Artificial immune surveillance chimeric antigen receptor (AI-CAR) and its expressing cells

Abstract

The present application provides a non-viral vector comprising an artificial immune surveillance chimeric antigen receptor (AI-CAR) expression cassette flanked by two transposons or viral terminal repeat sequences (IR), wherein the AI-CAR expression cassette comprises an inducible gene expression unit and a CAR expression unit.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 808,815 filed on February 21, 2019, U.S. Provisional Application Serial No. 62 / 808,823 filed on February 21, 2019, and U.S. Provisional Application Serial No. 62 / 808,833 filed on February 21, 2019 under 35 U.S.C. 119(e), the entire disclosures of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to a technology for improving the expansion, production, survival and efficacy of chimeric antigen receptor (CAR)-T cells or NK cells. Background Art

[0004] Unless otherwise indicated herein, the materials described in this section are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section.

[0005] Manufacturing CAR cells is laborious and may be complicated by the need for artificial antigen presenting cells (aAPC), antibody stimulation of TCR and costimulatory receptors and / or multiple cytokines to amplify autologous or allogeneic CAR cells before administration. For example, when the electroporation conditions are set to a high CAR expression percentage, electroporation of T cells, NK cells, PBL or PBMC with CAR DNA vectors usually results in cell death of most cells. Therefore, after electroporation, cells can be co-cultured with irradiated aAPC, antibodies and / or growth factors, and CAR cell populations can be specifically amplified multiple times to produce a single dose for therapeutic use. At present, standard CAR vectors (CAR) do not express genes that are usually required in immunosuppressive tumor microenvironments that can induce anti-tumor immune responses in patients.

[0006] Ideally, the efficacy of CAR cells after administration should be associated with T cells with an undifferentiated memory phenotype, which is characterized by persistence in vivo and maximum therapeutic potential. In order to selectively amplify CAR cells with this phenotype and / or prevent terminal differentiation, several cytokines have been used, including IL15, IL7 and IL21. It is known that IL15 and IL7 are critical for the production and support of early memory T cells, due to their ability to guide the production of human memory stem cells from naive precursors (Cieri et al., 2013; Boyman et al., 2012; Gattinoni L et al., 2011). IL15 and IL7 can be tools for making T cells (such as human CD8+ memory T cell subsets) respond to antigens or homeostatic cytokines and dedifferentiate (Geginat 2003). IL15 is required for innate-like T cell immune surveillance (Dadi S et al., 2016). Soluble and transported IL15 / IL-15Rα can maintain IL-15 activity and contribute to the long-term survival of CD8 memory T cells (Sato et al., 2007). Therefore, CART cells with an undifferentiated memory phenotype exhibit the greatest in vivo persistence and therapeutic efficacy.

[0007] However, due to the safety assessment of each component, all components for manufacturing and maintaining such CAR cells with high therapeutic potential cannot be co-administered. However, building these components into a CAR carrier with constitutive expression may not be a feasible practice because the possibility of toxicity over time is high. Alternatively, if the signaling pathway of CAR cell amplification and undifferentiated memory phenotype is under the control of a single molecule (such as a target tumor antigen), then it will not only greatly reduce costs but also make point-of-care treatment possible. In this way, CAR signaling can be sufficient to support the amplification of CAR cells without terminal differentiation.

[0008] From a clinical point of view, multiple factors lead to treatment relapse, including insufficient persistence of CAR cells (exhaustion or host anti-CAR), loss of target antigen, lack of induction of host anti-tumor response and / or inability to effectively locate to lymphoma / solid tumor. Almost all forms of CAR solve the loss of tumor antigens solved by targeting 2 or more tumor antigens. Therefore, it is very necessary to have one or more CARs and a persistent host response by including additional genes in CAR vectors / RNA. Summary of the invention

[0009] In one aspect, the present application provides a chimeric antigen receptor complex. In one embodiment, the chimeric antigen receptor complex comprises a first protein, the first protein comprising a first extracellular domain connected to a first intercellular domain by a first linker, wherein the first extracellular domain comprises a first scFv with affinity for a first tumor epitope, and wherein the first intercellular domain comprises a JAK1 binding domain, and a second protein, the second protein comprising a second extracellular domain connected to a second intercellular domain by a second linker, wherein the second extracellular domain comprises a second scFv with affinity for a second tumor epitope, and wherein the second intercellular domain comprises a JAK3 binding domain. The first tumor epitope is on a first tumor antigen. The second tumor epitope is on a second tumor antigen.

[0010] In one embodiment, the first intracellular domain comprises IL7Rα (CD127). In one embodiment, the first intracellular domain comprises the intracellular domain of IL15Rβ (CD122), IL21Rα (CD360) or a combination thereof. In one embodiment, the first intracellular domain further comprises a first cytotoxic signaling domain connected to a JAK1 binding domain.

[0011] In one embodiment, the first cytotoxic signaling domain comprises CD28, CD3ζ, CD137, OX40, CD27, ICOS, or a combination thereof.

[0012] In one embodiment, the first scFv domain or the second scFv domain independently has affinity for CD19 or CD22. In one embodiment, the first scFv domain has affinity for CD19. In one embodiment, the second scFv domain has affinity for CD22. In one embodiment, the second intracellular domain comprises γ (CD132).

[0013] In one embodiment, the second intracellular domain further comprises a second cytotoxic signaling domain connected to the JAK3 binding domain. In one embodiment, the second cytotoxic domain comprises CD28, CD3ζ, CD137, OX40, CD27, ICOS or a combination thereof. In one embodiment, the second intracellular domain comprises tandem γ (CD132), a JAK3 binding domain, CD28 and CD3ζ. In one embodiment, the first intracellular domain is configured to dimerize with the second intracellular domain.

[0014] In one embodiment, the first and second linkers independently comprise CD8. In one embodiment, the first and second linkers independently comprise a stem and a transmembrane domain.

[0015] In one embodiment, the stem comprises CD8, Fc hinge, Fc CH2-CH3, TCRα, TCRβ, truncated IL7Rα (CD127), truncated IL15Rβ (CD122), IL15Rα (CD215), truncated γ (CD132), truncated IL21Rα (CD360), or a combination thereof.

[0016] In one embodiment, the transmembrane domain comprises CD8, CD28, CD3ζ, CD3ε, CD3δ, CD3γ, CD3ζ, TCRα, TCRβ, IL15Rβ (CD122), γ (CD132), IL7Rα (CD127), IL21Rα (CD360), IL15Rα (CD215), or a combination thereof.

[0017] In one embodiment, the tumor antigen comprises CDH17, TROP2, CD19, CD22, CD37, BCMA, CD48, EGFR, HER2, EpCAM, CEACAM5, PSMA, GD2, GPC3, or a combination thereof.

[0018] On the other hand, the application provides an open reading frame (ORF). In one embodiment, the open reading frame (ORF) comprises CD19 scFv, stem transmembrane region and IL7α endodomain in sequence. In one embodiment, the open reading frame (ORF) comprises CD22 scFv, stem transmembrane region, γ chain endodomain, CD28 endodomain and CD3ζ endodomain in sequence. In one embodiment, the open reading frame (ORF) comprises PD-1 scFv, CCL21 and IL7 in sequence.

