag cattgccctt tccttcgaat ataacactga tgaggcggat actaactaga 1800 aatgaaaaga accgtcccag gcggaggttt ctttgccacc taagccgtca gcagcttcgt 1860 atggcaatga ggatacctgt gttgtatgag cagctcaaga gggagaagct gagagtacac 1920 aaggccagac agtggaaata tgatggtgag atgctgaaca ggtaccgaca ggccctagag 1980 acagctgtga acctctctgt gaagcacagc ctgcccctgc tgccaggccg cactgtcttg 2040 gtctatctga cagatgctaa tgcagacagg ctctgtccaa agagcaaccc acaagggccc 2100 ccgctgaact atgcactgct gttgattggg atgatgatca cgagggcgga gcaggtggac 2160 gtcgtgctgt gtggaggtga cactctgaag actgcagtgc ttaaggcaga agaaggcatc 2220 ctgaagactg ccatcaagct ccaggctcaa gtccaggagt ttgatgaaaa tgatggatgg 2280 tccctgaata cttttgggaa atacctgctg tctctggctg gccaaagggt tcctgtggac 2340 agggtcatcc tccttggcca aagcatggat gatggaatga taaatgtggc caaacagctt 2400 tactggcagc gtgtgaattc caagtgcctc tttgttggta tcctcctaag aagggtacaa 2460 tacctgtcaa cagatttgaa tcccaatgat gtgacactct caggctgtac tgatgcgata 2520 ctgaagttca ttgcagagca tggggcctcc catcttctgg aacatgtggg ccaaatggac 2580 aaaatattca agattccacc acccccagga aagacagggg tccagtctct ccggccactg 2640 gaagaggaca ctccaagccc cttggctcct gtttcccagc aaggatggcg cagcatccgg 2700 cttttcattt catccacttt ccgagacatg cacggggagc gggacctgct gctgaggtct 2760 gtgctgccag cactgcaggc ccgagcggcc cctcaccgta tcagccttca cggaatcgac 2820 ctccgctggg gcgtcactga ggaggagacc cgtaggaaca gacaactgga agtgtgcctt 2880 ggggaggtgg agaacgcaca gctgtttgtg gggattctgg gctcccgtta tggatacatt 2940 ccccccagct acaaccttcc tgaccatcca cacttccact gggcccagca gtacccttca 3000 gggcgctctg tgacagagat ggaggtgatg cagttcctga accggaacca acgtctgcag 3060 ccctctgccc aagctctcat ctacttccgg gattccagct tcctcagctc tgtgccagat 3120 gcctggaaat ctgactttgt ttctgagtct gaagaggccg catgtcggat ctcagaactg 3180 aagagctacc taagcagaca gaaagggata acctgccgca gatacccctg tgagtggggg 3240 ggtgtggcag ctggccggcc ctatgttggc gggctggagg agtttgggca gttggttctg 3300 caggatgtat ggaatatgat ccagaagctc tacctgcagc ctggggccct gctggagcag 3360 ccagtgtcca tcccagacga tgacttggtc caggccacct tccagcagct gcagaagcca 3420 ccgagtcctg cccggccacg ccttcttcag gacacagtgc aacagctgat gctgccccac 3480 ggaaggctga gcctggtgac ggggcagtca ggacagggca agacagcctt cctggcatct 3540 cttgtgtcag ccctgcaggc tcctgatggg gccaaggtgg caccattagt cttcttccac 3600 ttttctgggg ctcgtcctga ccagggtctt gccctcactc tgctcagacg cctctgtacc 3660 tatctgcgtg gccaactaaa agagccaggt gccctcccca gcacctaccg aagcctggtg 3720 tgggagctgc agcagaggct gctgcccaag tctgctgagt ccctgcatcc tggccagacc 3780 caggtcctga tcatcgatgg ggctgatagg ttagtggacc agaatgggca gctgatttca 3840 gactggatcc caaagaagct tccccggtgt gtacacctgg tgctgagtgt gtctagtgat 3900 gcaggcctag gggagaccct tgagcagagc cagggtgccc acgtgctggc cttggggcct 3960 ctggaggcct ctgctcgggc ccggctggtg agagaggagc tggccctgta cgggaagcgg 4020 ctggaggagt caccatttaa caaccagatg cgactgctgc tggtgaagcg ggaatcaggc 4080 cggccgctct acctgcgctt ggtcaccgat cacctgaggc tcttcacgct gtatgagcag 4140 gtgtctgaga gactccggac cctgcctgcc actgtccccc tgctgctgca gcacatcctg 4200 agcacactgg agaaggagca cgggcctgat gtccttcccc aggccttgac tgccctagaa 4260 gtcacacgga gtggtttgac tgtggaccag ctgcacggag tgctgagtgt gtggcggaca 4320 ctaccgaagg ggactaagag ctgggaagaa gcagtggctg ctggtaacag tggagacccc 4380 taccccatgg gcccgtttgc ctgcctcgtc cagagtctgc gcagtttgct aggggagggc 4440 cctctggagc gccctggtgc ccggctgtgc ctccctgatg ggcccctgag aacagcagct 4500 aaacgttgct atgggaagag gccagggcta gaggacacgg cacacatcct cattgcagct 4560 cagctctgga agacatgtga cgctgatgcc tcaggcacct tccgaagttg ccctcctgag 4620 gctctgggag acctgcctta ccacctgctc cagagcggga accgtggact tctttcgaag 4680 ttccttacca acctccatgt ggtggctgca cacttggaat tgggtctggt ctctcggctc 4740 ttggaggccc atgccctcta tgcttcttca gtccccaaag aggaacaaaa gctccccgag 4800 gctgacgttg cagtgtttcg caccttcctg aggcagcagg cttcaatcct cagccagtac 4860 ccccggctcc tgccccagca ggcagccaac cagcccctgg actcacctct ttgccaccaa 4920 gcctcgctgc tctcccggag atggcacctc caacacacac tacgatggct taataaaccc 4980 cggaccatga aaaatcagca aagctccagc ctgtctctgg cagtttcctc atcccctact 5040 gctgtggcct tctccaccaa tgggcaaaga gcagctgtgg gcactgccaa tgggacagtt 5100 tacctgttgg acctgagaac ttggcaggag gagaagtctg tggtgagtgg ctgtgatgga 5160 atctctgctt gtttgttcct ctccgatgat acactctttc ttactgcctt cgacgggctc 5220 ctggagctct gggacctgca gcatggttgt cgggtgctgc agactaaggc tcaccagtac 5280 caaatcactg gctgctgcct gagcccagac tgccggctgc tagccaccgt gtgcttggga 5340 ggatgcctaa agctgtggga cacagtccgt gggcagctgg ccttccagca cacctacccc 5400 aagtccctga actgtgttgc cttccaccca gaggggcagg taatagccac aggcagctgg 5460 gctggcagca tcagcttctt ccaggtggat gggctcaaag tcaccaagga cctgggggca 5520 cccggagcct ctatccgtac cttggccttc aatgtgcctg ggggggttgt ggctgtgggc 5580 cggctggaca gtatggtgga gctgtgggcc tggcgagaag gggcacggct ggctgccttc 5640 cctgcccacc atggctttgt tgctgctgcg cttttcctgc atgcgggttg ccagttactg 5700 acggctggag aggatggcaa ggttcaggtg tggtcagggt ctctgggtcg gccccgtggg 5760 cacctgggtt ccctttctct ctctcctgcc ctctctgtgg cactcagccc agatggtgat 5820 cgggtggctg ttggatatcg agcggatggc attaggatct acaaaatctc ttcaggttcc 5880 cagggggctc agggtcaggc actggatgtg gcagtgtccg ccctggcctg gctaagcccc 5940 aaggtattgg tgagtggtgc agaagatggg tccttgcagg gctgggcact caaggaatgc 6000 tcccttcagt ccctctggct cctgtccaga ttccagaagc ctgtgctagg actggccact 6060 tcccaggagc tcttggcttc tgcctcagag gatttcacag tgcagctgtg gccaaggcag 6120 ctgctgacgc ggccacacaa ggcagaagac tttccctgtg gcactgagct gcggggacat 6180 gagggccctg tgagctgctg tagtttcagc actgatggag gcagcctggc caccgggggc 6240 cgggatcgga gtctcctctg ctgggacgtg aggacaccca aaacccctgt tttgatccac 6300 tccttccctg cctgtcaccg tgactgggtc actggctgtg cctggaccaa agataaccta 6360 ctgatatcct gctccagtga tggctctgtg gggctctggg acccagagtc aggacagcgg 6420 cttggtcagt tcctgggtca tcagagtgct gtgagcgctg tggcagctgt ggaggagcac 6480 gtggtgtctg tgagccggga tgggaccttg aaagtgtggg accatcaagg cgtggagctg 6540 accagcatcc ctgctcactc aggacccatt agccactgtg cagctgccat ggagccccgt 6600 gcagctggac agcctgggtc agagcttctg gtggtaaccg tcgggctaga tggggccaca 6660 cggttatggc atccactctt ggtgtgccaa acccacaccc tcctgggaca cagcggccca 6720 gtccgtgctg ctgctgtttc agaaacctca ggcctcatgc tgaccgcctc tgaggatggt 6780 tctgtacggc tctggcaggt tcctaaggaa gcagatgaca catgtatacc aaggagttct 6840 gcagccgtca ctgctgtggc ttgggcacca gatggttcca tggcagtatc tggaaatcaa 6900 gctggggaac taatcttgtg gcaggaagct aaggctgtgg ccacagcaca ggctccaggc 6960 cacattggtg ctctgatctg gtcctcggca cacacctttt ttgtcctcag tgctgatgag 7020 aaaatcagcg agtggcaagt gaaactgcgg aagggttcgg cacccggaaa tttgagtctt 7080 cacctgaacc gaattctaca ggaggactta ggggtgctga caagtctgga ttgggctcct 7140 gatggtcact ttctcatctt ggccaaagca gatttgaagt tactttgcat gaagccaggg 7200 gatgctccat ctgaaatctg gagcagctat acagaaaatc ctatgatatt gtccacccac 7260 aaggagtatg gcatatttgt cctgcagccc aaggatcctg gagttctttc tttcttgagg 7320 caaaaggaat caggagagtt tgaagagagg ctgaactttg atataaactt agagaatcct 7380 agtaggaccc taatatcgat aactcaagcc aaacctgaat ctgagtcctc atttttgtgt 7440 gccagctctg atgggatcct atggaacctg gccaaatgca gcccagaagg agaatggacc 7500 acaggtaaca tgtggcagaa aaaagcaaac actccagaaa cccaaactcc agggacagac 7560 ccatctacct gcagggaatc tgatgccagc atggatagtg atgccagcat ggatagtgag 7620 ccaacaccac atctaaagac acggcagcgt agaaagattc actcgggctc tgtcacagcc 7680 ctccatgtgc tacctgagtt gctggtgaca gcttcgaagg acagagatgt taagctatgg 7740 gagagaccca gtatgcagct gctgggcctg ttccgatgcg aagggtcagt gagctgcctg 7800 gaaccttggc tgggcgctaa ctccaccctg cagcttgccg tgggagacgt gcagggcaat 7860 gtgtactttc tgaattggga atga 7884 <210> SEQ ID NO 13 <211> LENGTH: 98 <212> TYPE: RNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 ggcuggcuuu agcucagcgg uuacuucgac aguucuuuaa uugaaacaag caaccugucu 60 ggguuguucg agacccgcgg gcgcucucca guccuuuu 98 <210> SEQ ID NO 14 <211> LENGTH: 88 <212> TYPE: RNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 ggcuggcuuu agcucagcgg uuacuucgag uacauuguaa ccaccucucu gggugguucg 60 agacccgcgg gugcuuucca gcucuuuu 88 <210> SEQ ID NO 15 <211> LENGTH: 88 <212> TYPE: RNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 ggcuggcuuu agcucagcgg uuacuucgcg ugucaucaaa ccaccucucu ggguuguucg 60 agacccgcgg gcgcucucca gcccucuu 88 <210> SEQ ID NO 16 <211> LENGTH: 252 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Ala Asn Leu Arg Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys 1 5 10 15 Ser Gln Ser Arg Thr Thr Pro Val Asp Leu Cys Leu Leu Glu Glu Ser 20 25 30 Val Gly Ser Leu Glu Gly Ser Arg Cys Pro Val Phe Ala Phe Gln Ser 35 40 45 Ser Asp Thr Glu Ser Asp Glu Leu Ser Glu Val Leu Gln Asp Ser Cys 50 55 60 Phe Leu Gln Ile Lys Cys Asp Thr Lys Asp Asp Ser Ile Pro Cys Phe 65 70 75 80 Leu Glu Leu Lys Glu Glu Asp Glu Ile Val Cys Thr Gln His Trp Gln 85 90 95 Asp Ala Val Pro Trp Thr Glu Leu Leu Ser Leu Gln Thr Glu Asp Gly 100 105 110 Phe Trp Lys Leu Thr Pro Glu Leu Gly Leu Ile Leu Asn Leu Asn Thr 115 120 125 Asn Gly Leu His Ser Phe Leu Lys Gln Lys Gly Ile Gln Ser Leu Gly 130 135 140 Val Lys Gly Arg Glu Cys Leu Leu Asp Leu Ile Ala Thr Met Leu Val 145 150 155 160 Leu Gln Phe Ile Arg Thr Arg Leu Glu Lys Glu Gly Ile Val Phe Lys 165 170 175 Ser Leu Met Lys Met Asp Asp Pro Ser Ile Ser Arg Asn Ile Pro Trp 180 185 190 Ala Phe Glu Ala Ile Lys Gln Ala Ser Glu Trp Val Arg Arg Thr Glu 195 200 205 Gly Gln Tyr Pro Ser Ile Cys Pro Arg Leu Glu Leu Gly Asn Asp Trp 210 215 220 Asp Ser Ala Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser Thr Val 225 230 235 240 Ser Pro Leu His Arg Val Leu His Tyr Ser Gln Gly 245 250 <210> SEQ ID NO 17 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 17 Ser Ile Ile Asn Phe Glu Lys Leu 1 5 <210> SEQ ID NO 18 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 18 Thr Glu Trp Thr Ser Ser Asn Val Met Glu Glu Arg Lys Ile Lys Val 1 5 10 15 <210> SEQ ID NO 19 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 19 ccccactagt ccatgggctc catcgg 26 <210> SEQ ID NO 20 <211> LENGTH: 44 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 20 tcctgccagt gttgtgtgca gctagcaggg gaaacacatc tgcc 44 <210> SEQ ID NO 21 <211> LENGTH: 46 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 21 ttggcagatg tgtttcccct gctagctgca cacaacactg gcagga 46 <210> SEQ ID NO 22 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 22 gggctcgagt tagccttgac tgtaatggag 30

1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 22 <210> SEQ ID NO 1 <211> LENGTH: 489 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 tgcacacaac actggcagga tgctgtgcct tggacagaac tcctcagtct acagacagag 60 gatggcttct ggaaacttac accagaactg ggacttatat taaatcttaa tacaaatggt 120 ttgcacagct ttcttaaaca aaaaggcatt caatctctag gtgtaaaagg aagagaatgt 180 ctcctggacc taattgccac aatgctggta ctacagttta ttcgcaccag gttggaaaaa 240 gagggaatag tgttcaaatc actgatgaaa atggatgacc cttctatttc caggaatatt 300 ccctgggctt ttgaggcaat aaagcaagca agtgaatggg taagaagaac tgaaggacag 360 tacccatcta tctgcccacg gcttgaactg gggaacgact gggactctgc caccaagcag 420 ttgctgggac tccagcccat aagcactgtg tcccctcttc atagagtcct ccattacagt 480 caaggctaa 489 <210> SEQ ID NO 2 <211> LENGTH: 162 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Cys Thr Gln His Trp Gln Asp Ala Val Pro Trp Thr Glu Leu Leu Ser 1 5 10 15 Leu Gln Thr Glu Asp Gly Phe Trp Lys Leu Thr Pro Glu Leu Gly Leu 20 25 30 Ile Leu Asn Leu Asn Thr Asn Gly Leu His Ser Phe Leu Lys Gln Lys 35 40 45 Gly Ile Gln Ser Leu Gly Val Lys Gly Arg Glu Cys Leu Leu Asp Leu 50 55 60 Ile Ala Thr Met Leu Val Leu Gln Phe Ile Arg Thr Arg Leu Glu Lys 65 70 75 80 Glu Gly Ile Val Phe Lys Ser Leu Met Lys Met Asp Asp Pro Ser Ile 85 90 95 Ser Arg Asn Ile Pro Trp Ala Phe Glu Ala Ile Lys Gln Ala Ser Glu 100 105 110 Trp Val Arg Arg Thr Glu Gly Gln Tyr Pro Ser Ile Cys Pro Arg Leu 115 120 125 Glu Leu Gly Asn Asp Trp Asp Ser Ala Thr Lys Gln Leu Leu Gly Leu 130 135 140 Gln Pro Ile Ser Thr Val Ser Pro Leu His Arg Val Leu His Tyr Ser 145 150 155 160 Gln Gly <210> SEQ ID NO 3 <211> LENGTH: 1724 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 Met Val Met Gly Ile Phe Ala Asn Cys Ile Phe Cys Leu Lys Val Lys 1 5 10 15 Tyr Leu Pro Gln Gln Gln Lys Lys Lys Leu Gln Thr Asp Ile Lys Glu 20 25 30 Asn Gly Gly Lys Phe Ser Phe Ser Leu Asn Pro Gln Cys Thr His Ile 35 40 45 Ile Leu Asp Asn Ala Asp Val Leu Ser Gln Tyr Gln Leu Asn Ser Ile 50 55 60 Gln Lys Asn His Val His Ile Ala Asn Pro Asp Phe Ile Trp Lys Ser 65 70 75 80 Ile Arg Glu Lys Arg Leu Leu Asp Val Lys Asn Tyr Asp Pro Tyr Lys 85 90 95 Pro Leu Asp Ile Thr Pro Pro Pro Asp Gln Lys Ala Ser Ser Ser Glu 100 105 110 Val Lys Thr Glu Gly Leu Cys Pro Asp Ser Ala Thr Glu Glu Glu Asp 115 120 125 Thr Val Glu Leu Thr Glu Phe Gly Met Gln Asn Val Glu Ile Pro His 130 135 140 Leu Pro Gln Asp Phe Glu Val Ala Lys Tyr Asn Thr Leu Glu Lys Val 145 150 155 160 Gly Met Glu Gly Gly Gln Glu Ala Val Val Val Glu Leu Gln Cys Ser 165 170 175 Arg Asp Ser Arg Asp Cys Pro Phe Leu Ile Ser Ser His Phe Leu Leu 180 185 190 Asp Asp Gly Met Glu Thr Arg Arg Gln Phe Ala Ile Lys Lys Thr Ser 195 200 205 Glu Asp Ala Ser Glu Tyr Phe Glu Asn Tyr Ile Glu Glu Leu Lys Lys 210 215 220 Gln Gly Phe Leu Leu Arg Glu His Phe Thr Pro Glu Ala Thr Gln Leu 225 230 235 240 Ala Ser Glu Gln Leu Gln Ala Leu Leu Leu Glu Glu Val Met Asn Ser 245 250 255 Ser Thr Leu Ser Gln Glu Val Ser Asp Leu Val Glu Met Ile Trp Ala 260 265 270 Glu Ala Leu Gly His Leu Glu His Met Leu Leu Lys Pro Val Asn Arg 275 280 285 Ile Ser Leu Asn Asp Val Ser Lys Ala Glu Gly Ile Leu Leu Leu Val 290 295 300 Lys Ala Ala Leu Lys Asn Gly Glu Thr Ala Glu Gln Leu Gln Lys Met 305 310 315 320 Met Thr Glu Phe Tyr Arg Leu Ile Pro His Lys Gly Thr Met Pro Lys 325 330 335 Glu Val Asn Leu Gly Leu Leu Ala Lys Lys Ala Asp Leu Cys Gln Leu 340 345 350 Ile Arg Asp Met Val Asn Val Cys Glu Thr Asn Leu Ser Lys Pro Asn 355 360 365 Pro Pro Ser Leu Ala Lys Tyr Arg Ala Leu Arg Cys Lys Ile Glu His 370 375 380 Val Glu Gln Asn Thr Glu Glu Phe Leu Arg Val Arg Lys Glu Val Leu 385 390 395 400 Gln Asn His His Ser Lys Ser Pro Val Asp Val Leu Gln Ile Phe Arg 405 410 415 Val Gly Arg Val Asn Glu Thr Thr Glu Phe Leu Ser Lys Leu Gly Asn 420 425 430 Val Arg Pro Leu Leu His Gly Ser Pro Val Gln Asn Ile Val Gly Ile 435 440 445 Leu Cys Arg Gly Leu Leu Leu Pro Lys Val Val Glu Asp Arg Gly Val 450 455 460 Gln Arg Thr Asp Val Gly Asn Leu Gly Ser Gly Ile Tyr Phe Ser Asp 465 470 475 480 Ser Leu Ser Thr Ser Ile Lys Tyr Ser His Pro Gly Glu Thr Asp Gly 485 490 495 Thr Arg Leu Leu Leu Ile Cys Asp Val Ala Leu Gly Lys Cys Met Asp 500 505 510 Leu His Glu Lys Asp Phe Pro Leu Thr Glu Ala Pro Pro Gly Tyr Asp 515 520 525 Ser Val His Gly Val Ser Gln Thr Ala Ser Val Thr Thr Asp Phe Glu 530 535 540 Asp Asp Glu Phe Val Val Tyr Lys Thr Asn Gln Val Lys Met Lys Tyr 545 550 555 560 Ile Ile Lys Phe Ser Met Pro Gly Asp Gln Ile Lys Asp Phe His Pro 565 570 575 Ser Asp His Thr Glu Leu Glu Glu Tyr Arg Pro Glu Phe Ser Asn Phe 580 585 590 Ser Lys Val Glu Asp Tyr Gln Leu Pro Asp Ala Lys Thr Ser Ser Ser 595 600 605 Thr Lys Ala Gly Leu Gln Asp Ala Ser Gly Asn Leu Val Pro Leu Glu 610 615 620 Asp Val His Ile Lys Gly Arg Ile Ile Asp Thr Val Ala Gln Val Ile 625 630 635 640 Val Phe Gln Thr Tyr Thr Asn Lys Ser His Val Pro Ile Glu Ala Lys 645 650 655 Tyr Ile Phe Pro Leu Asp Asp Lys Ala Ala Val Cys Gly Phe Glu Ala 660 665 670 Phe Ile Asn Gly Lys His Ile Val Gly Glu Ile Lys Glu Lys Glu Glu 675 680 685 Ala Gln Gln Glu Tyr Leu Glu Ala Val Thr Gln Gly His Gly Ala Tyr 690 695 700 Leu Met Ser Gln Asp Ala Pro Asp Val Phe Thr Val Ser Val Gly Asn 705 710 715 720 Leu Pro Pro Lys Ala Lys Val Leu Ile Lys Ile Thr Tyr Ile Thr Glu 725 730 735 Leu Ser Ile Leu Gly Thr Val Gly Val Phe Phe Met Pro Ala Thr Val 740 745 750 Ala Pro Trp Gln Gln Asp Lys Ala Leu Asn Glu Asn Leu Gln Asp Thr 755 760 765 Val Glu Lys Ile Cys Ile Lys Glu Ile Gly Thr Lys Gln Ser Phe Ser 770 775 780 Leu Thr Met Ser Ile Glu Met Pro Tyr Val Ile Glu Phe Ile Phe Ser 785 790 795 800 Asp Thr His Glu Leu Lys Gln Lys Arg Thr Asp Cys Lys Ala Val Ile 805 810 815 Ser Thr Met Glu Gly Ser Ser Leu Asp Ser Ser Gly Phe Ser Leu His 820 825 830 Ile Gly Leu Ser Ala Ala Tyr Leu Pro Arg Met Trp Val Glu Lys His 835 840 845 Pro Glu Lys Glu Ser Glu Ala Cys Met Leu Val Phe Gln Pro Asp Leu 850 855 860 Asp Val Asp Leu Pro Asp Leu Ala Ser Glu Ser Glu Val Ile Ile Cys 865 870 875 880 Leu Asp Cys Ser Ser Ser Met Glu Gly Val Thr Phe Leu Gln Ala Lys 885 890 895 Gln Ile Thr Leu His Ala Leu Ser Leu Val Gly Glu Lys Gln Lys Val 900 905 910 Asn Ile Ile Gln Phe Gly Thr Gly Tyr Lys Glu Leu Phe Ser Tyr Pro