[0019] In another aspect, the present application provides a biomolecule complex. In one embodiment, the biomolecule complex comprises a first protein, the first protein comprising a first extracellular domain connected to a first intercellular domain by a first linker, wherein the first extracellular domain comprises a first scFv having affinity for a first tumor epitope, and wherein the first intercellular domain comprises a JAK1 binding domain, a second protein, the first protein comprising a second extracellular domain connected to a second intercellular domain by a second linker, wherein the second extracellular domain comprises a second scFv having affinity for a second tumor epitope, and wherein the second intercellular domain comprises a JAK3 domain, a first tumor antigen, and a second tumor antigen. The first tumor epitope binds to the first tumor antigen. The second tumor epitope binds to the tumor antigen.

[0020] In one embodiment, the first intracellular domain dimerizes with the second intracellular domain. In one embodiment, JAK1 dimerizes with JAK3.

[0021] On the other hand, the present application provides a non-viral DNA construct. In one embodiment, the non-viral DNA construct comprises an inducible promoter from 5' to 3', followed by a first ORF, wherein the first ORF comprises anti-PD-1 scFV, CLL21 and IL7, each guided by a single peptide and ending with a ribosomal skipping peptide, a second ORF comprising at least one constitutive chimeric antigen receptor, and a third promoter, followed by at least one RNA sequence.

[0022] In another aspect, the present application provides a chimeric antigen receptor. In one embodiment, the chimeric antigen receptor comprises a cytokine domain, a linker, a truncated CD8 domain, and a signaling endodomain in sequence.

[0023] In one embodiment, the cytokine domain comprises IL7, IL12, IL21, or a combination thereof. In one embodiment, the truncated CD8 domain comprises at least a portion of a hinge, a transmembrane domain, and a cytoplasmic domain. In one embodiment, the cytoplasmic domain comprises CD28 / CD170, CD3ζ, or a combination thereof.

[0024] In one embodiment, the chimeric antigen receptor further comprises a tumor antigen domain between the cytokine domain and the truncated CD8 domain.

[0025] In one embodiment, the present application provides a biomolecular complex comprising a chimeric antigen receptor as disclosed herein bound to a tumor antigen.

[0026] On the other hand, the present application provides a non-viral vector comprising an artificial immune surveillance chimeric antigen receptor (AI-CAR) expression cassette flanked by two transposons or viral terminal repeat sequences (IR), wherein the AI-CAR expression cassette comprises an inducible gene expression unit and a CAR expression unit.

[0027] In one embodiment, the inducible gene expression unit comprises a STAT, NFAT or NF-κB inducible promoter, a coding region of one or more genes connected by an IRES or a self-cleaving ribosome skipping peptide, followed by a first polyA signal sequence. In one embodiment, the self-cleaving ribosome skipping peptide comprises TA2. In one embodiment, the inducible gene expression unit comprises genes for expressing at least two different cytokine receptors. In one embodiment, the inducible gene expression unit comprises genes for expressing antigen binding proteins. In one embodiment, the inducible gene expression unit comprises genes for expressing anti-PD1 scFv. In one embodiment, the inducible gene expression unit comprises genes for expressing CCL21. In one embodiment, the inducible gene expression unit comprises genes for expressing IL7.

[0028] In one embodiment, the CAR expression unit comprises a gene for expressing anti-CDH17 scFv, anti-TROP2 scFv, and CAR. In one embodiment, the CAR expression unit comprises a promoter, one or two CAR genes, followed by a second polyA signal sequence. In one embodiment, the CAR expression unit further comprises a gene for expressing a safety switch. In one embodiment, the safety switch comprises a truncated EGFR (tEGFR) or a truncated CD20. In one embodiment, the AI-CAR expression cassette is configured to express shRNA, wherein the shRNA is configured to inhibit the endogenous TCR.

[0029] In another aspect, the present application provides isolated nucleic acids encoding the biomolecular complexes, biomolecules, antigens and proteins as disclosed herein.

[0030] On the other hand, the application provides an expression vector comprising an isolated nucleic acid as disclosed therein. In one embodiment, the expression vector comprises an ORF as disclosed therein. In one embodiment, the expression vector comprises a non-viral DNA construct as disclosed therein. The expression vector may be viral or non-viral. The vector may be expressed in a cell.

[0031] In a further embodiment, the application provides a host cell. In one embodiment, the host cell comprises an isolated nucleic acid and / or expression vector as disclosed therein. In one embodiment, the host cell comprises a non-viral DNA construct as disclosed therein. In one embodiment, the host cell comprises a non-viral vector as disclosed therein.

[0032] In another embodiment, the present application provides a mammalian cell comprising a chimeric antigen receptor complex, a biomolecule complex, a biomolecule, an antigen, and a protein as disclosed therein. In one embodiment, the mammalian cell comprises a chimeric antigen receptor as disclosed therein. In one embodiment, the mammalian cell comprises a biomolecule complex as disclosed therein.

[0033] In a further embodiment, the present application provides a CAR-T or CAR-NK cell. In one embodiment, the CAR-T or CAR-NK cell expresses a chimeric antigen receptor complex as disclosed therein. In one embodiment, the CAR-T or CAR-NK cell expresses a chimeric antigen receptor as disclosed therein.

[0034] In another embodiment, the present application provides a method for treating a tumor in a subject, comprising administering to the subject a sufficient amount of CAR-T or CAR-NK cells as disclosed herein.

[0035] On the other hand, the present application provides a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a vector, a non-viral vector, a CAR-T or CAR-NK cell, a protein, a biomolecule, or a biomolecule complex as disclosed therein. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The foregoing and other features of the present disclosure will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. Understanding that these drawings depict only several embodiments arranged in accordance with the present disclosure and are therefore not to be considered limiting of its scope, the present disclosure will be described with additional specificity and detail through use of the accompanying drawings, in which:

[0037] Figure 1 An AI-CAR gene expression cassette comprising an inducible gene expression unit and a CAR expression unit in a non-viral vector (pPI) is described for constitutively expressing one or two CARs to induce gene expression for host anti-tumor response;

[0038] Figure 2 The general concept of AI-CAR is shown;

[0039] Figure 3 Depicted is an AI-CAR expression vector encoding a constitutively expressed dual CAR that targets CDH17 and TROP2 and an anti-PD1 scFv, CCL21, and IL17 gene cassette under an inducible promoter in a non-viral vector (pPI) for CAR-induced host anti-tumor response; an AI-CAR expression vector encoding a constitutively expressed dual CAR that targets CDH17 and TROP2 and an anti-PD1 scFv, CCL21, and IL17 gene cassette under an inducible promoter in a non-viral vector (pPI) for CAR-induced host anti-tumor response;

[0040] Figure 4 Tumor antigen induction of integrated pPI anti-CDH17 AI-CAR vector genes is shown; Tumor antigen induction of integrated pPI-anti-CDH17-AI-CAR vector genes. (A) Expression of integrated pPI-anti-CDH17-AI-CAR vectors was measured by GFP levels in T cells (Jurkat) in response to different concentrations of CDH17; (B) Induction with recombinant CDH17 in colon cancer cells (SW480); and (C) Cytotoxicity of pPI-anti-CDH17-AI-CAR integrated T cells to SW480 cells expressing CDH17;

[0041] Figure 5The expression and binding specificity of pPI-anti-CDH17-TROP2 AI-CAR were shown; and

[0042] Figure 6 iPro variants that support AI-CAR proliferation and persistence are described. iPro variants that support AI-CAR proliferation and persistence. (A) Examples of iPro7 expression; (B) Induction of CD25 T cell population proliferation; and (C) Increased T cell survival. DETAILED DESCRIPTION

[0043] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols generally identify similar components unless the context indicates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure as generally described herein and illustrated in the accompanying drawings may be arranged, substituted, combined, separated, and designed into a variety of different configurations, all of which are expressly contemplated herein.

[0044] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols generally identify similar components unless the context indicates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure as generally described herein and illustrated in the accompanying drawings may be arranged, substituted, combined, separated, and designed into a variety of different configurations, all of which are expressly contemplated herein.

[0045] The present disclosure provides, inter alia, isolated antibodies, methods of making such antibodies, bispecific or multispecific molecules, antibody-drug conjugates and / or immunoconjugates composed of such antibodies or antigen-binding fragments, pharmaceutical compositions containing the antibodies, bispecific or multispecific molecules, antibody-drug conjugates and / or immunoconjugates, methods of making the molecules and compositions, and methods of treating cancer using the molecules and compositions disclosed herein.

[0046] The term "antibody" is used in the broadest sense and specifically covers single monoclonal antibodies (including agonist antibodies and antagonist antibodies), antibody compositions with multiple epitope specificities, and antibody fragments (e.g., Fab, F(ab')2, and Fv), as long as they exhibit the desired biological activity. In some embodiments, the antibody may be a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a bispecific antibody or a bi-effective antibody, a mimetic antibody, a human antibody, and a humanized antibody and active fragments thereof. Examples of active fragments of molecules that bind to known antigens include Fab, F(ab')2, scFv, and Fv fragments, including products of Fab immunoglobulin expression libraries and epitope-binding fragments of any of the above antibodies and fragments. In some embodiments, antibodies may include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain binding sites that immunospecifically bind to antigens. Immunoglobulins can be of any type (IgG, IgM, IgD, IgE, IgA and IgY) or class (IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecules. In one embodiment, antibodies can be whole antibodies and any antigen-binding fragments derived from whole antibodies. Typical antibodies refer to heterotetrameric proteins that usually contain two heavy (H) chains and two light (L) chains. Each heavy chain consists of a heavy chain variable domain (abbreviated as VH) and a heavy chain constant domain. Each light chain consists of a light chain variable domain (abbreviated as VL) and a light chain constant domain. The VH and VL regions can be further subdivided into domains of hypervariable complementary determining regions (CDRs) and more conservative regions called framework regions (FRs). Each variable domain (VH or VL) is usually composed of three CDRs and four FRs, arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from amino terminus to carboxyl terminus. Within the variable domains of the light chain and heavy chain are binding regions that interact with antigens.

[0047] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody group, that is, each antibody comprising the group is identical, except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific and are directed against a single antigenic site. In addition, in contrast to conventional (polyclonal) antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous because they are synthesized by hybridoma cultures without being contaminated by other immunoglobulins. The modifier "monoclonal" indicates that the characteristic of an antibody is obtained from a substantially homogeneous antibody group, and should not be interpreted as requiring antibodies to be produced by any particular method. For example, the monoclonal antibodies used according to the present disclosure can be prepared by the hybridoma method first described by Kohler & Milstein, Nature, 256:495 (1975), or can be prepared by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567).

[0048] Monoclonal antibodies may include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855

[1984] ).

[0049] Monoclonal antibodies can be produced using a variety of methods, including mouse hybridoma or phage display (see Siegel. Transfus. Clin. Biol. 9: 15-22 (2002) for review) or molecular cloning of antibodies directly from primary B cells (see Tiller. New Biotechnol. 28: 453-7 (2011)). In the present disclosure, antibodies are produced by immunizing rabbits with human PD-L1 protein and cells transiently expressing human PD-L1 on the cell surface. Rabbits are known to produce antibodies with high affinity, diversity, and specificity (Weber et al., Exp. Mol. Med. 49: e305). B cells from immunized animals are cultured in vitro and screened for the production of anti-PD-L1 antibodies. Antibody variable genes are isolated using recombinant DNA technology, and the resulting antibodies are recombinantly expressed and further screened for desired characteristics, such as the ability to inhibit PD-L1 binding to PD-1, the ability to bind to non-primate PD-L1, and the ability to enhance human T cell activation. This general approach to antibody discovery is similar to that described by Seeber et al., PLOS One. 9:e86184 (2014).

[0050] The term "antigen or epitope binding part or fragment" refers to an antibody fragment that is capable of binding to an antigen (in this case CD19). These fragments may have antigen binding function and other functions of a complete antibody. Examples of binding fragments include, but are not limited to, single-chain Fv fragments (scFv) consisting of the VL and VH domains of a single arm of an antibody connected in a single polypeptide chain by a synthetic linker, or Fab fragments, which are monovalent fragments consisting of VL, constant light chain (CL), VH, and constant heavy chain 1 (CH1) domains. Antibody fragments may be even smaller subfragments and may consist of domains as small as a single CDR domain, particularly CDR3 regions from VL and / or VH domains (see, e.g., Beiboer et al., J. Mol. Biol. 296: 833-49 (2000)). Antibody fragments may be produced using conventional methods known to those skilled in the art. The utility of antibody fragments may be screened using the same techniques used with complete antibodies.

[0051] "Antigen- or epitope-binding fragments" can be derived from antibodies of the present disclosure by a number of techniques known in the art. For example, purified monoclonal antibodies can be cleaved with an enzyme such as pepsin and subjected to HPLC gel filtration. Appropriate fractions containing Fab fragments are then collected and concentrated by membrane filtration or the like. For further description of general techniques for isolating active fragments of antibodies, see, e.g., Khaw, BA et al., J. Nucl. Med. 23: 1011-1019 (1982); Rousseaux et al., Methods Enzymology, 121: 663-69, Academic Press, 1986.

[0052] Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, whose name reflects its ability to crystallize readily. Pepsin treatment produces an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.

[0053] The Fab fragment may contain the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. The Fab' fragment differs from the Fab fragment in that a few residues are added to the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH herein refers to Fab' in which the cysteine ​​residues of the constant domains bear free sulfhydryl groups. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0054] "Fv" is the smallest antibody fragment containing a complete antigen recognition and binding site. This region consists of a heavy chain and a light chain variable domain in a tight, non-covalently associated dimer. In this configuration, the three CDRs of each variable domain interact to define an antigen binding site on the surface of the VH-VL dimer. The six CDRs together give the antibody antigen binding specificity. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind to an antigen, although the affinity is lower than that of the entire binding site.