915 920 925 Lys His Ile Thr Ser Asn Thr Thr Ala Ala Glu Phe Ile Met Ser Ala 930 935 940 Thr Pro Thr Met Gly Asn Thr Asp Phe Trp Lys Thr Leu Arg Tyr Leu 945 950 955 960 Ser Leu Leu Tyr Pro Ala Arg Gly Ser Arg Asn Ile Leu Leu Val Ser 965 970 975 Asp Gly His Leu Gln Asp Glu Ser Leu Thr Leu Gln Leu Val Lys Arg 980 985 990 Ser Arg Pro His Thr Arg Leu Phe Ala Cys Gly Ile Gly Ser Thr Ala 995 1000 1005 Asn Arg His Val Leu Arg Ile Leu Ser Gln Cys Gly Ala Gly Val 1010 1015 1020 Phe Glu Tyr Phe Asn Ala Lys Ser Lys His Ser Trp Arg Lys Gln 1025 1030 1035 Ile Glu Asp Gln Met Thr Arg Leu Cys Ser Pro Ser Cys His Ser 1040 1045 1050 Val Ser Val Lys Trp Gln Gln Leu Asn Pro Asp Ala Pro Glu Ala 1055 1060 1065 Leu Gln Ala Pro Ala Gln Val Pro Ser Leu Phe Arg Asn Asp Arg 1070 1075 1080 Leu Leu Val Tyr Gly Phe Ile Pro His Cys Thr Gln Ala Thr Leu 1085 1090 1095 Cys Ala Leu Ile Gln Glu Lys Glu Phe Cys Thr Met Val Ser Thr 1100 1105 1110 Thr Glu Leu Gln Lys Thr Thr Gly Thr Met Ile His Lys Leu Ala 1115 1120 1125 Ala Arg Ala Leu Ile Arg Asp Tyr Glu Asp Gly Ile Leu His Glu 1130 1135 1140 Asn Glu Thr Ser His Glu Met Lys Lys Gln Thr Leu Lys Ser Leu 1145 1150 1155 Ile Ile Lys Leu Ser Lys Glu Asn Ser Leu Ile Thr Gln Phe Thr 1160 1165 1170 Ser Phe Val Ala Val Glu Lys Arg Asp Glu Asn Glu Ser Pro Phe 1175 1180 1185 Pro Asp Ile Pro Lys Val Ser Glu Leu Ile Ala Lys Glu Asp Val 1190 1195 1200 Asp Phe Leu Pro Tyr Met Ser Trp Gln Gly Glu Pro Gln Glu Ala 1205 1210 1215 Val Arg Asn Gln Ser Leu Leu Ala Ser Ser Glu Trp Pro Glu Leu 1220 1225 1230 Arg Leu Ser Lys Arg Lys His Arg Lys Ile Pro Phe Ser Lys Arg 1235 1240 1245 Lys Met Glu Leu Ser Gln Pro Glu Val Ser Glu Asp Phe Glu Glu 1250 1255 1260 Asp Gly Leu Gly Val Leu Pro Ala Phe Thr Ser Asn Leu Glu Arg 1265 1270 1275 Gly Gly Val Glu Lys Leu Leu Asp Leu Ser Trp Thr Glu Ser Cys 1280 1285 1290 Lys Pro Thr Ala Thr Glu Pro Leu Phe Lys Lys Val Ser Pro Trp 1295 1300 1305 Glu Thr Ser Thr Ser Ser Phe Phe Pro Ile Leu Ala Pro Ala Val 1310 1315 1320 Gly Ser Tyr Leu Thr Pro Thr Thr Arg Ala His Ser Pro Ala Ser 1325 1330 1335 Leu Ser Phe Ala Ser Tyr Arg Gln Val Ala Ser Phe Gly Ser Ala 1340 1345 1350 Ala Pro Pro Arg Gln Phe Asp Ala Ser Gln Phe Ser Gln Gly Pro 1355 1360 1365 Val Pro Gly Thr Cys Ala Asp Trp Ile Pro Gln Ser Ala Ser Cys 1370 1375 1380 Pro Thr Gly Pro Pro Gln Asn Pro Pro Ser Ala Pro Tyr Cys Gly 1385 1390 1395 Ile Val Phe Ser Gly Ser Ser Leu Ser Ser Ala Gln Ser Ala Pro 1400 1405 1410 Leu Gln His Pro Gly Gly Phe Thr Thr Arg Pro Ser Ala Gly Thr 1415 1420 1425 Phe Pro Glu Leu Asp Ser Pro Gln Leu His Phe Ser Leu Pro Thr 1430 1435 1440 Asp Pro Asp Pro Ile Arg Gly Phe Gly Ser Tyr His Pro Ser Ala 1445 1450 1455 Tyr Ser Pro Phe His Phe Gln Pro Ser Ala Ala Ser Leu Thr Ala 1460 1465 1470 Asn Leu Arg Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys 1475 1480 1485 Ser Gln Ser Arg Thr Thr Pro Val Asp Leu Cys Leu Leu Glu Glu 1490 1495 1500 Ser Val Gly Ser Leu Glu Gly Ser Arg Cys Pro Val Phe Ala Phe 1505 1510 1515 Gln Ser Ser Asp Thr Glu Ser Asp Glu Leu Ser Glu Val Leu Gln 1520 1525 1530 Asp Ser Cys Phe Leu Gln Ile Lys Cys Asp Thr Lys Asp Asp Ser 1535 1540 1545 Ile Pro Cys Phe Leu Glu Leu Lys Glu Glu Asp Glu Ile Val Cys 1550 1555 1560 Thr Gln His Trp Gln Asp Ala Val Pro Trp Thr Glu Leu Leu Ser 1565 1570 1575 Leu Gln Thr Glu Asp Gly Phe Trp Lys Leu Thr Pro Glu Leu Gly 1580 1585 1590 Leu Ile Leu Asn Leu Asn Thr Asn Gly Leu His Ser Phe Leu Lys 1595 1600 1605 Gln Lys Gly Ile Gln Ser Leu Gly Val Lys Gly Arg Glu Cys Leu 1610 1615 1620 Leu Asp Leu Ile Ala Thr Met Leu Val Leu Gln Phe Ile Arg Thr 1625 1630 1635 Arg Leu Glu Lys Glu Gly Ile Val Phe Lys Ser Leu Met Lys Met 1640 1645 1650 Asp Asp Pro Ser Ile Ser Arg Asn Ile Pro Trp Ala Phe Glu Ala 1655 1660 1665 Ile Lys Gln Ala Ser Glu Trp Val Arg Arg Thr Glu Gly Gln Tyr 1670 1675 1680 Pro Ser Ile Cys Pro Arg Leu Glu Leu Gly Asn Asp Trp Asp Ser 1685 1690 1695 Ala Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser Thr Val Ser 1700 1705 1710 Pro Leu His Arg Val Leu His Tyr Ser Gln Gly 1715 1720 <210> SEQ ID NO 4 <400> SEQUENCE: 4 000 <210> SEQ ID NO 5 <211> LENGTH: 5175 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5 atggtgatgg gaatctttgc aaattgtatc ttctgtttga aagtgaagta cttacctcag 60 cagcagaaga aaaagctaca aactgacatt aaggaaaatg gcggaaagtt ttccttttcg 120 ttaaatcctc agtgcacaca tataatctta gataatgctg atgttctgag tcagtaccaa 180 ctgaattcta tccaaaagaa ccacgttcat attgcaaacc cagattttat atggaaatct 240 atcagagaaa agagactctt ggatgtaaag aattatgatc cttataagcc cctggacatc 300 acaccacctc ctgatcagaa ggcgagcagt tctgaagtga aaacagaagg tctatgcccg 360 gacagtgcca cagaggagga agacactgtg gaactcactg agtttggtat gcagaatgtt 420 gaaattcctc atcttcctca agattttgaa gttgcaaaat ataacacctt ggagaaagtg 480 ggaatggagg gaggccagga agctgtggtg gtggagcttc agtgttcgcg ggactccagg 540 gactgtcctt tcctgatatc ctcacacttc ctcctggatg atggcatgga gactagaaga 600 cagtttgcta taaagaaaac ctctgaagat gcaagtgaat actttgaaaa ttacattgaa 660 gaactgaaga aacaaggatt tctactaaga gaacatttca cacctgaagc aacccaatta 720 gcatctgaac aattgcaagc attgcttttg gaggaagtca tgaattcaag cactctgagc 780 caagaggtga gcgatttagt agagatgatt tgggcagagg ccctgggcca cctggaacac 840 atgcttctca agccagtgaa caggattagc ctcaacgatg tgagcaaggc agaggggatt 900 ctccttctag taaaggcagc actgaaaaat ggagaaacag cagagcaatt gcaaaagatg 960 atgacagagt tttacagact gatacctcac aaaggcacaa tgcccaaaga agtgaacctg 1020 ggactattgg ctaagaaagc agacctctgc cagctaataa gagacatggt taatgtctgt 1080 gaaactaatt tgtccaaacc caacccacca tccctggcca aataccgagc tttgaggtgc 1140 aaaattgagc atgttgaaca gaatactgaa gaatttctca gggttagaaa agaggttttg 1200 cagaatcatc acagtaagag cccagtggat gtcttgcaga tatttagagt tggcagagtg 1260 aatgaaacca cagagttttt gagcaaactt ggtaatgtga ggcccttgtt gcatggttct 1320 cctgtacaaa acatcgtggg aatcttgtgt cgagggttgc ttttacccaa agtagtggaa 1380 gatcgtggtg tgcaaagaac agacgtcgga aaccttggaa gtgggattta tttcagtgat 1440 tcgctcagta caagtatcaa gtactcacac ccgggagaga cagatggcac cagactcctg 1500 ctcatttgtg acgtagccct cggaaagtgt atggacttac atgagaagga ctttccctta 1560 actgaagcac caccaggcta cgacagtgtg catggagttt cacaaacagc ctctgtcacc 1620 acagactttg aggatgatga atttgttgtc tataaaacca atcaggttaa aatgaaatat 1680 attattaaat tttccatgcc tggagatcag ataaaggact ttcatcctag tgatcatact 1740 gaattagagg aatacagacc tgagttttca aatttttcaa aggttgaaga ttaccagtta 1800 ccagatgcca aaacttccag cagcaccaag gccggcctcc aggatgcctc tgggaacttg 1860 gttcctctgg aggatgtcca catcaaaggg agaatcatag acactgtagc ccaggtcatt 1920 gtttttcaga catacacaaa taaaagtcac gtgcccattg aggcaaaata tatctttcct 1980 ttggatgaca aggccgctgt gtgtggcttc gaagccttca tcaatgggaa gcacatagtt 2040 ggagagatta aagagaagga agaagcccag caagagtacc tagaagccgt gacccagggc 2100 catggcgctt acctgatgag tcaggatgct ccggacgttt ttactgtaag tgttggaaac 2160 ttacccccta aggctaaggt tcttataaaa attacctaca tcacagaact cagcatcctg 2220 ggcactgttg gtgtcttttt catgcccgcc accgtagcac cctggcaaca ggacaaggct 2280