[0055] The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.

[0056] According to the amino acid sequence of the constant domain of the immunoglobulin heavy chain, immunoglobulins can be divided into different classes. There are five main types of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and some of these can be further divided into subclasses (isotypes), for example, IgG-1, IgG-2, IgG-3 and IgG-4; IgA-1 and IgA-2. The heavy chain constant domains corresponding to different immunoglobulin classes are respectively called α, δ, ε, γ and μ. The subunit structure and three-dimensional configuration of different classes of immunoglobulins are well known.

[0057] "Humanized antibodies" refer to a class of engineered antibodies whose CDRs are derived from non-human donor immunoglobulins and the remaining immunoglobulin-derived portions of the molecule are derived from one (or more) human immunoglobulins. In addition, framework support residues may be altered to maintain binding affinity. Methods for obtaining "humanized antibodies" are well known to those skilled in the art. (See, e.g., Queen et al., Proc. Natl Acad Sci USA, 86: 10029-10032 (1989), Hodgson et al., Bio / Technology, 9: 421 (1991)).

[0058] As used herein, the terms "polypeptide," "peptide," and "protein" are interchangeable and are defined to mean a biological molecule composed of amino acids linked by peptide bonds.

[0059] The terms "a," "an," and "the" as used herein are defined to mean "one or more" and include the plural unless the context is inappropriate.

[0060] "Isolated" refers to a biological molecule that is free of at least some of its naturally occurring components. "Isolated," when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and / or recovered from the cell or cell culture in which it is expressed. Typically, an isolated polypeptide will be prepared by at least one purification step. An "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen-binding specificities.

[0061] "Recombinant" means that the antibody is produced in a foreign host cell using recombinant nucleic acid technology.

[0062] The term "antigen" refers to an entity or fragment thereof that can induce an immune response in an organism, particularly an animal, more particularly a mammal (including a human). The term includes immunogens and regions thereof that are responsible for antigenicity or antigenic determinants.

[0063] In addition, as used herein, the term "immunogenic" refers to a substance that causes or enhances the production of antibodies, T-cells or other reactive immune cells to an immunogenic agent and contributes to an immune response in a human or animal. An immune response occurs when an individual produces sufficient antibodies, T-cells and other reactive immune cells to reduce or alleviate the condition to be treated in response to the administered immunogenic composition of the present disclosure.

[0064] "Specific binding" or "specifically binds to" or "specific for" a particular antigen or epitope refers to binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by measuring the binding of a molecule to a control molecule, which is typically a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0065] For example, specific binding to a particular antigen or epitope can be achieved by having at least about 10 -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -7 M, at least about 10 -8 M, at least about 10 -9 M, or at least about 10 -10 M, at least about 10 -11 M, at least about 10 -12 24 or greater, where KD refers to the off-rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds an antigen will have a KD of 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000-, or more times greater than a control molecule relative to the antigen or epitope.

[0066] In addition, specific binding to a particular antigen or epitope can be demonstrated, for example, by an antibody having a KA or Ka for the antigen or epitope that is at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000-, or more times that of a control, where KA or Ka refers to the association rate of a specific antibody-antigen interaction.

[0067] "Homology" between two sequences is determined by sequence identity. If the two sequences to be compared are of different lengths, sequence identity preferably refers to the percentage of nucleotide residues of the shorter sequence that are identical to the nucleotide residues of the longer sequence. Sequence identity can be routinely determined using computer programs. Deviations that occur in a comparison between a given sequence and the above sequences of the present disclosure may be caused, for example, by additions, deletions, substitutions, insertions or recombination.

[0068] The present disclosure may be more readily understood by reference to the following detailed description of specific embodiments and examples included herein.While the present disclosure has been described with reference to specific details of certain embodiments of the present disclosure, it is not intended that these details should be construed as limiting the scope of the present disclosure.

[0069] In previous disclosures, CAR exhaustion was addressed through cytokine signaling pathways to drive expansion without terminal differentiation. The compositions and methods of use disclosed herein relate to AI-CAR vectors for artificial immune monitoring chimeric antigen receptors. The advancement of this AI-CAR technology is intended to replace standard CAR manufacturing and achieve effective "combination" and point-of-care treatments. While other CAR technologies may require the expression of soluble cytokine growth factors and / or multiple administrations of sustained activity to produce a complete and durable response, the AI-CAR vector incorporates these activities and is able to produce effective and sustained CAR cells in the absence of multiple CAR administrations of constitutively active drivers of proliferation or durable anti-tumor responses.

[0070] Second, while maintaining the same function as standard CAR, AI-CAR signaling increases the efficiency of manufacturing CAR cells. AI-CAR may require only one target antigen in vitro and in vivo to obtain full proliferation and cytotoxic activity. In this article, since the expansion of standard CAR-T cells usually requires the use of a combination of growth factors and aAPCs to manufacture, AI-CAR can significantly reduce manufacturing costs.

[0071] Third, after AI-CAR engagement of tumor cells in vivo, the expression of several anti-tumor genes encoded by the integrated AI-CAR vector can be induced. The expression of these endogenous genes can enable patients to produce anti-tumor responses that target different tumor antigens such as new antigens more widely. For example, the STAT5 reporter system is used to induce STAT5 responsive genes in human T cells (Kanai et al., 2014; Zeng et al., 2016; Bednorz et al., 2011; and Fang et al., 2008). This feature is unique because standard CAR constructs are generally unable to induce gene expression. Together with these auxiliary factors, AI-CAR will become a platform technology that provides practical, economical and effective solutions for cancer care point treatment. Many forms of cancer can exist in an immunosuppressive tumor environment. AI-CAR will be highly desirable because the AI-CAR vector is designed to express additional anti-cancer genes that can reduce tumor immunosuppression and activate the patient's anti-tumor immune response. One of the unique features of AI-CAR is its ability to regulate the expression of relevant anti-tumor genes at the tumor site, rather than constitutively expressing them, which may be toxic. Another feature is that AI-CAR is designed to have a single dose when administered, followed by its long-term activity and greater efficacy. With these favorable features, AI-CAR is a better solution to the challenges that are not met on the market, which predicts the efficacy of treating most (if not all) types of cancer.

[0072] Regarding CAR therapy for the treatment of blood cancer, targets include CD19 and CD22, CD20, CD9, CD38, which can be targeted by dual bispecific AI-CAR using non-viral DNA vectors or RNA-CAR (transient). In this way, AI-CAR can be used as a transient treatment bridge for transplantation or more continuous treatment. In addition, AI-CAR can be used as a point-of-care treatment for inducing host anti-tumor immune responses against new antigens.

[0073] In addition, for certain solid tumors, RNA encoding AI-CAR combination therapy can be applied. For other aggressive tumors that have failed treatment, readily available RNA CARs can be manufactured efficiently and quickly due to the high electroporation efficiency of RNA. Multiple anti-tumor mechanisms transiently expressed by RNA AI-CAR, such as induced AI-CAR vector genes, should be able to achieve more effective and safer anti-tumor activity and potentially induce patient immune responses. Multi-dose RNA AI-CAR can be used as a bridge to determine efficacy before treatment with certain persistent AI-CAR cells.

[0074] Example

[0075] Example 1. Construction of AI-CAR vectors for continuous and combined therapy

[0076] The purpose of AI-CAR cells is to improve the efficacy of cancer immunotherapy by continuous, long-term immune surveillance in a quiescent state until stimulated by tumor cells. After tumor stimulation, the inducible AI-CAR gene enables local, safe and more effective "combination" treatment involving other mechanisms of anti-tumor activity. For a higher frequency of complete and durable responses, it is expected to stimulate the anti-tumor response of patients.

[0077] Typically, the AI-CAR construct consists of an AI-CAR expression cassette in a non-viral vector (pPI) such as a transposon-based integration system (Ivics and Izsvák, 2010; Z Cooper et al., US9,629,877; Uckert et al., US20190071484A1). Figure 1 As shown, the AI-CAR vector comprises an inducible gene expression unit and a CAR expression unit, i.e., an AI-CAR expression cassette flanked by transposon terminal inverted repeats (IR). STAT, NFAT or NF-κB inducible promoters can be used, the coding region of one or more genes connected by IRES or self-cutting ribosomal jumping peptides such as P2A or T2A (e.g., SEQ ID 18-21), and the subsequent polyA signal sequence to construct an AI-CAR expression cassette. This can be followed by another promoter for constitutive expression of one or two CARs, followed by another polyA signal. Examples of AI-CAR chain pairs are shown in SEQID 1 and 2, 3 and 4, 5 and 6, 7 and 8, 9 and 10. The two coding regions can be located between two transposons or viral terminal repeats (IR) for integration. Alternatively, the coding region of the AI-CAR construct can be integrated into a specific genomic site using zinc fingers, TALEN or CRISPR / Cas9 nucleases (Eyquem 2017).

[0078] like Figure 2 As shown, the constitutive expression of one or two CARs on the T cell surface is combined with tumor-associated antigens at the tumor. The AI-CAR induces the expression of inducible genes, achieving the safety of anti-tumor activity and effective stimulation of multiple mechanisms and host anti-tumor responses. Ideally, the expression of these genes will be induced after AI-CAR engages with tumor antigens or antigens in the tumor microenvironment (TME). In order to extend the library of these genes, the second AI-CAR chain can be expressed from the second vector.

[0079] There is at least some flexibility in the composition of AI-CAR non-viral vectors, such as piggyBac, Tol2, and SleepingBeauty (Ivics and Izsvák, 2010). In addition, AI-CAR can express a safety switch, such as a truncated EGFR (tEGFR), which can be targeted for elimination by the FDA-approved antibody cetuximab. Alternatively, the safety target can be a truncated CD20, which can be targeted by rituximab for CAR cell elimination. The AI-CAR vector can express shRNA, which, for example, inhibits endogenous TCR to enable the generation of universal AI-CAR cells.

[0080] As an alternative to inducible promoters, AI-CARs may include weak promoters, such as a modified PGK promoter, to safely express other mechanisms of anti-tumor activity.

[0081] Example 2. Single and Dual AI-CAR Designs

[0082] Single or dual AI-CARs are designed to signal through cytokine receptor pathways to achieve greater CAR cell persistence and induce vector-encoded genes for additional antitumor mechanisms and enhanced efficacy. In addition, simple conjugation of AI-CARs can promote efficient AI-CAR expansion and can be used in manufacturing to simplify in vitro expansion before administration.

[0083] Dual AI-CAR is constructed with IL12, IL7, IL21 or IL15 cytokine receptor endodomains to enable vector genes to be sustained and induced for additional anti-tumor mechanisms. As listed in Table 2, the cytokine endodomain is fused to one or more TCR or TCR costimulatory cytoplasmic regions (also referred to as costimulatory domains), such as CD3ζ, CD28, CD137, CD27, OX40 and ICOS. For example, a CAR consisting of a tumor antigen-specific scFv composed of an intracellular (inner) domain and a fragment of CD3ζ fused to a stem and a transmembrane domain and an IL12β1 chain and a fragment of CD3ζ can be used to construct dual AIL-CAR. The second CAR can be composed of a tumor antigen-specific scFv fused to a stem and a transmembrane domain, a fragment of a common β2 chain endodomain and a CD137 costimulatory endodomain.

[0084] AI-CAR can induce gene expression through transcription factors such as STAT4. The IL12β1 chain has a Ty2k binding site, while the β2 chain has a JAK2 binding site. The binding of the two chains can be stabilized by binding to adjacent target antigens or to two different but adjacent epitopes of the same tumor target antigen. When CAR binds to tumor antigens, Ty2k and JAK2 will phosphorylate the β chain and ultimately phosphorylate STAT4, which then dimerizes and translocates to the nucleus. STAT4 can then bind to promoter transcription factor (TF) response elements and promote the induction of gene expression. Promoters and downstream genes that can be regulated by STAT4 can be incorporated into CAR transposons or viral vectors. Once integrated, these genes can be induced after CAR cells engage tumor or TME antigens. Endogenous genes induced by STAT4 also support CAR cell persistence (DeRenzo 2019).

[0085] Most dual AI-CAR components are independent functional units, i.e., anti-tumor scFv, stem, transmembrane domain and internal domain, as well as different fragments of IL15, IL7 and IL21 chains, CD3ζ and co-stimulatory proteins, and are replaced for many specific purposes. As shown in Tables 1 and 2, there may be many combinations for making specific AI-CARs.

[0086] Monospecific AI-CAR can be constructed so that CAR cell persistence is supported by inducible genes encoded in CAR vectors. AI-CAR can be composed of scFv, stem, transmembrane domain and co-stimulatory CD137 and CD3ζ internal domains targeting tumor or TME-related antigens. After engaging NFAT with tumor antigen activity, NFAT bound to the response element in the integrated CAR vector will be produced, and the response element induces the expression of one or more genes (such as IL15, IL12 and IL7) supporting persistence and other mechanisms of anti-tumor activity.

[0087] Table 2 shows additional genes encoding proteins or miRNAs with persistent activity or anti-tumor activity, such as anti-immune checkpoint inhibitors (ICI), OX40 agonists, TLR agonists, cytokines, bispecific antibodies, iPro, chemokines and chemokine receptors, which can be placed under the control of an inducible promoter. Alternatively, mRNA encoding these proteins (such as SEQID18-20) can be co-transfected with AI-CAR vectors for transient expression. Alternatively, mRNA encoding CAR and these proteins can be used as transient, safe treatment of AI-CAR (SEQ ID 11-17). AI-CARs of several doses of transiently expressed these genes can be sufficient to reduce immunosuppression in the tumor microenvironment and activate the patient's anti-tumor immune response.