ttgaatgaaa accttcagga tacagtagag aagatttgta taaaagaaat aggaacaaag 2340 caaagcttct ctttgactat gtctattgag atgccgtatg tgattgaatt cattttcagt 2400 gatacacatg aactgaaaca aaagcgcaca gactgcaaag ctgtcattag caccatggaa 2460 ggcagctcct tagacagcag tggattttct ctccacatcg gtttgtctgc tgcctatctc 2520 ccaagaatgt gggttgaaaa acatccagaa aaagaaagcg aggcttgcat gcttgtcttt 2580 caacccgatc tcgatgtcga cctccctgac ctagccagtg agagcgaagt gattatttgt 2640 cttgactgct ccagttccat ggagggtgtg acattcttgc aagccaagca aatcaccttg 2700 catgcgctgt ccttggtggg tgagaagcag aaagtaaata ttatccagtt cggcacaggt 2760 tacaaggagc tattttcgta tcctaagcat atcacaagca ataccacggc agcagagttc 2820 atcatgtctg ccacacctac catggggaac acagacttct ggaaaacact ccgatatctt 2880 agcttattgt accctgctcg agggtcacgg aacatcctcc tggtgtctga tgggcacctc 2940 caggatgaga gcctgacatt acagctcgtg aagaggagcc gcccgcacac caggttattc 3000 gcctgcggta tcggttctac agcaaatcgt cacgtcttaa ggattttgtc ccagtgtggt 3060 gccggagtat ttgaatattt taatgcaaaa tccaagcata gttggagaaa acagatagaa 3120 gaccaaatga ccaggctatg ttctccgagt tgccactctg tctccgtcaa atggcagcaa 3180 ctcaatccag atgcgcccga ggccctgcag gccccagccc aggtgccatc cttgtttcgc 3240 aatgatcgac tccttgtcta tggattcatt cctcactgca cacaagcaac tctgtgtgca 3300 ctaattcaag agaaagaatt ttgtacaatg gtgtcgacta ctgagcttca gaagacaact 3360 ggaactatga tccacaagct ggcagcccga gctctaatca gagattatga agatggcatt 3420 cttcacgaaa atgaaaccag tcatgagatg aaaaaacaaa ccttgaaatc tctgattatt 3480 aaactcagta aagaaaactc tctcataaca caatttacaa gctttgtggc agttgagaaa 3540 agggatgaga atgagtcgcc ttttcctgat attccaaaag tttctgaact tattgccaaa 3600 gaagatgtag acttcctgcc ctacatgagc tggcaggggg agccccaaga agccgtcagg 3660 aaccagtctc ttttagcatc ctctgagtgg ccagaattac gtttatccaa acgaaaacat 3720 aggaaaattc cattttccaa aagaaaaatg gaattatctc agccagaagt ttctgaagat 3780 tttgaagagg atggcttagg tgtactacca gctttcacat caaatttgga acgtggaggt 3840 gtggaaaagc tattggattt aagttggaca gagtcatgta aaccaacagc aactgaacca 3900 ctatttaaga aagtcagtcc atgggaaaca tctacttcta gcttttttcc tattttggct 3960 ccggccgttg gttcctatct taccccgact acccgcgctc acagtcctgc ttccttgtct 4020 tttgcctcat atcgtcaggt agctagtttc ggttcagctg ctcctcccag acagtttgat 4080 gcatctcaat tcagccaagg ccctgtgcct ggcacttgtg ctgactggat cccacagtcg 4140 gcgtcttgtc ccacaggacc tccccagaac ccaccttctg caccctattg tggcattgtt 4200 ttttcaggga gctcattaag ctctgcacag tctgctccac tgcaacatcc tggaggcttt 4260 actaccaggc cttctgctgg caccttccct gagctggatt ctccccagct tcatttctct 4320 cttcctacag accctgatcc catcagaggt tttgggtctt atcatccctc tgcttactct 4380 ccttttcatt ttcaaccttc cgcagcctct ttgactgcca accttaggct gccaatggcc 4440 tctgctttac ctgaggctct ttgcagtcag tcccggacta ccccagtaga tctctgtctt 4500 ctagaagaat cagtaggcag tctcgaagga agtcgatgtc ctgtctttgc ttttcaaagt 4560 tctgacacag aaagtgatga gctatcagaa gtacttcaag acagctgctt tttacaaata 4620 aagtgtgata caaaagatga cagtatcccg tgctttctgg aattaaaaga agaggatgaa 4680 atagtgtgca cacaacactg gcaggatgct gtgccttgga cagaactcct cagtctacag 4740 acagaggatg gcttctggaa acttacacca gaactgggac ttatattaaa tcttaataca 4800 aatggtttgc acagctttct taaacaaaaa ggcattcaat ctctaggtgt aaaaggaaga 4860 gaatgtctcc tggacctaat tgccacaatg ctggtactac agtttattcg caccaggttg 4920 gaaaaagagg gaatagtgtt caaatcactg atgaaaatgg atgacccttc tatttccagg 4980 aatattccct gggcttttga ggcaataaag caagcaagtg aatgggtaag aagaactgaa 5040 ggacagtacc catctatctg cccacggctt gaactgggga acgactggga ctctgccacc 5100 aagcagttgc tgggactcca gcccataagc actgtgtccc ctcttcatag agtcctccat 5160 tacagtcaag gctaa 5175 <210> SEQ ID NO 6 <211> LENGTH: 893 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Met Ala Thr Glu Glu Phe Ile Ile Arg Ile Pro Pro Tyr His Tyr Ile 1 5 10 15 His Val Leu Asp Gln Asn Ser Asn Val Ser Arg Val Glu Val Gly Pro 20 25 30 Lys Thr Tyr Ile Arg Gln Asp Asn Glu Arg Val Leu Phe Ala Pro Met 35 40 45 Arg Met Val Thr Val Pro Pro Arg His Tyr Cys Thr Val Ala Asn Pro 50 55 60 Val Ser Arg Asp Ala Gln Gly Leu Val Leu Phe Asp Val Thr Gly Gln 65 70 75 80 Val Arg Leu Arg His Ala Asp Leu Glu Ile Arg Leu Ala Gln Asp Pro 85 90 95 Phe Pro Leu Tyr Pro Gly Glu Val Leu Glu Lys Asp Ile Thr Pro Leu 100 105 110 Gln Val Val Leu Pro Asn Thr Ala Leu His Leu Lys Ala Leu Leu Asp 115 120 125 Phe Glu Asp Lys Asp Gly Asp Lys Val Val Ala Gly Asp Glu Trp Leu 130 135 140 Phe Glu Gly Pro Gly Thr Tyr Ile Pro Arg Lys Glu Val Glu Val Val 145 150 155 160 Glu Ile Ile Gln Ala Thr Ile Ile Arg Gln Asn Gln Ala Leu Arg Leu 165 170 175 Arg Ala Arg Lys Glu Cys Trp Asp Arg Asp Gly Lys Glu Arg Val Thr 180 185 190 Gly Glu Glu Trp Leu Val Thr Thr Val Gly Ala Tyr Leu Pro Ala Val 195 200 205 Phe Glu Glu Val Leu Asp Leu Val Asp Ala Val Ile Leu Thr Glu Lys 210 215 220 Thr Ala Leu His Leu Arg Ala Arg Arg Asn Phe Arg Asp Phe Arg Gly 225 230 235 240 Val Ser Arg Arg Thr Gly Glu Glu Trp Leu Val Thr Val Gln Asp Thr 245 250 255 Glu Ala His Val Pro Asp Val His Glu Glu Val Leu Gly Val Val Pro 260 265 270 Ile Thr Thr Leu Gly Pro His Asn Tyr Cys Val Ile Leu Asp Pro Val 275 280 285 Gly Pro Asp Gly Lys Asn Gln Leu Gly Gln Lys Arg Val Val Lys Gly 290 295 300 Glu Lys Ser Phe Phe Leu Gln Pro Gly Glu Gln Leu Glu Gln Gly Ile 305 310 315 320 Gln Asp Val Tyr Val Leu Ser Glu Gln Gln Gly Leu Leu Leu Arg Ala 325 330 335 Leu Gln Pro Leu Glu Glu Gly Glu Asp Glu Glu Lys Val Ser His Gln 340 345 350 Ala Gly Asp His Trp Leu Ile Arg Gly Pro Leu Glu Tyr Val Pro Ser 355 360 365 Ala Lys Val Glu Val Val Glu Glu Arg Gln Ala Ile Pro Leu Asp Glu 370 375 380 Asn Glu Gly Ile Tyr Val Gln Asp Val Lys Thr Gly Lys Val Arg Ala 385 390 395 400 Val Ile Gly Ser Thr Tyr Met Leu Thr Gln Asp Glu Val Leu Trp Glu 405 410 415 Lys Glu Leu Pro Pro Gly Val Glu Glu Leu Leu Asn Lys Gly Gln Asp 420 425 430 Pro Leu Ala Asp Arg Gly Glu Lys Asp Thr Ala Lys Ser Leu Gln Pro 435 440 445 Leu Ala Pro Arg Asn Lys Thr Arg Val Val Ser Tyr Arg Val Pro His 450 455 460 Asn Ala Ala Val Gln Val Tyr Asp Tyr Arg Glu Lys Arg Ala Arg Val 465 470 475 480 Val Phe Gly Pro Glu Leu Val Ser Leu Gly Pro Glu Glu Gln Phe Thr 485 490 495 Val Leu Ser Leu Ser Ala Gly Arg Pro Lys Arg Pro His Ala Arg Arg 500 505 510 Ala Leu Cys Leu Leu Leu Gly Pro Asp Phe Phe Thr Asp Val Ile Thr 515 520 525 Ile Glu Thr Ala Asp His Ala Arg Leu Gln Leu Gln Leu Ala Tyr Asn 530 535 540 Trp His Phe Glu Val Asn Asp Arg Lys Asp Pro Gln Glu Thr Ala Lys 545 550 555 560 Leu Phe Ser Val Pro Asp Phe Val Gly Asp Ala Cys Lys Ala Ile Ala 565 570 575 Ser Arg Val Arg Gly Ala Val Ala Ser Val Thr Phe Asp Asp Phe His 580 585 590 Lys Asn Ser Ala Arg Ile Ile Arg Thr Ala Val Phe Gly Phe Glu Thr 595 600 605 Ser Glu Ala Lys Gly Pro Asp Gly Met Ala Leu Pro Arg Pro Arg Asp 610 615 620 Gln Ala Val Phe Pro Gln Asn Gly Leu Val Val Ser Ser Val Asp Val 625 630 635 640 Gln Ser Val Glu Pro Val Asp Gln Arg Thr Arg Asp Ala Leu Gln Arg 645 650 655 Ser Val Gln Leu Ala Ile Glu Ile Thr Thr Asn Ser Gln Glu Ala Ala 660 665 670 Ala Lys His Glu Ala Gln Arg Leu Glu Gln Glu Ala Arg Gly Arg Leu 675 680 685 Glu Arg Gln Lys Ile Leu Asp Gln Ser Glu Ala Glu Lys Ala Arg Lys 690 695 700 Glu Leu Leu Glu Leu Glu Ala Leu Ser Met Ala Val Glu Ser Thr Gly 705 710 715 720 Thr Ala Lys Ala Glu Ala Glu Ser Arg Ala Glu Ala Ala Arg Ile Glu 725 730 735 Gly Glu Gly Ser Val Leu Gln Ala Lys Leu Lys Ala Gln Ala Leu Ala 740 745 750 Ile Glu Thr Glu Ala Glu Leu Gln Arg Val Gln Lys Val Arg Glu Leu 755 760 765

Glu Leu Val Tyr Ala Arg Ala Gln Leu Glu Leu Glu Val Ser Lys Ala 770 775 780 Gln Gln Leu Ala Glu Val Glu Val Lys Lys Phe Lys Gln Met Thr Glu 785 790 795 800 Ala Ile Gly Pro Ser Thr Ile Arg Asp Leu Ala Val Ala Gly Pro Glu 805 810 815 Met Gln Val Lys Leu Leu Gln Ser Leu Gly Leu Lys Ser Thr Leu Ile 820 825 830 Thr Asp Gly Ser Thr Pro Ile Asn Leu Phe Asn Thr Ala Phe Gly Leu 835 840 845 Leu Gly Met Gly Pro Glu Gly Gln Pro Leu Gly Arg Arg Val Ala Ser 850 855 860 Gly Pro Ser Pro Gly Glu Gly Ile Ser Pro Gln Ser Ala Gln Ala Pro 865 870 875 880 Gln Ala Pro Gly Asp Asn His Val Val Pro Val Leu Arg 885 890 <210> SEQ ID NO 7 <211> LENGTH: 2682 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 atggcaactg aagagttcat catccgcatc cccccatacc actatatcca tgtgctggac 60 cagaacagca acgtgtcccg tgtggaggtc gggccaaaga cctacatccg gcaggacaat 120 gagagggtac tgtttgcccc catgcgcatg gtgaccgtcc ccccacgtca ctactgcaca 180 gtggccaacc ctgtgtctcg ggatgcccag ggcttggtgc tgtttgatgt cacagggcaa 240 gttcggcttc gccacgctga cctcgagatc cggctggccc aggacccctt ccccctgtac 300 ccaggggagg tgctggaaaa ggacatcaca cccctgcagg tggttctgcc caacactgcc 360 ctccatctaa aggcgctgct tgattttgag gataaagatg gagacaaggt ggtggcagga 420 gatgagtggc ttttcgaggg acctggcacg tacatccccc ggaaggaagt ggaggtcgtg 480 gagatcattc aggccaccat catcaggcag aaccaggctc tgcggctcag ggcccgcaag 540 gagtgctggg accgggacgg caaggagagg gtgacagggg aagaatggct ggtcaccaca 600 gtaggggcgt acctcccagc ggtgtttgag gaggttctgg atttggtgga cgccgtcatc 660 cttacggaaa agacagccct gcacctccgg gctcggcgga acttccggga cttcagggga 720 gtgtcccgcc gcactgggga ggagtggctg gtaacagtgc aggacacaga ggcccacgtg 780 ccagatgtcc acgaggaggt gctgggggtt gtgcccatca ccaccctggg cccccacaac 840 tactgcgtga ttctcgaccc tgtcggaccg gatggcaaga atcagctggg gcagaagcgc 900 gtggtcaagg gagagaagtc ttttttcctc cagccaggag agcagctgga acaaggcatc 960 caggatgtgt atgtgctgtc ggagcagcag gggctgctgc tgagggccct gcagcccctg 1020 gaggaggggg aggatgagga gaaggtctca caccaggctg gggaccactg gctcatccgc 1080 ggacccctgg agtatgtgcc atctgccaaa gtggaggtgg tggaggagcg ccaggccatc 1140 cctctagacg agaacgaggg catctatgtg caggatgtca agaccggaaa ggtgcgcgct 1200 gtgattggaa gcacctacat gctgacccag gacgaagtcc tgtgggagaa agagctgcct 1260 cccggggtgg aggagctgct gaacaagggg caggaccctc tggcagacag gggtgagaag 1320 gacacagcta agagcctcca gcccttggcg ccccggaaca agacccgtgt ggtcagctac 1380 cgcgtgcccc acaacgctgc ggtgcaggtg tacgactacc gagagaagcg agcccgcgtg 1440 gtcttcgggc ctgagctggt gtcgctgggt cctgaggagc agttcacagt gttgtccctc 1500 tcagctgggc ggcccaagcg tccccatgcc cgccgtgcgc tctgcctgct gctggggcct 1560 gacttcttca cagacgtcat caccatcgaa acggcggatc atgccaggct gcaactgcag 1620 ctggcctaca actggcactt tgaggtgaat gaccggaagg acccccaaga gacggccaag 1680 ctcttttcag tgccagactt tgtaggtgat gcctgcaaag ccatcgcatc ccgggtgcgg 1740 ggggccgtgg cctctgtcac tttcgatgac ttccataaga actcagcccg catcattcgc 1800 actgctgtct ttggctttga gacctcggaa gcgaagggcc ccgatggcat ggccctgccc 1860 aggccccggg accaggctgt cttcccccaa aacgggctgg tggtcagcag tgtggacgtg 1920 cagtcagtgg agcctgtgga tcagaggacc cgggacgccc tgcaacgcag cgtccagctg 1980 gccatcgaga tcaccaccaa ctcccaggaa gcggcggcca agcatgaggc tcagagactg 2040 gagcaggaag cccgcggccg gcttgagcgg cagaagatcc tggaccagtc agaagccgag 2100 aaagctcgca aggaactttt ggagctggag gctctgagca tggccgtgga gagcaccggg 2160 actgccaagg cggaggccga gtcccgtgcg gaggcagccc ggattgaggg agaagggtcc 2220 gtgctgcagg ccaagctaaa agcacaggcc ttggccattg aaacggaggc tgagctccag 2280 agggtccaga aggtccgaga gctggaactg gtctatgccc gggcccagct ggagctggag 2340 gtgagcaagg ctcagcagct ggctgaggtg gaggtgaaga agttcaagca gatgacagag 2400 gccataggcc ccagcaccat cagggacctt gctgtggctg ggcctgagat gcaggtaaaa 2460 ctgctccagt ccctgggcct gaaatcaacc ctcatcaccg atggctccac tcccatcaac 2520 ctcttcaaca cagcctttgg gctgctgggg atggggcccg agggtcagcc cctgggcaga 2580 agggtggcca gtgggcccag ccctggggag gggatatccc cccagtctgc tcaggcccct 2640 caagctcctg gagacaacca cgtggtgcct gtactgcgct aa 2682 <210> SEQ ID NO 8 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 8 Met Ala Gly Cys Gly Cys Pro Cys Gly Cys Gly Ala 1 5 10 <210> SEQ ID NO 9 <211> LENGTH: 905 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 9 Met Ala Gly Cys Gly Cys Pro Cys Gly Cys Gly Ala Met Ala Thr Glu 1 5 10 15 Glu Phe Ile Ile Arg Ile Pro Pro Tyr His Tyr Ile His Val Leu Asp 20 25 30 Gln Asn Ser Asn Val Ser Arg Val Glu Val Gly Pro Lys Thr Tyr Ile 35 40 45 Arg Gln Asp Asn Glu Arg Val Leu Phe Ala Pro Met Arg Met Val Thr 50 55 60 Val Pro Pro Arg His Tyr Cys Thr Val Ala Asn Pro Val Ser Arg Asp 65 70 75 80 Ala Gln Gly Leu Val Leu Phe Asp Val Thr Gly Gln Val Arg Leu Arg 85 90 95 His Ala Asp Leu Glu Ile Arg Leu Ala Gln Asp Pro Phe Pro Leu Tyr 100 105 110 Pro Gly Glu Val Leu Glu Lys Asp Ile Thr Pro Leu Gln Val Val Leu 115 120 125 Pro Asn Thr Ala Leu His Leu Lys Ala Leu Leu Asp Phe Glu Asp Lys 130 135 140 Asp Gly Asp Lys Val Val Ala Gly Asp Glu Trp Leu Phe Glu Gly Pro 145 150 155 160 Gly Thr Tyr Ile Pro Arg Lys Glu Val Glu Val Val Glu Ile Ile Gln 165 170 175 Ala Thr Ile Ile Arg Gln Asn Gln Ala Leu Arg Leu Arg Ala Arg Lys 180 185 190 Glu Cys Trp Asp Arg Asp Gly Lys Glu Arg Val Thr Gly Glu Glu Trp 195 200 205 Leu Val Thr Thr Val Gly Ala Tyr Leu Pro Ala Val Phe Glu Glu Val 210 215 220 Leu Asp Leu Val Asp Ala Val Ile Leu Thr Glu Lys Thr Ala Leu His 225 230 235 240 Leu Arg Ala Arg Arg Asn Phe Arg Asp Phe Arg Gly Val Ser Arg Arg 245 250 255 Thr Gly Glu Glu Trp Leu Val Thr Val Gln Asp Thr Glu Ala His Val 260 265 270 Pro Asp Val His Glu Glu Val Leu Gly Val Val Pro Ile Thr Thr Leu 275 280 285 Gly Pro His Asn Tyr Cys Val Ile Leu Asp Pro Val Gly Pro Asp Gly 290 295 300 Lys Asn Gln Leu Gly Gln Lys Arg Val Val Lys Gly Glu Lys Ser Phe 305 310 315 320 Phe Leu Gln Pro Gly Glu Gln Leu Glu Gln Gly Ile Gln Asp Val Tyr 325 330 335 Val Leu Ser Glu Gln Gln Gly Leu Leu Leu Arg Ala Leu Gln Pro Leu 340 345 350 Glu Glu Gly Glu Asp Glu Glu Lys Val Ser His Gln Ala Gly Asp His 355 360 365 Trp Leu Ile Arg Gly Pro Leu Glu Tyr Val Pro Ser Ala Lys Val Glu 370 375 380 Val Val Glu Glu Arg Gln Ala Ile Pro Leu Asp Glu Asn Glu Gly Ile 385 390 395 400 Tyr Val Gln Asp Val Lys Thr Gly Lys Val Arg Ala Val Ile Gly Ser 405 410 415 Thr Tyr Met Leu Thr Gln Asp Glu Val Leu Trp Glu Lys Glu Leu Pro 420 425 430 Pro Gly Val Glu Glu Leu Leu Asn Lys Gly Gln Asp Pro Leu Ala Asp 435 440 445 Arg Gly Glu Lys Asp Thr Ala Lys Ser Leu Gln Pro Leu Ala Pro Arg 450 455 460 Asn Lys Thr Arg Val Val Ser Tyr Arg Val Pro His Asn Ala Ala Val 465 470 475 480 Gln Val Tyr Asp Tyr Arg Glu Lys Arg Ala Arg Val Val Phe Gly Pro 485 490 495 Glu Leu Val Ser Leu Gly Pro Glu Glu Gln Phe Thr Val Leu Ser Leu 500 505 510 Ser Ala Gly Arg Pro Lys Arg Pro His Ala Arg Arg Ala Leu Cys Leu 515 520 525 Leu Leu Gly Pro Asp Phe Phe Thr Asp Val Ile Thr Ile Glu Thr Ala 530 535 540