[0088] Example 3. Encoding bispecific anti-CDH17 and anti-TROP2 CAR's AI-CAR and use for continuity and enhancement Inducible genes for anti-tumor response

[0089] like Figure 3 As shown, an AI-CAR vector can be constructed with an NFAT inducible promoter, one or more genes such as anti-PD-1, CCL21 and IL7 coding regions connected by ribosomal jumping peptides such as T2A, and a subsequent polyA signal sequence. This can be followed by a promoter for a single bispecific CAR targeting CDH17 and TROP2 with CD137 and CD3ζ internal domains, followed by T2A, signal peptide, tEGFR and polyA signals. The two coding regions can be located between transposons or viral terminal repeats (IR) for integration. Alternatively, TALEN or CRISPR / Cas9 (Eyquem 2017) can be used to integrate the AI-CAR expression cassette at a specific genomic site.

[0090] Example 4. AI-CAR gene induction of tumor target antigens

[0091] Recombinant and cell tumor target antigens are used to induce AI-CAR vector genes after integration into T cell lines. The pPI-anti-CDH17-AI-CAR construct expressing GFP under the control of NFAT inducible promoter is electroporated into Jurkat T cell line. The pBac transposon construct is co-electroporated with the transposase expression vector for AI-CAR vector integration. The T cell line (Jurkat) with integrated pPI anti-CDH17 AI-CAR vector is incubated (37°C, 5% CO2) in microtiter wells coated with 0, 1.25, 2.5, 5, 10 or 20 μg / mlCDH17-Fc for 2 hours or 14 hours. The pPI anti-CDH17 AI-CAR vector contains GFP regulated by NFAT inducible promoter. At 14 hours, GFP expression levels were determined by flow cytometry. The levels of GFP expression are relative to the levels maximally induced at 14 h of immune culture treatment (anti-CD3, CD28, and CD2; stem cells). For CDH17 exposed for only 2 h, low levels of GFP were detected by flow cytometry, as shown in Figure 4 As shown in A. After 14 hours, GFP increased to 70% in a concentration-dependent manner after CDH17 exposure relative to the immune culture. Acceptable levels of GFP were present in unstimulated cells. CDH17 was expressed at different levels in SW480 cells by electroporation with 0, 1.25, 5, 10, or 20 μg CDH17 RNA (per 10^7 cells). The expression of CDH17 was determined by standard flow cytometry, as shown in Figure 5. Figure 4As shown in B. Jurkat lines integrated with pPI anti-CDH17 AI-CAR vectors were incubated with monolayers of SW480 expressing different levels of CDH17 for 2 or 14 hours. At 14 hours, GFP expression levels were determined by flow cytometry. GFP expression levels were relative to the maximum induction level at 14 hours of immune culture. Figure 4 As shown in C, similar levels of GFP induction (50-80%) were detected after AI-CAR was exposed to CDH17 expressing Sw480 for 2 or 14 hours. Therefore, tumor cells expressing target antigens appear to effectively induce AI-CAR vector gene expression. Therefore, this AI-CAR construct can be used to express proteins with anti-tumor activity at tumor sites to safely and enhance tumor killing.

[0092] Example 5. Expression of dual AI-CAR

[0093] The expression and binding activity of the double-chain dual AI-CAR are shown. Dual AI-CARs were expressed in CHO cells, one with IL15β and CD28 endodomains and the other with IL15γ and CD3ζ endodomains (SEQ ID 1 and 2). Figure 5 As shown, single chains, pSh3C15b28 and pSh3A4C15g3, or the expression of two chains were determined by staining with biotinylated protein-L (for scFv). Binding to tumor antigens, CDH17-Fc or TROP2-Fc was also determined by flow cytometry. Expression and tumor antigen binding were determined using streptavidin-phycoerythrin (for protein-L) and anti-human IgG-Alexa647 (for CDH17 and TROP2). These results show that the transfection, expression, and ligand binding functions of dual CARs can be easily achieved.

[0094] Example 6. iPro design and expression to support AI-CAR proliferation and persistence

[0095] Proliferation inducers (iPro) can be induced in a single AI-CAR to support proliferation and persistence. iPro can be constructed with an N-terminal cytokine or scFv binding to TME antigens, followed by a linker, stem, transmembrane domain, and an endodomain with JAK family and STAT binding sites, such as Figure 6 A. After the N-terminal domain engages with a cytokine receptor or tumor antigen, iPro can signal through STAT to induce the expression of T or NK cell proteins that support and survival and maintenance of the Tcm stem phenotype. Has an N-terminal cytokine domain, such as IL7, IL15, or IL12. iPro can support bidirectional inside-out and outside-in stimulation, activating patient T cells and NK cells in addition to AI-CAR cells. In addition to enhancing AI-CAR activity in vivo, iPro expression can promote intronic amplification of AI-CAR for manufacturing.

[0096] iPro with N-terminal IL7 (iPro7; SEQ ID 19) transiently expressed in PBMCs by electroporation of its in vitro transcribed mRNA was detected by flow cytometry at 24 hours but not 48 hours ( Figure 6 B, left panel). On day 2, flow cytometry confirmed the induced expression of IL2 receptor CD25 ( Figure 6 C, middle panel). In the absence of further stimulation, T cell counts remained stable over 10 days, whereas mock control T cell counts decreased significantly ( Figure 6 D, right). These results suggest that variants of AI-CAR inducible genes (e.g., iPro) can be designed to support AI-CAR proliferation and persistence.

[0097] References

[0098] Rodríguez-Galán A, Fernández-Messina L, Sánchez-Madrid F. Control of Immunoregulatory Molecules by miRNAs in T Cell Activation. Front Immunol. 2018 Sep 25;9:2148.

[0099] Lykken EA,Li QJ.The MicroRNA miR-191Supports T Cell SurvivalFollowing CommonγChain Signaling.J Biol Chem.2016Nov 4;291(45):23532-23544.Epub 2016Sep 15.

[0100] Ivics, Z., Izsvák, Z. The expanding universe of transposon technologies for gene and cell engineering. Mobile DNA 1, 25 (2010).

[0101] Cooper Lj,Torikai H,Zhang L,Huls H,Wang-Johanning F,Hurton L,OlivaresS,Krishnamurthy J.Human application of engineered chimeric antigen receptor(CAR)T-cells.US9629877B2.Uckert W,Bunse M,Clauss J,Izsvák ZA transposon-based transfection system for primary cells US20190071484A1.

[0102] surface

[0103] Table 1 lists examples of AI-CAR compositions. AI-CAR can be constructed using fragments of different genes encoding different functional fragments, including anti-tumor associated antigen (TAA) scFv, stem, transmembrane domain and internal domain. Different types of internal domains can, for example, play a role in signaling cytokine receptor proliferation and survival response or tumor cell toxicity response. Cytokine receptors, CD3ζ and costimulatory internal domains can be fused in various tandem arrangements.

[0104]

[0105]

[0106] Table 2 lists examples of inducible genes that can be incorporated into AI-CAR vectors. These genes can be selected to enhance CAR localization to tumors (e.g., lymphomas), reverse tumor immunosuppression and stimulate host immune responses or for direct anti-tumor cell activity. The gene can be placed downstream of the STAT5 inducible promoter to avoid any toxicity that may occur with long-term constitutive expression. Alternatively, certain chemokines and chemokine receptor genes and cytokines, such as IL7, can be located downstream of a weak promoter. Low levels of expression can avoid toxicity.