Asp His Ala Arg Leu Gln Leu Gln Leu Ala Tyr Asn Trp His Phe Glu 545 550 555 560 Val Asn Asp Arg Lys Asp Pro Gln Glu Thr Ala Lys Leu Phe Ser Val 565 570 575 Pro Asp Phe Val Gly Asp Ala Cys Lys Ala Ile Ala Ser Arg Val Arg 580 585 590 Gly Ala Val Ala Ser Val Thr Phe Asp Asp Phe His Lys Asn Ser Ala 595 600 605 Arg Ile Ile Arg Thr Ala Val Phe Gly Phe Glu Thr Ser Glu Ala Lys 610 615 620 Gly Pro Asp Gly Met Ala Leu Pro Arg Pro Arg Asp Gln Ala Val Phe 625 630 635 640 Pro Gln Asn Gly Leu Val Val Ser Ser Val Asp Val Gln Ser Val Glu 645 650 655 Pro Val Asp Gln Arg Thr Arg Asp Ala Leu Gln Arg Ser Val Gln Leu 660 665 670 Ala Ile Glu Ile Thr Thr Asn Ser Gln Glu Ala Ala Ala Lys His Glu 675 680 685 Ala Gln Arg Leu Glu Gln Glu Ala Arg Gly Arg Leu Glu Arg Gln Lys 690 695 700 Ile Leu Asp Gln Ser Glu Ala Glu Lys Ala Arg Lys Glu Leu Leu Glu 705 710 715 720 Leu Glu Ala Leu Ser Met Ala Val Glu Ser Thr Gly Thr Ala Lys Ala 725 730 735 Glu Ala Glu Ser Arg Ala Glu Ala Ala Arg Ile Glu Gly Glu Gly Ser 740 745 750 Val Leu Gln Ala Lys Leu Lys Ala Gln Ala Leu Ala Ile Glu Thr Glu 755 760 765 Ala Glu Leu Gln Arg Val Gln Lys Val Arg Glu Leu Glu Leu Val Tyr 770 775 780 Ala Arg Ala Gln Leu Glu Leu Glu Val Ser Lys Ala Gln Gln Leu Ala 785 790 795 800 Glu Val Glu Val Lys Lys Phe Lys Gln Met Thr Glu Ala Ile Gly Pro 805 810 815 Ser Thr Ile Arg Asp Leu Ala Val Ala Gly Pro Glu Met Gln Val Lys 820 825 830 Leu Leu Gln Ser Leu Gly Leu Lys Ser Thr Leu Ile Thr Asp Gly Ser 835 840 845 Thr Pro Ile Asn Leu Phe Asn Thr Ala Phe Gly Leu Leu Gly Met Gly 850 855 860 Pro Glu Gly Gln Pro Leu Gly Arg Arg Val Ala Ser Gly Pro Ser Pro 865 870 875 880 Gly Glu Gly Ile Ser Pro Gln Ser Ala Gln Ala Pro Gln Ala Pro Gly 885 890 895 Asp Asn His Val Val Pro Val Leu Arg 900 905 <210> SEQ ID NO 10 <211> LENGTH: 2718 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 10 atggcaggct gcggttgtcc atgcggttgt ggcgccatgg caactgaaga gttcatcatc 60 cgcatccccc cataccacta tatccatgtg ctggaccaga acagcaacgt gtcccgtgtg 120 gaggtcgggc caaagaccta catccggcag gacaatgaga gggtactgtt tgcccccatg 180 cgcatggtga ccgtcccccc acgtcactac tgcacagtgg ccaaccctgt gtctcgggat 240 gcccagggct tggtgctgtt tgatgtcaca gggcaagttc ggcttcgcca cgctgacctc 300 gagatccggc tggcccagga ccccttcccc ctgtacccag gggaggtgct ggaaaaggac 360 atcacacccc tgcaggtggt tctgcccaac actgccctcc atctaaaggc gctgcttgat 420 tttgaggata aagatggaga caaggtggtg gcaggagatg agtggctttt cgagggacct 480 ggcacgtaca tcccccggaa ggaagtggag gtcgtggaga tcattcaggc caccatcatc 540 aggcagaacc aggctctgcg gctcagggcc cgcaaggagt gctgggaccg ggacggcaag 600 gagagggtga caggggaaga atggctggtc accacagtag gggcgtacct cccagcggtg 660 tttgaggagg ttctggattt ggtggacgcc gtcatcctta cggaaaagac agccctgcac 720 ctccgggctc ggcggaactt ccgggacttc aggggagtgt cccgccgcac tggggaggag 780 tggctggtaa cagtgcagga cacagaggcc cacgtgccag atgtccacga ggaggtgctg 840 ggggttgtgc ccatcaccac cctgggcccc cacaactact gcgtgattct cgaccctgtc 900 ggaccggatg gcaagaatca gctggggcag aagcgcgtgg tcaagggaga gaagtctttt 960 ttcctccagc caggagagca gctggaacaa ggcatccagg atgtgtatgt gctgtcggag 1020 cagcaggggc tgctgctgag ggccctgcag cccctggagg agggggagga tgaggagaag 1080 gtctcacacc aggctgggga ccactggctc atccgcggac ccctggagta tgtgccatct 1140 gccaaagtgg aggtggtgga ggagcgccag gccatccctc tagacgagaa cgagggcatc 1200 tatgtgcagg atgtcaagac cggaaaggtg cgcgctgtga ttggaagcac ctacatgctg 1260 acccaggacg aagtcctgtg ggagaaagag ctgcctcccg gggtggagga gctgctgaac 1320 aaggggcagg accctctggc agacaggggt gagaaggaca cagctaagag cctccagccc 1380 ttggcgcccc ggaacaagac ccgtgtggtc agctaccgcg tgccccacaa cgctgcggtg 1440 caggtgtacg actaccgaga gaagcgagcc cgcgtggtct tcgggcctga gctggtgtcg 1500 ctgggtcctg aggagcagtt cacagtgttg tccctctcag ctgggcggcc caagcgtccc 1560 catgcccgcc gtgcgctctg cctgctgctg gggcctgact tcttcacaga cgtcatcacc 1620 atcgaaacgg cggatcatgc caggctgcaa ctgcagctgg cctacaactg gcactttgag 1680 gtgaatgacc ggaaggaccc ccaagagacg gccaagctct tttcagtgcc agactttgta 1740 ggtgatgcct gcaaagccat cgcatcccgg gtgcgggggg ccgtggcctc tgtcactttc 1800 gatgacttcc ataagaactc agcccgcatc attcgcactg ctgtctttgg ctttgagacc 1860 tcggaagcga agggccccga tggcatggcc ctgcccaggc cccgggacca ggctgtcttc 1920 ccccaaaacg ggctggtggt cagcagtgtg gacgtgcagt cagtggagcc tgtggatcag 1980 aggacccggg acgccctgca acgcagcgtc cagctggcca tcgagatcac caccaactcc 2040 caggaagcgg cggccaagca tgaggctcag agactggagc aggaagcccg cggccggctt 2100 gagcggcaga agatcctgga ccagtcagaa gccgagaaag ctcgcaagga acttttggag 2160 ctggaggctc tgagcatggc cgtggagagc accgggactg ccaaggcgga ggccgagtcc 2220 cgtgcggagg cagcccggat tgagggagaa gggtccgtgc tgcaggccaa gctaaaagca 2280 caggccttgg ccattgaaac ggaggctgag ctccagaggg tccagaaggt ccgagagctg 2340 gaactggtct atgcccgggc ccagctggag ctggaggtga gcaaggctca gcagctggct 2400 gaggtggagg tgaagaagtt caagcagatg acagaggcca taggccccag caccatcagg 2460 gaccttgctg tggctgggcc tgagatgcag gtaaaactgc tccagtccct gggcctgaaa 2520 tcaaccctca tcaccgatgg ctccactccc atcaacctct tcaacacagc ctttgggctg 2580 ctggggatgg ggcccgaggg tcagcccctg ggcagaaggg tggccagtgg gcccagccct 2640 ggggagggga tatcccccca gtctgctcag gcccctcaag ctcctggaga caaccacgtg 2700 gtgcctgtac tgcgctaa 2718 <210> SEQ ID NO 11 <211> LENGTH: 2627 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 Met Glu Lys Leu His Gly His Val Ser Ala His Pro Asp Ile Leu Ser 1 5 10 15 Leu Glu Asn Arg Cys Leu Ala Met Leu Pro Asp Leu Gln Pro Leu Glu 20 25 30 Lys Leu His Gln His Val Ser Thr His Ser Asp Ile Leu Ser Leu Lys 35 40 45 Asn Gln Cys Leu Ala Thr Leu Pro Asp Leu Lys Thr Met Glu Lys Pro 50 55 60 His Gly Tyr Val Ser Ala His Pro Asp Ile Leu Ser Leu Glu Asn Gln 65 70 75 80 Cys Leu Ala Thr Leu Ser Asp Leu Lys Thr Met Glu Lys Pro His Gly 85 90 95 His Val Ser Ala His Pro Asp Ile Leu Ser Leu Glu Asn Arg Cys Leu 100 105 110 Ala Thr Leu Pro Ser Leu Lys Ser Thr Val Ser Ala Ser Pro Leu Phe 115 120 125 Gln Ser Leu Gln Ile Ser His Met Thr Gln Ala Asp Leu Tyr Arg Val 130 135 140 Asn Asn Ser Asn Cys Leu Leu Ser Glu Pro Pro Ser Trp Arg Ala Gln 145 150 155 160 His Phe Ser Lys Gly Leu Asp Leu Ser Thr Cys Pro Ile Ala Leu Lys 165 170 175 Ser Ile Ser Ala Thr Glu Thr Ala Gln Glu Ala Thr Leu Gly Arg Trp 180 185 190 Phe Asp Ser Glu Glu Lys Lys Gly Ala Glu Thr Gln Met Pro Ser Tyr 195 200 205 Ser Leu Ser Leu Gly Glu Glu Glu Glu Val Glu Asp Leu Ala Val Lys 210 215 220 Leu Thr Ser Gly Asp Ser Glu Ser His Pro Glu Pro Thr Asp His Val 225 230 235 240 Leu Gln Glu Lys Lys Met Ala Leu Leu Ser Leu Leu Cys Ser Thr Leu 245 250 255 Val Ser Glu Val Asn Met Asn Asn Thr Ser Asp Pro Thr Leu Ala Ala 260 265 270 Ile Phe Glu Ile Cys Arg Glu Leu Ala Leu Leu Glu Pro Glu Phe Ile 275 280 285 Leu Lys Ala Ser Leu Tyr Ala Arg Gln Gln Leu Asn Val Arg Asn Val 290 295 300 Ala Asn Asn Ile Leu Ala Ile Ala Ala Phe Leu Pro Ala Cys Arg Pro 305 310 315 320 His Leu Arg Arg Tyr Phe Cys Ala Ile Val Gln Leu Pro Ser Asp Trp 325 330 335 Ile Gln Val Ala Glu Leu Tyr Gln Ser Leu Ala Glu Gly Asp Lys Asn 340 345 350 Lys Leu Val Pro Leu Pro Ala Cys Leu Arg Thr Ala Met Thr Asp Lys 355 360 365 Phe Ala Gln Phe Asp Glu Tyr Gln Leu Ala Lys Tyr Asn Pro Arg Lys

370 375 380 His Arg Ala Lys Arg His Pro Arg Arg Pro Pro Arg Ser Pro Gly Met 385 390 395 400 Glu Pro Pro Phe Ser His Arg Cys Phe Pro Arg Tyr Ile Gly Phe Leu 405 410 415 Arg Glu Glu Gln Arg Lys Phe Glu Lys Ala Gly Asp Thr Val Ser Glu 420 425 430 Lys Lys Asn Pro Pro Arg Phe Thr Leu Lys Lys Leu Val Gln Arg Leu 435 440 445 His Ile His Lys Pro Ala Gln His Val Gln Ala Leu Leu Gly Tyr Arg 450 455 460 Tyr Pro Ser Asn Leu Gln Leu Phe Ser Arg Ser Arg Leu Pro Gly Pro 465 470 475 480 Trp Asp Ser Ser Arg Ala Gly Lys Arg Met Lys Leu Ser Arg Pro Glu 485 490 495 Thr Trp Glu Arg Glu Leu Ser Leu Arg Gly Asn Lys Ala Ser Val Trp 500 505 510 Glu Glu Leu Ile Glu Asn Gly Lys Leu Pro Phe Met Ala Met Leu Arg 515 520 525 Asn Leu Cys Asn Leu Leu Arg Val Gly Ile Ser Ser Arg His His Glu 530 535 540 Leu Ile Leu Gln Arg Leu Gln His Gly Lys Ser Val Ile His Ser Arg 545 550 555 560 Gln Phe Pro Phe Arg Phe Leu Asn Ala His Asp Ala Ile Asp Ala Leu 565 570 575 Glu Ala Gln Leu Arg Asn Gln Ala Leu Pro Phe Pro Ser Asn Ile Thr 580 585 590 Leu Met Arg Arg Ile Leu Thr Arg Asn Glu Lys Asn Arg Pro Arg Arg 595 600 605 Arg Phe Leu Cys His Leu Ser Arg Gln Gln Leu Arg Met Ala Met Arg 610 615 620 Ile Pro Val Leu Tyr Glu Gln Leu Lys Arg Glu Lys Leu Arg Val His 625 630 635 640 Lys Ala Arg Gln Trp Lys Tyr Asp Gly Glu Met Leu Asn Arg Tyr Arg 645 650 655 Gln Ala Leu Glu Thr Ala Val Asn Leu Ser Val Lys His Ser Leu Pro 660 665 670 Leu Leu Pro Gly Arg Thr Val Leu Val Tyr Leu Thr Asp Ala Asn Ala 675 680 685 Asp Arg Leu Cys Pro Lys Ser Asn Pro Gln Gly Pro Pro Leu Asn Tyr 690 695 700 Ala Leu Leu Leu Ile Gly Met Met Ile Thr Arg Ala Glu Gln Val Asp 705 710 715 720 Val Val Leu Cys Gly Gly Asp Thr Leu Lys Thr Ala Val Leu Lys Ala 725 730 735 Glu Glu Gly Ile Leu Lys Thr Ala Ile Lys Leu Gln Ala Gln Val Gln 740 745 750 Glu Phe Asp Glu Asn Asp Gly Trp Ser Leu Asn Thr Phe Gly Lys Tyr 755 760 765 Leu Leu Ser Leu Ala Gly Gln Arg Val Pro Val Asp Arg Val Ile Leu 770 775 780 Leu Gly Gln Ser Met Asp Asp Gly Met Ile Asn Val Ala Lys Gln Leu 785 790 795 800 Tyr Trp Gln Arg Val Asn Ser Lys Cys Leu Phe Val Gly Ile Leu Leu 805 810 815 Arg Arg Val Gln Tyr Leu Ser Thr Asp Leu Asn Pro Asn Asp Val Thr 820 825 830 Leu Ser Gly Cys Thr Asp Ala Ile Leu Lys Phe Ile Ala Glu His Gly 835 840 845 Ala Ser His Leu Leu Glu His Val Gly Gln Met Asp Lys Ile Phe Lys 850 855 860 Ile Pro Pro Pro Pro Gly Lys Thr Gly Val Gln Ser Leu Arg Pro Leu 865 870 875 880 Glu Glu Asp Thr Pro Ser Pro Leu Ala Pro Val Ser Gln Gln Gly Trp 885 890 895 Arg Ser Ile Arg Leu Phe Ile Ser Ser Thr Phe Arg Asp Met His Gly 900 905 910 Glu Arg Asp Leu Leu Leu Arg Ser Val Leu Pro Ala Leu Gln Ala Arg 915 920 925 Ala Ala Pro His Arg Ile Ser Leu His Gly Ile Asp Leu Arg Trp Gly 930 935 940 Val Thr Glu Glu Glu Thr Arg Arg Asn Arg Gln Leu Glu Val Cys Leu 945 950 955 960 Gly Glu Val Glu Asn Ala Gln Leu Phe Val Gly Ile Leu Gly Ser Arg 965 970 975 Tyr Gly Tyr Ile Pro Pro Ser Tyr Asn Leu Pro Asp His Pro His Phe 980 985 990 His Trp Ala Gln Gln Tyr Pro Ser Gly Arg Ser Val Thr Glu Met Glu 995 1000 1005 Val Met Gln Phe Leu Asn Arg Asn Gln Arg Leu Gln Pro Ser Ala 1010 1015 1020 Gln Ala Leu Ile Tyr Phe Arg Asp Ser Ser Phe Leu Ser Ser Val 1025 1030 1035 Pro Asp Ala Trp Lys Ser Asp Phe Val Ser Glu Ser Glu Glu Ala 1040 1045 1050 Ala Cys Arg Ile Ser Glu Leu Lys Ser Tyr Leu Ser Arg Gln Lys 1055 1060 1065 Gly Ile Thr Cys Arg Arg Tyr Pro Cys Glu Trp Gly Gly Val Ala 1070 1075 1080 Ala Gly Arg Pro Tyr Val Gly Gly Leu Glu Glu Phe Gly Gln Leu 1085 1090 1095 Val Leu Gln Asp Val Trp Asn Met Ile Gln Lys Leu Tyr Leu Gln 1100 1105 1110 Pro Gly Ala Leu Leu Glu Gln Pro Val Ser Ile Pro Asp Asp Asp 1115 1120 1125 Leu Val Gln Ala Thr Phe Gln Gln Leu Gln Lys Pro Pro Ser Pro 1130 1135 1140 Ala Arg Pro Arg Leu Leu Gln Asp Thr Val Gln Gln Leu Met Leu 1145 1150 1155 Pro His Gly Arg Leu Ser Leu Val Thr Gly Gln Ser Gly Gln Gly 1160 1165 1170 Lys Thr Ala Phe Leu Ala Ser Leu Val Ser Ala Leu Gln Ala Pro 1175 1180 1185 Asp Gly Ala Lys Val Ala Pro Leu Val Phe Phe His Phe Ser Gly 1190 1195 1200 Ala Arg Pro Asp Gln Gly Leu Ala Leu Thr Leu Leu Arg Arg Leu 1205 1210 1215 Cys Thr Tyr Leu Arg Gly Gln Leu Lys Glu Pro Gly Ala Leu Pro 1220 1225 1230 Ser Thr Tyr Arg Ser Leu Val Trp Glu Leu Gln Gln Arg Leu Leu 1235 1240 1245 Pro Lys Ser Ala Glu Ser Leu His Pro Gly Gln Thr Gln Val Leu 1250 1255 1260 Ile Ile Asp Gly Ala Asp Arg Leu Val Asp Gln Asn Gly Gln Leu 1265 1270 1275 Ile Ser Asp Trp Ile Pro Lys Lys Leu Pro Arg Cys Val His Leu 1280 1285 1290 Val Leu Ser Val Ser Ser Asp Ala Gly Leu Gly Glu Thr Leu Glu 1295 1300 1305 Gln Ser Gln Gly Ala His Val Leu Ala Leu Gly Pro Leu Glu Ala 1310 1315 1320 Ser Ala Arg Ala Arg Leu Val Arg Glu Glu Leu Ala Leu Tyr Gly 1325 1330 1335 Lys Arg Leu Glu Glu Ser Pro Phe Asn Asn Gln Met Arg Leu Leu 1340 1345 1350 Leu Val Lys Arg Glu Ser Gly Arg Pro Leu Tyr Leu Arg Leu Val 1355 1360 1365 Thr Asp His Leu Arg Leu Phe Thr Leu Tyr Glu Gln Val Ser Glu 1370 1375 1380 Arg Leu Arg Thr Leu Pro Ala Thr Val Pro Leu Leu Leu Gln His 1385 1390 1395 Ile Leu Ser Thr Leu Glu Lys Glu His Gly Pro Asp Val Leu Pro 1400 1405 1410 Gln Ala Leu Thr Ala Leu Glu Val Thr Arg Ser Gly Leu Thr Val 1415 1420 1425 Asp Gln Leu His Gly Val Leu Ser Val Trp Arg Thr Leu Pro Lys 1430 1435 1440 Gly Thr Lys Ser Trp Glu Glu Ala Val Ala Ala Gly Asn Ser Gly 1445 1450 1455 Asp Pro Tyr Pro Met Gly Pro Phe Ala Cys Leu Val Gln Ser Leu 1460 1465 1470 Arg Ser Leu Leu Gly Glu Gly Pro Leu Glu Arg Pro Gly Ala Arg 1475 1480 1485 Leu Cys Leu Pro Asp Gly Pro Leu Arg Thr Ala Ala Lys Arg Cys 1490 1495 1500 Tyr Gly Lys Arg Pro Gly Leu Glu Asp Thr Ala His Ile Leu Ile 1505 1510 1515 Ala Ala Gln Leu Trp Lys Thr Cys Asp Ala Asp Ala Ser Gly Thr 1520 1525 1530 Phe Arg Ser Cys Pro Pro Glu Ala Leu Gly Asp Leu Pro Tyr His 1535 1540 1545 Leu Leu Gln Ser Gly Asn Arg Gly Leu Leu Ser Lys Phe Leu Thr 1550 1555 1560 Asn Leu His Val Val Ala Ala His Leu Glu Leu Gly Leu Val Ser 1565 1570 1575 Arg Leu Leu Glu Ala His Ala Leu Tyr Ala Ser Ser Val Pro Lys 1580 1585 1590 Glu Glu Gln Lys Leu Pro Glu Ala Asp Val Ala Val Phe Arg Thr 1595 1600 1605 Phe Leu Arg Gln Gln Ala Ser Ile Leu Ser Gln Tyr Pro Arg Leu 1610 1615 1620 Leu Pro Gln Gln Ala Ala Asn Gln Pro Leu Asp Ser Pro Leu Cys 1625 1630 1635 His Gln Ala Ser Leu Leu Ser Arg Arg Trp His Leu Gln His Thr 1640 1645 1650 Leu Arg Trp Leu Asn Lys Pro Arg Thr Met Lys Asn Gln Gln Ser 1655 1660 1665