[0107]

[0108]

[0109] Sequence Listing

[0110] SEQ ID NO:1

[0111] TROP2-specific AI-CAR (pSh3A4C15g3)

[0112] MEFGLSWVFLVALLRGVQCQVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMNWVRQAPGQGLEWMGRVNPSNGDTNYNQKFKGRVTSTRDTSISTAYMELSRLRSDDTAVYYCARERIYYGISWYFDVWDTGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLLYNAKTLAEGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCHHYYSTPPTFGQGTKLEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0113] SEQ ID NO:2

[0114] CDH17-specific AI-CAR (pSh3C15b28)

[0115] MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS P

[0116] SEQ ID NO:3

[0117] h2FM19AIg3z (CD19-specific AI-CAR-g3z)

[0118] MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGGAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0119] SEQ ID NO:4

[0120] hAT38AIa7 (CD38 specific, AI-CAR-a7)

[0121] MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVRPSQTLSLTCTVSGFTFTSYGVHWVRQPPGRGLEWIGVMWRGGSTDYNAAFMSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAKSMITTGFVMDSWGQGSLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASEDIYNRLTWYQQKPGKAPKLLISGATSLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYWSNPYTFGQGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ

[0122] SEQ ID NO:5

[0123] h81AIaI7 (CD81 specific, AI-CAR-a7)

[0124] MKHLWFFLLLVAAPRWVLSQVQLVQSGAEVKKPGASVKVSCKASGYTFSSSWMNWVRQAPGQRLEWMGRIYSGDGDAIYNGKFKGRVTITADTSASTAYMELSSLRSEDTAVYYCAREGKTGDLLLRSWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCRASKSVSTSIYSYMHWYQQKPGQPPKLLIYYASYLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCEHSREFPFTFGQGTKLEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQSEQ ID NO:6

[0125] hRF22AIgC7 (CD22 specific, AI-CAR-gC7)

[0126] MKHLWFFLLLVAAPRWVLSEVQLVESGGGLVQPGGSLRLSCAASGFAFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTVSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSP

[0127] SEQ ID NO:7

[0128] h2FM19b1AI3z (CD19-specific AI-CAR–IL12b1 CD137-CD3z)

[0129] MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGGAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADWLIFFASLGSFLSILLVGVLGYLGLNRAARHLCPPLPTPCASSAIEFPGGKETWQWINPVDFQEEASLQEALVVEMSWDKGERTEPLEKTELPEGAPELALDTELSLEDGDRCKAKMKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0130] SEQ ID NO:8

[0131] hAT38bAI2 (CD38 specific, AI-CAR–IL12b2)

[0132] MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVRPSQTLSLTCTVSGFTFTSYGVHWVRQPPGRGLEWIGVMWRGGSTDYNAAFMSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAKSMITTGFVMDSWGQGSLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASEDIYNRLTWYQQKPGKAPKLLISGATSLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYWSNPYTFGQGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADWMAFVAPSICIAIIMVGIFSTHYFQQKVFVLLAALRPQWCSREIPDPANSTCAKKYPIAEEKTQLPLDRLLIDWPTPEDPEPLVISEVLHQVTPVFRHPPCSNWPQREKGIQGHQASEKDMMHSASSPPPPRALQAESRQLVDLYKVLESRGSDPKPENPACPWTVLPAGDLPTHDGYLPSNIDDLPSHEAPLADSLEELEPQHISLSVFPSSSLHPLTFSCGDKLTLDQLKMRCDSLML

[0133] SEQ ID NO:9

[0134] h5AIg137.3z (CDH17-specific AI-CARγ / CD137 / CD3z)

[0135] MEFGLSWVFLVALLRGVQCQVQLVQSGAEVKKPGASVKVSCKVSAYAFSSSWMNWVRQAPGKGLEWMGRIYPRDGDTNYNGKFKGRVTMTADTSTDTAYMELSSLRSEDTAVYYCAREGDGYYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSIRNYLHWYQQKPGEAPRLLIYYASQSISGIPARFSGSGSGTDFTLTISSLETEDFAMYYCQHSNSWPLTFGQGTKLEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0136] SEQ ID NO:10

[0137] h10AIa7 (CDH17 specific a7)

[0138] MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAVIDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ

[0139] Examples of RNA AI-CAR

[0140] SEQ ID NO:11

[0141] h10C7-P2A-IL18(CDH17 CAR-IL18)

[0142] MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTF SSYAMS WVRQTPGKGLEWVA V IDSNGGSTYYPDTVK DRFTISRDNSKNTLYLQMNSLRAEDTAVYYCS SYTNLGAY WGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC RASQDISGYLN WLQQKPGGAIKRLIY TTSTLDS GVPKRFSGSGSGTDFTLTISSLQSEDFATYYC LQYASSPFT FGGGTKVEIK GAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYC KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR AS GSGATNFSLLKQAGDVEEN PGP MEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

[0143] SEQ ID NO:12

[0144] h10C7-P2A-INFg(CDH17 CAR-INFγ)