Ser Ser Leu Ser Leu Ala Val Ser Ser Ser Pro Thr Ala Val Ala 1670 1675 1680 Phe Ser Thr Asn Gly Gln Arg Ala Ala Val Gly Thr Ala Asn Gly 1685 1690 1695 Thr Val Tyr Leu Leu Asp Leu Arg Thr Trp Gln Glu Glu Lys Ser 1700 1705 1710 Val Val Ser Gly Cys Asp Gly Ile Ser Ala Cys Leu Phe Leu Ser 1715 1720 1725 Asp Asp Thr Leu Phe Leu Thr Ala Phe Asp Gly Leu Leu Glu Leu 1730 1735 1740 Trp Asp Leu Gln His Gly Cys Arg Val Leu Gln Thr Lys Ala His 1745 1750 1755 Gln Tyr Gln Ile Thr Gly Cys Cys Leu Ser Pro Asp Cys Arg Leu 1760 1765 1770 Leu Ala Thr Val Cys Leu Gly Gly Cys Leu Lys Leu Trp Asp Thr 1775 1780 1785 Val Arg Gly Gln Leu Ala Phe Gln His Thr Tyr Pro Lys Ser Leu 1790 1795 1800 Asn Cys Val Ala Phe His Pro Glu Gly Gln Val Ile Ala Thr Gly 1805 1810 1815 Ser Trp Ala Gly Ser Ile Ser Phe Phe Gln Val Asp Gly Leu Lys 1820 1825 1830 Val Thr Lys Asp Leu Gly Ala Pro Gly Ala Ser Ile Arg Thr Leu 1835 1840 1845 Ala Phe Asn Val Pro Gly Gly Val Val Ala Val Gly Arg Leu Asp 1850 1855 1860 Ser Met Val Glu Leu Trp Ala Trp Arg Glu Gly Ala Arg Leu Ala 1865 1870 1875 Ala Phe Pro Ala His His Gly Phe Val Ala Ala Ala Leu Phe Leu 1880 1885 1890 His Ala Gly Cys Gln Leu Leu Thr Ala Gly Glu Asp Gly Lys Val 1895 1900 1905 Gln Val Trp Ser Gly Ser Leu Gly Arg Pro Arg Gly His Leu Gly 1910 1915 1920 Ser Leu Ser Leu Ser Pro Ala Leu Ser Val Ala Leu Ser Pro Asp 1925 1930 1935 Gly Asp Arg Val Ala Val Gly Tyr Arg Ala Asp Gly Ile Arg Ile 1940 1945 1950 Tyr Lys Ile Ser Ser Gly Ser Gln Gly Ala Gln Gly Gln Ala Leu 1955 1960 1965 Asp Val Ala Val Ser Ala Leu Ala Trp Leu Ser Pro Lys Val Leu 1970 1975 1980 Val Ser Gly Ala Glu Asp Gly Ser Leu Gln Gly Trp Ala Leu Lys 1985 1990 1995 Glu Cys Ser Leu Gln Ser Leu Trp Leu Leu Ser Arg Phe Gln Lys 2000 2005 2010 Pro Val Leu Gly Leu Ala Thr Ser Gln Glu Leu Leu Ala Ser Ala 2015 2020 2025 Ser Glu Asp Phe Thr Val Gln Leu Trp Pro Arg Gln Leu Leu Thr 2030 2035 2040 Arg Pro His Lys Ala Glu Asp Phe Pro Cys Gly Thr Glu Leu Arg 2045 2050 2055 Gly His Glu Gly Pro Val Ser Cys Cys Ser Phe Ser Thr Asp Gly 2060 2065 2070 Gly Ser Leu Ala Thr Gly Gly Arg Asp Arg Ser Leu Leu Cys Trp 2075 2080 2085 Asp Val Arg Thr Pro Lys Thr Pro Val Leu Ile His Ser Phe Pro 2090 2095 2100 Ala Cys His Arg Asp Trp Val Thr Gly Cys Ala Trp Thr Lys Asp 2105 2110 2115 Asn Leu Leu Ile Ser Cys Ser Ser Asp Gly Ser Val Gly Leu Trp 2120 2125 2130 Asp Pro Glu Ser Gly Gln Arg Leu Gly Gln Phe Leu Gly His Gln 2135 2140 2145 Ser Ala Val Ser Ala Val Ala Ala Val Glu Glu His Val Val Ser 2150 2155 2160 Val Ser Arg Asp Gly Thr Leu Lys Val Trp Asp His Gln Gly Val 2165 2170 2175 Glu Leu Thr Ser Ile Pro Ala His Ser Gly Pro Ile Ser His Cys 2180 2185 2190 Ala Ala Ala Met Glu Pro Arg Ala Ala Gly Gln Pro Gly Ser Glu 2195 2200 2205 Leu Leu Val Val Thr Val Gly Leu Asp Gly Ala Thr Arg Leu Trp 2210 2215 2220 His Pro Leu Leu Val Cys Gln Thr His Thr Leu Leu Gly His Ser 2225 2230 2235 Gly Pro Val Arg Ala Ala Ala Val Ser Glu Thr Ser Gly Leu Met 2240 2245 2250 Leu Thr Ala Ser Glu Asp Gly Ser Val Arg Leu Trp Gln Val Pro 2255 2260 2265 Lys Glu Ala Asp Asp Thr Cys Ile Pro Arg Ser Ser Ala Ala Val 2270 2275 2280 Thr Ala Val Ala Trp Ala Pro Asp Gly Ser Met Ala Val Ser Gly 2285 2290 2295 Asn Gln Ala Gly Glu Leu Ile Leu Trp Gln Glu Ala Lys Ala Val 2300 2305 2310 Ala Thr Ala Gln Ala Pro Gly His Ile Gly Ala Leu Ile Trp Ser 2315 2320 2325 Ser Ala His Thr Phe Phe Val Leu Ser Ala Asp Glu Lys Ile Ser 2330 2335 2340 Glu Trp Gln Val Lys Leu Arg Lys Gly Ser Ala Pro Gly Asn Leu 2345 2350 2355 Ser Leu His Leu Asn Arg Ile Leu Gln Glu Asp Leu Gly Val Leu 2360 2365 2370 Thr Ser Leu Asp Trp Ala Pro Asp Gly His Phe Leu Ile Leu Ala 2375 2380 2385 Lys Ala Asp Leu Lys Leu Leu Cys Met Lys Pro Gly Asp Ala Pro 2390 2395 2400 Ser Glu Ile Trp Ser Ser Tyr Thr Glu Asn Pro Met Ile Leu Ser 2405 2410 2415 Thr His Lys Glu Tyr Gly Ile Phe Val Leu Gln Pro Lys Asp Pro 2420 2425 2430 Gly Val Leu Ser Phe Leu Arg Gln Lys Glu Ser Gly Glu Phe Glu 2435 2440 2445 Glu Arg Leu Asn Phe Asp Ile Asn Leu Glu Asn Pro Ser Arg Thr 2450 2455 2460 Leu Ile Ser Ile Thr Gln Ala Lys Pro Glu Ser Glu Ser Ser Phe 2465 2470 2475 Leu Cys Ala Ser Ser Asp Gly Ile Leu Trp Asn Leu Ala Lys Cys 2480 2485 2490 Ser Pro Glu Gly Glu Trp Thr Thr Gly Asn Met Trp Gln Lys Lys 2495 2500 2505 Ala Asn Thr Pro Glu Thr Gln Thr Pro Gly Thr Asp Pro Ser Thr 2510 2515 2520 Cys Arg Glu Ser Asp Ala Ser Met Asp Ser Asp Ala Ser Met Asp 2525 2530 2535 Ser Glu Pro Thr Pro His Leu Lys Thr Arg Gln Arg Arg Lys Ile 2540 2545 2550 His Ser Gly Ser Val Thr Ala Leu His Val Leu Pro Glu Leu Leu 2555 2560 2565 Val Thr Ala Ser Lys Asp Arg Asp Val Lys Leu Trp Glu Arg Pro 2570 2575 2580 Ser Met Gln Leu Leu Gly Leu Phe Arg Cys Glu Gly Ser Val Ser 2585 2590 2595 Cys Leu Glu Pro Trp Leu Gly Ala Asn Ser Thr Leu Gln Leu Ala 2600 2605 2610 Val Gly Asp Val Gln Gly Asn Val Tyr Phe Leu Asn Trp Glu 2615 2620 2625 <210> SEQ ID NO 12 <211> LENGTH: 7884 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 atggaaaaac tccatgggca tgtgtctgcc catccagaca tcctctcctt ggagaaccgg 60 tgcctggcta tgctccctga cttacagccc ttggagaaac tacatcagca tgtatctacc 120 cactcagata tcctctcctt gaagaaccag tgcctagcca cgcttcctga cctgaagacc 180 atggaaaaac cacatggata tgtgtctgcc cacccagaca tcctctcctt ggagaaccag 240 tgcctggcca cactttctga cctgaagacc atggagaaac cacatggaca tgtttctgcc 300 cacccagaca tcctctcctt ggagaaccgg tgcctggcca ccctccctag tctaaagagc 360 actgtgtctg ccagcccctt gttccagagt ctacagatat ctcacatgac gcaagctgat 420 ttgtaccgtg tgaacaacag caattgcctg ctctctgagc ctccaagttg gagggctcag 480 catttctcta agggactaga cctttcaacc tgccctatag ccctgaaatc catctctgcc 540 acagagacag ctcaggaagc aactttgggt cgttggtttg attcagaaga gaagaaaggg 600 gcagagaccc aaatgccttc ttatagtctg agcttgggag aggaggagga ggtggaggat 660 ctggccgtga agctcacctc tggagactct gaatctcatc cagagcctac tgaccatgtc 720 cttcaggaaa agaagatggc tctactgagc ttgctgtgct ctactctggt ctcagaagta 780 aacatgaaca atacatctga ccccaccctg gctgccattt ttgaaatctg tcgtgaactt 840 gccctcctgg agcctgagtt tatcctcaag gcatctttgt atgccaggca gcagctgaac 900 gtccggaatg tggccaataa catcttggcc attgctgctt tcttgccggc gtgtcgcccc 960 cacctgcgac gatatttctg tgccattgtc cagctgcctt ctgactggat ccaggtggct 1020 gagctttacc agagcctggc tgagggagat aagaataagc tggtgcccct gcccgcctgt 1080 ctccgtactg ccatgacgga caaatttgcc cagtttgacg agtaccagct ggctaagtac 1140 aaccctcgga agcaccgggc caagagacac ccccgccggc caccccgctc tccagggatg 1200 gagcctccat tttctcacag atgttttcca aggtacatag ggtttctcag agaagagcag 1260 agaaagtttg agaaggccgg tgatacagtg tcagagaaaa agaatcctcc aaggttcacc 1320 ctgaagaagc tggttcagcg actgcacatc cacaagcctg cccagcacgt tcaagccctg 1380 ctgggttaca gatacccctc caacctacag ctcttttctc gaagtcgcct tcctgggcct 1440 tgggattcta gcagagctgg gaagaggatg aagctgtcta ggccagagac ctgggagcgg 1500 gagctgagcc tacgggggaa caaagcgtcg gtctgggagg aactcattga aaatgggaag 1560

cttcccttca tggccatgct tcggaacctg tgcaacctgc tgcgggttgg aatcagttcc 1620 cgccaccatg agctcattct ccagagactc cagcatggga agtcggtgat ccacagtcgg 1680 cagtttccat tcagatttct taacgcccat gatgccattg atgccctcga ggctcaactc 1740 agaaatcaag cattgccctt tccttcgaat ataacactga tgaggcggat actaactaga 1800 aatgaaaaga accgtcccag gcggaggttt ctttgccacc taagccgtca gcagcttcgt 1860 atggcaatga ggatacctgt gttgtatgag cagctcaaga gggagaagct gagagtacac 1920 aaggccagac agtggaaata tgatggtgag atgctgaaca ggtaccgaca ggccctagag 1980 acagctgtga acctctctgt gaagcacagc ctgcccctgc tgccaggccg cactgtcttg 2040 gtctatctga cagatgctaa tgcagacagg ctctgtccaa agagcaaccc acaagggccc 2100 ccgctgaact atgcactgct gttgattggg atgatgatca cgagggcgga gcaggtggac 2160 gtcgtgctgt gtggaggtga cactctgaag actgcagtgc ttaaggcaga agaaggcatc 2220 ctgaagactg ccatcaagct ccaggctcaa gtccaggagt ttgatgaaaa tgatggatgg 2280 tccctgaata cttttgggaa atacctgctg tctctggctg gccaaagggt tcctgtggac 2340 agggtcatcc tccttggcca aagcatggat gatggaatga taaatgtggc caaacagctt 2400 tactggcagc gtgtgaattc caagtgcctc tttgttggta tcctcctaag aagggtacaa 2460 tacctgtcaa cagatttgaa tcccaatgat gtgacactct caggctgtac tgatgcgata 2520 ctgaagttca ttgcagagca tggggcctcc catcttctgg aacatgtggg ccaaatggac 2580 aaaatattca agattccacc acccccagga aagacagggg tccagtctct ccggccactg 2640 gaagaggaca ctccaagccc cttggctcct gtttcccagc aaggatggcg cagcatccgg 2700 cttttcattt catccacttt ccgagacatg cacggggagc gggacctgct gctgaggtct 2760 gtgctgccag cactgcaggc ccgagcggcc cctcaccgta tcagccttca cggaatcgac 2820 ctccgctggg gcgtcactga ggaggagacc cgtaggaaca gacaactgga agtgtgcctt 2880 ggggaggtgg agaacgcaca gctgtttgtg gggattctgg gctcccgtta tggatacatt 2940 ccccccagct acaaccttcc tgaccatcca cacttccact gggcccagca gtacccttca 3000 gggcgctctg tgacagagat ggaggtgatg cagttcctga accggaacca acgtctgcag 3060 ccctctgccc aagctctcat ctacttccgg gattccagct tcctcagctc tgtgccagat 3120 gcctggaaat ctgactttgt ttctgagtct gaagaggccg catgtcggat ctcagaactg 3180 aagagctacc taagcagaca gaaagggata acctgccgca gatacccctg tgagtggggg 3240 ggtgtggcag ctggccggcc ctatgttggc gggctggagg agtttgggca gttggttctg 3300 caggatgtat ggaatatgat ccagaagctc tacctgcagc ctggggccct gctggagcag 3360 ccagtgtcca tcccagacga tgacttggtc caggccacct tccagcagct gcagaagcca 3420 ccgagtcctg cccggccacg ccttcttcag gacacagtgc aacagctgat gctgccccac 3480 ggaaggctga gcctggtgac ggggcagtca ggacagggca agacagcctt cctggcatct 3540 cttgtgtcag ccctgcaggc tcctgatggg gccaaggtgg caccattagt cttcttccac 3600 ttttctgggg ctcgtcctga ccagggtctt gccctcactc tgctcagacg cctctgtacc 3660 tatctgcgtg gccaactaaa agagccaggt gccctcccca gcacctaccg aagcctggtg 3720 tgggagctgc agcagaggct gctgcccaag tctgctgagt ccctgcatcc tggccagacc 3780 caggtcctga tcatcgatgg ggctgatagg ttagtggacc agaatgggca gctgatttca 3840 gactggatcc caaagaagct tccccggtgt gtacacctgg tgctgagtgt gtctagtgat 3900 gcaggcctag gggagaccct tgagcagagc cagggtgccc acgtgctggc cttggggcct 3960 ctggaggcct ctgctcgggc ccggctggtg agagaggagc tggccctgta cgggaagcgg 4020 ctggaggagt caccatttaa caaccagatg cgactgctgc tggtgaagcg ggaatcaggc 4080 cggccgctct acctgcgctt ggtcaccgat cacctgaggc tcttcacgct gtatgagcag 4140 gtgtctgaga gactccggac cctgcctgcc actgtccccc tgctgctgca gcacatcctg 4200 agcacactgg agaaggagca cgggcctgat gtccttcccc aggccttgac tgccctagaa 4260 gtcacacgga gtggtttgac tgtggaccag ctgcacggag tgctgagtgt gtggcggaca 4320 ctaccgaagg ggactaagag ctgggaagaa gcagtggctg ctggtaacag tggagacccc 4380 taccccatgg gcccgtttgc ctgcctcgtc cagagtctgc gcagtttgct aggggagggc 4440 cctctggagc gccctggtgc ccggctgtgc ctccctgatg ggcccctgag aacagcagct 4500 aaacgttgct atgggaagag gccagggcta gaggacacgg cacacatcct cattgcagct 4560 cagctctgga agacatgtga cgctgatgcc tcaggcacct tccgaagttg ccctcctgag 4620 gctctgggag acctgcctta ccacctgctc cagagcggga accgtggact tctttcgaag 4680 ttccttacca acctccatgt ggtggctgca cacttggaat tgggtctggt ctctcggctc 4740 ttggaggccc atgccctcta tgcttcttca gtccccaaag aggaacaaaa gctccccgag 4800 gctgacgttg cagtgtttcg caccttcctg aggcagcagg cttcaatcct cagccagtac 4860 ccccggctcc tgccccagca ggcagccaac cagcccctgg actcacctct ttgccaccaa 4920 gcctcgctgc tctcccggag atggcacctc caacacacac tacgatggct taataaaccc 4980 cggaccatga aaaatcagca aagctccagc ctgtctctgg cagtttcctc atcccctact 5040 gctgtggcct tctccaccaa tgggcaaaga gcagctgtgg gcactgccaa tgggacagtt 5100 tacctgttgg acctgagaac ttggcaggag gagaagtctg tggtgagtgg ctgtgatgga 5160 atctctgctt gtttgttcct ctccgatgat acactctttc ttactgcctt cgacgggctc 5220 ctggagctct gggacctgca gcatggttgt cgggtgctgc agactaaggc tcaccagtac 5280 caaatcactg gctgctgcct gagcccagac tgccggctgc tagccaccgt gtgcttggga 5340 ggatgcctaa agctgtggga cacagtccgt gggcagctgg ccttccagca cacctacccc 5400 aagtccctga actgtgttgc cttccaccca gaggggcagg taatagccac aggcagctgg 5460 gctggcagca tcagcttctt ccaggtggat gggctcaaag tcaccaagga cctgggggca 5520 cccggagcct ctatccgtac cttggccttc aatgtgcctg ggggggttgt ggctgtgggc 5580 cggctggaca gtatggtgga gctgtgggcc tggcgagaag gggcacggct ggctgccttc 5640 cctgcccacc atggctttgt tgctgctgcg cttttcctgc atgcgggttg ccagttactg 5700 acggctggag aggatggcaa ggttcaggtg tggtcagggt ctctgggtcg gccccgtggg 5760 cacctgggtt ccctttctct ctctcctgcc ctctctgtgg cactcagccc agatggtgat 5820 cgggtggctg ttggatatcg agcggatggc attaggatct acaaaatctc ttcaggttcc 5880 cagggggctc agggtcaggc actggatgtg gcagtgtccg ccctggcctg gctaagcccc 5940 aaggtattgg tgagtggtgc agaagatggg tccttgcagg gctgggcact caaggaatgc 6000 tcccttcagt ccctctggct cctgtccaga ttccagaagc ctgtgctagg actggccact 6060 tcccaggagc tcttggcttc tgcctcagag gatttcacag tgcagctgtg gccaaggcag 6120 ctgctgacgc ggccacacaa ggcagaagac tttccctgtg gcactgagct gcggggacat 6180 gagggccctg tgagctgctg tagtttcagc actgatggag gcagcctggc caccgggggc 6240 cgggatcgga gtctcctctg ctgggacgtg aggacaccca aaacccctgt tttgatccac 6300 tccttccctg cctgtcaccg tgactgggtc actggctgtg cctggaccaa agataaccta 6360 ctgatatcct gctccagtga tggctctgtg gggctctggg acccagagtc aggacagcgg 6420 cttggtcagt tcctgggtca tcagagtgct gtgagcgctg tggcagctgt ggaggagcac 6480 gtggtgtctg tgagccggga tgggaccttg aaagtgtggg accatcaagg cgtggagctg 6540 accagcatcc ctgctcactc aggacccatt agccactgtg cagctgccat ggagccccgt 6600 gcagctggac agcctgggtc agagcttctg gtggtaaccg tcgggctaga tggggccaca 6660 cggttatggc atccactctt ggtgtgccaa acccacaccc tcctgggaca cagcggccca 6720 gtccgtgctg ctgctgtttc agaaacctca ggcctcatgc tgaccgcctc tgaggatggt 6780 tctgtacggc tctggcaggt tcctaaggaa gcagatgaca catgtatacc aaggagttct 6840 gcagccgtca ctgctgtggc ttgggcacca gatggttcca tggcagtatc tggaaatcaa 6900 gctggggaac taatcttgtg gcaggaagct aaggctgtgg ccacagcaca ggctccaggc 6960 cacattggtg ctctgatctg gtcctcggca cacacctttt ttgtcctcag tgctgatgag 7020 aaaatcagcg agtggcaagt gaaactgcgg aagggttcgg cacccggaaa tttgagtctt 7080 cacctgaacc gaattctaca ggaggactta ggggtgctga caagtctgga ttgggctcct 7140 gatggtcact ttctcatctt ggccaaagca gatttgaagt tactttgcat gaagccaggg 7200 gatgctccat ctgaaatctg gagcagctat acagaaaatc ctatgatatt gtccacccac 7260 aaggagtatg gcatatttgt cctgcagccc aaggatcctg gagttctttc tttcttgagg 7320 caaaaggaat caggagagtt tgaagagagg ctgaactttg atataaactt agagaatcct 7380 agtaggaccc taatatcgat aactcaagcc aaacctgaat ctgagtcctc atttttgtgt 7440 gccagctctg atgggatcct atggaacctg gccaaatgca gcccagaagg agaatggacc 7500 acaggtaaca tgtggcagaa aaaagcaaac actccagaaa cccaaactcc agggacagac 7560 ccatctacct gcagggaatc tgatgccagc atggatagtg atgccagcat ggatagtgag 7620 ccaacaccac atctaaagac acggcagcgt agaaagattc actcgggctc tgtcacagcc 7680 ctccatgtgc tacctgagtt gctggtgaca gcttcgaagg acagagatgt taagctatgg 7740 gagagaccca gtatgcagct gctgggcctg ttccgatgcg aagggtcagt gagctgcctg 7800 gaaccttggc tgggcgctaa ctccaccctg cagcttgccg tgggagacgt gcagggcaat 7860 gtgtactttc tgaattggga atga 7884 <210> SEQ ID NO 13 <211> LENGTH: 98 <212> TYPE: RNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 ggcuggcuuu agcucagcgg uuacuucgac aguucuuuaa uugaaacaag caaccugucu 60 ggguuguucg agacccgcgg gcgcucucca guccuuuu 98 <210> SEQ ID NO 14 <211> LENGTH: 88 <212> TYPE: RNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 ggcuggcuuu agcucagcgg uuacuucgag uacauuguaa ccaccucucu gggugguucg 60 agacccgcgg gugcuuucca gcucuuuu 88 <210> SEQ ID NO 15 <211> LENGTH: 88 <212> TYPE: RNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 ggcuggcuuu agcucagcgg uuacuucgcg ugucaucaaa ccaccucucu ggguuguucg 60 agacccgcgg gcgcucucca gcccucuu 88 <210> SEQ ID NO 16

<211> LENGTH: 252 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Ala Asn Leu Arg Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys 1 5 10 15 Ser Gln Ser Arg Thr Thr Pro Val Asp Leu Cys Leu Leu Glu Glu Ser 20 25 30 Val Gly Ser Leu Glu Gly Ser Arg Cys Pro Val Phe Ala Phe Gln Ser 35 40 45 Ser Asp Thr Glu Ser Asp Glu Leu Ser Glu Val Leu Gln Asp Ser Cys 50 55 60 Phe Leu Gln Ile Lys Cys Asp Thr Lys Asp Asp Ser Ile Pro Cys Phe 65 70 75 80 Leu Glu Leu Lys Glu Glu Asp Glu Ile Val Cys Thr Gln His Trp Gln 85 90 95 Asp Ala Val Pro Trp Thr Glu Leu Leu Ser Leu Gln Thr Glu Asp Gly 100 105 110 Phe Trp Lys Leu Thr Pro Glu Leu Gly Leu Ile Leu Asn Leu Asn Thr 115 120 125 Asn Gly Leu His Ser Phe Leu Lys Gln Lys Gly Ile Gln Ser Leu Gly 130 135 140 Val Lys Gly Arg Glu Cys Leu Leu Asp Leu Ile Ala Thr Met Leu Val 145 150 155 160 Leu Gln Phe Ile Arg Thr Arg Leu Glu Lys Glu Gly Ile Val Phe Lys 165 170 175 Ser Leu Met Lys Met Asp Asp Pro Ser Ile Ser Arg Asn Ile Pro Trp 180 185 190 Ala Phe Glu Ala Ile Lys Gln Ala Ser Glu Trp Val Arg Arg Thr Glu 195 200 205 Gly Gln Tyr Pro Ser Ile Cys Pro Arg Leu Glu Leu Gly Asn Asp Trp 210 215 220 Asp Ser Ala Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser Thr Val 225 230 235 240 Ser Pro Leu His Arg Val Leu His Tyr Ser Gln Gly 245 250 <210> SEQ ID NO 17 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 17 Ser Ile Ile Asn Phe Glu Lys Leu 1 5 <210> SEQ ID NO 18 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 18 Thr Glu Trp Thr Ser Ser Asn Val Met Glu Glu Arg Lys Ile Lys Val 1 5 10 15 <210> SEQ ID NO 19 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 19 ccccactagt ccatgggctc catcgg 26 <210> SEQ ID NO 20 <211> LENGTH: 44 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 20 tcctgccagt gttgtgtgca gctagcaggg gaaacacatc tgcc 44 <210> SEQ ID NO 21 <211> LENGTH: 46 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 21 ttggcagatg tgtttcccct gctagctgca cacaacactg gcagga 46 <210> SEQ ID NO 22 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer <400> SEQUENCE: 22 gggctcgagt tagccttgac tgtaatggag 30

Claims

1. A method for stimulating a cellular immune response in a subject, comprising administering to the subject an effective amount of an antigenic peptide or an antigenic fragment or variant thereof incorporated within a vault complex.

2. The method of claim 1, wherein the antigenic peptide is a tumor antigen.

3. The method of claim 1, wherein the vault complex comprises two or more vault complexes, wherein each vault complex comprises two or more different antigenic peptides or antigenic fragments or variants.

4. The method of claim 1, wherein the antigenic peptide is fused to INT.

5. The method of claim 4, wherein the INT comprises the amino acid sequence of SEQ ID NO: 2.

6. The method of claim 1, wherein the antigenic peptide is fused to MVP.

7. The method of claim 6, wherein the antigenic peptide is fused to the N-terminus of MVP.

8. The method of claim 1, wherein the vault complex comprises MVP.

9. The method of claim 8, wherein the number of MVP is 1-78.

10. The method of claim 8, wherein the number of MVP is 78.

11. The method of claim 8, wherein the vault complex further comprises VPARP or modified VPARP, or a portion of VPARP, or a modified portion of VPARP.

12. The method of claim 1, wherein the cellular immune response is induction of CD8.sup.+ and CD4.sup.+ memory T-cells.

13. The method of claim 1, wherein the cellular immune response is production of INF.gamma..

14. The method of claim 1, further comprising administering to the subject a vault complex containing a chemokine.

15. The method of claim 14, wherein the chemokine is CCL21.

16. A pharmaceutical composition for preventing or treating a subject for cancer, comprising a tumor antigen or an antigenic fragment or variant thereof incorporated within a vault complex, and at least one pharmaceutically acceptable excipient, sufficient to stimulate a cellular immune response.

17. The pharmaceutical composition of claim 16, wherein tumor antigen is fused to INT.

18. The method of claim 17, wherein the INT comprises the amino acid sequence of SEQ ID NO: 2.

19. The pharmaceutical composition of claim 16, wherein the antigenic peptide is fused to MVP.

20. The pharmaceutical composition of claim 16, wherein the vault complex comprises MVP.

21. The pharmaceutical composition of claim 20, wherein the number of MVP is 1-78.

22. The pharmaceutical composition of claim 20, wherein the number of MVP is 78.

23. The pharmaceutical composition of claim 20, wherein the vault complex further comprises VPARP or modified VPARP, or a portion of VPARP, or a modified portion of VPARP.

24. The pharmaceutical composition of claim 15, wherein the cellular immune response is induction of CD8.sup.+ and CD4.sup.+ memory T-cells.

25. The pharmaceutical composition of claim 15, wherein the cellular immune response is production of INF.gamma..

26. The pharmaceutical composition of claim 15, further comprising a vault complex containing a chemokine.

27. The pharmaceutical composition of claim 26, wherein the chemokine is CCL21.

28. A method of preventing or treating cancer in a subject, comprising administering to the subject an effective amount of a tumor antigen or an antigenic fragment or variant thereof incorporated within a vault complex, sufficient to stimulate a cellular immune response.

29. The method of claim 28, wherein tumor antigen is fused to INT.

30. The method of claim 4, wherein the INT comprises the amino acid sequence of SEQ ID NO: 2.

31. The method of claim 28, wherein the antigenic peptide is fused to MVP.

32. The method of claim 28, wherein the vault complex comprises MVP.

33. The method of claim 32, wherein the number of MVP is 1-78.

34. The method of claim 32, wherein the number of MVP is 78.

35. The method of claim 32, wherein the vault complex further comprises VPARP or modified VPARP, or a portion of VPARP, or a modified portion of VPARP.

36. The method of claim 28, wherein the cellular immune response is induction of CD8.sup.+ and CD4.sup.+ memory T-cells.

37. The method of claim 28, wherein the cellular immune response is production of INF.gamma..

38. The method of claim 28, further comprising administering to the subject a vault complex containing a chemokine.

39. The method of claim 38, wherein the chemokine is CCL21.

40. The method of claims 28-39, wherein the administering reduces tumor volume.

41. The method of claims 28-39, wherein the administering reduces tumor growth.

42. A method of preparing a vault complex comprising a) mixing an INT or INT fusion protein generated in insect Sf9 cells with a MVP or MVP fusion protein generated in insect Sf9 cells to generate a mixture; b) incubating the mixture for a sufficient period of time to allow formation of vault complexes, thereby generating the vault complex of claims 1-41.