[0145] -MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTF SSYAMS WVRQTPGKGLEWVA VIDSNGGSTYYPDTVK DRFTISRDNSKNTLYLQMNSLRAEDTAVYYCS SYTNLGAY WGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC RASQDISGYLN WLQQKPGGAIKRLIY TTSTLDS GVPKRFSGSGSGTDFTLTISSLQSEDFATYYC LQYASSPFT FGGGTKVEIK GAP TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYC<h2 style=";text-align:left;direction:ltr">KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR<h2 style=";text-align:left;direction:ltr"> AS <h2 style=";text-align:left;direction:ltr"> GSGATNFSLLKQAGDVEEN<h2 style=";text-align:left;direction:ltr"> PGP <h2 style=";text-align:left;direction:ltr"> MKHLWFFLLLVAAPRWVLSQDPYVKEAENLKKYFNAGHSDVADNGTLFLGILKNWKEESDRKIMQSQIVSFYFKLFKNFKDDQSIQKSVETIKEDMNVKFFNSNKKKRDDFEKLTNYSVTDLNVQRKAIHELIQVMAELSPAAKTGKRKRSQMLFRGRRASQ<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0146] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:13<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0147] <h2 style=";text-align:left;direction:ltr"> h10C7-P2A-IL18-pro-CCL21(CDH17 CAR-IL18-proCCL21)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0148] <h2 style=";text-align:left;direction:ltr"> MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTF<h2 style=";text-align:left;direction:ltr"> SSYAMS <h2 style=";text-align:left;direction:ltr"> WVRQTPGKGLEWVA<h2 style=";text-align:left;direction:ltr"> V <h2 style=";text-align:left;direction:ltr"> IDSNGGSTYYPDTVK <h2 style=";text-align:left;direction:ltr"> DRFTISRDNSKNTLYLQMNSLRAEDTAVYYCS<h2 style=";text-align:left;direction:ltr"> SYTNLGAY <h2 style=";text-align:left;direction:ltr"> WGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSSASVGDRVTITC<h2 style=";text-align:left;direction:ltr"> RASQDISGYLN <h2 style=";text-align:left;direction:ltr"> WLQQKPGGAIKRLIY<h2 style=";text-align:left;direction:ltr"> TTSTLDS <h2 style=";text-align:left;direction:ltr"> GVPKRFSGSGSGTDFTLTISSLQSEDFATYYC<h2 style=";text-align:left;direction:ltr"> LQYASSPFT <h2 style=";text-align:left;direction:ltr"> FGGGTKVEIK<h2 style=";text-align:left;direction:ltr"> GAP <h2 style=";text-align:left;direction:ltr"> TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT<h2 style=";text-align:left;direction:ltr"> LYC<h2 style=";text-align:left;direction:ltr">KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR<h2 style=";text-align:left;direction:ltr"> AS <h2 style=";text-align:left;direction:ltr"> GSGATNFSLLKQAGDVEEN<h2 style=";text-align:left;direction:ltr"> PGP <h2 style=";text-align:left;direction:ltr"> MEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED<h2 style=";text-align:left;direction:ltr"> P <h2 style=";text-align:left;direction:ltr"> AG <h2 style=";text-align:left;direction:ltr"> GGTKTESSSRSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQAELCADPKELWVQQLMQHLDKTPSPQKPAQGCRKDRGASKTGKKGKGSKGCKRTERSQTPKGP<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0149] <h2 style=";text-align:left;direction:ltr"> SEQ ID NO:14<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0150] <h2 style=";text-align:left;direction:ltr"> h10C7-P2A-h8C7-P2A-IL18(CDH17 CAR-TROP2CAR-IL18)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0151] <h2 style=";text-align:left;direction:ltr"> MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTF<h2 style=";text-align:left;direction:ltr"> SSYAMS <h2 style=";text-align:left;direction:ltr"> WVRQTPGKGLEWVA<h2 style=";text-align:left;direction:ltr"> V <h2 style=";text-align:left;direction:ltr"> IDSNGGSTYYPDTVK <h2 style=";text-align:left;direction:ltr"> DRFTISRDNSKNTLYLQMNSLRAEDTAVYYCS<h2 style=";text-align:left;direction:ltr"> SYTNLGAY <h2 style=";text-align:left;direction:ltr"> WGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSSASVGDRVTITC<h2 style=";text-align:left;direction:ltr"> RASQDISGYLN <h2 style=";text-align:left;direction:ltr"> WLQQKPGGAIKRLIY<h2 style=";text-align:left;direction:ltr"> TTSTLDS <h2 style=";text-align:left;direction:ltr"> GVPKRFSGSGSGTDFTLTISSLQSEDFATYYC<h2 style=";text-align:left;direction:ltr"> LQYASSPFT <h2 style=";text-align:left;direction:ltr"> FGGGTKVEIK<h2 style=";text-align:left;direction:ltr"> GAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYC KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR AS GSGATNFSLLKQAGDVEEN PGP MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYTMSWVRQTPAKGLVWVSTINSDGYNIYYSDSMKGRFTISRDNAKYTLYLQMNSLRAEDTAMYYCARCSYYSYDYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASENIDNYLAWYQQKQGKVPKLLIYAATNLADGMPSRFSGSGSGTDFTLTISSLQPEDVATYYCQHYYSNQLTFGQGTKLEIK GAP TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT L YC KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR AS GSGATNFSLLKQAGDVEEN PGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

[0152] SEQ ID NO:15

[0153] h10C7 - P2A - h3U1 (CDH17 CAR - bispecific antibody anti - CDH17xCD3)

[0154] MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTF SSYAMS WVRQTPGKGLEWVA V IDSNGGSTYYPDTVK DRFTISRDNSKNTLYLQMNSLRAEDTAVYYCS SYTNLGAY WGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC RASQDISGYLN WLQQKPGGAIKRLIY TTSTLDS GVPKRFSGSGSGTDFTLTISSLQSEDFATYYC LQYASSPFT FGGGTKVEIK GAP TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYC KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR AS GSGATNFSLLKQAGDVEEN PGPMEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELK PAG GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK

[0155] SEQ ID NO:16

[0156] h10C7 - P2A - h3U1 - pro - IL18 (CDH17 CAR - bispecific antibody anti - CDH17xCD3 - pro - IL18)

[0157] MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTF SSYAMS WVRQTPGKGLEWVA V IDSNGGSTYYPDTVK DRFTISRDNSKNTLYLQMNSLRAEDTAVYYCS SYTNLGAY WGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC RASQDISGYLN WLQQKPGGAIKRLIY TTSTLDS GVPKRFSGSGSGTDFTLTISSLQSEDFATYYC LQYASSPFT FGGGTKVEIK GAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYC KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR AS GSGATNFSLLKQAGDVEEN PGP MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELK PAG GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK PAG GGTKTESSSRGYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

[0158] SEQ ID NO:17

[0159] h10C7-P2A-h3U1-pro-IL18-pro-XCL1 (CDH17 CAR-bispecific antibody anti-CDH17xCD3-proIL18-proXCL1)

[0160] MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTF SSYAMS WVRQTPGKGLEWVA V IDSNGGSTYYPDTVK DRFTISRDNSKNTLYLQMNSLRAEDTAVYYCS SYTNLGAY WGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC RASQDISGYLN WLQQKPGGAIKRLIY TTSTLDS GVPKRFSGSGSGTDFTLTISSLQSEDFATYYC LQYASSPFT FGGGTKVEIK GAP TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYC KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR AS GSGATNFSLLKQAGDVEEN PGP MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELK PAG GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK PAG GGTKTESSSRGYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNEDSGGGTKTESSSRGVGSEVSDKRTCVSLTTQRLPVSRIKTYTITEGSLRAVIFITKRGLKVCA

[0161] DPQATWVRDVVRSMDRKSNTRNNMIQTKPTGTQQSTNTAVTLTG

[0162] Examples of AI-CAR Inducible Gene Combinations

[0163] SEQ ID NO:18

[0164] h3U1–P2A-IL18 (Bispecific Antibody Anti-CDH17xCD3-IL18)

[0165] MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELK PASS GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK AS GSGATNFSLLKQAGDVEEN PGP MEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

[0166] SEQ ID NO:19

[0167] iPro7 (iPro with n - terminal IL7)

[0168] MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHGGGSGGGS GAP TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYCKK PAGRNTGPWLKKV LKCNTPDP SKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLNTDAYLSLQELQGQDP

[0169] SEQ ID NO:20

[0170] iPro7-P2A-h3U1–P2A-IL18 (iProIL7-Bispecific antibody anti-CDH17xCD3-IL18)

[0171] MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHGGGSGGGS GAP TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYCKK PAGRNTGPWLKKV LKCNTPDP SKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLNTDAYLSLQELQGQDP AS GSGATNFSLLKQAGDVEEN PGPQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELK PASS SGATNFSLLKQAGDVEEN PGP MEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

[0172] SEQ ID NO:21

[0173] iPro7-P2A-h3U1–P2A-IL18-pro-CCL21 (iProIL7-Bispecific antibody anti-CDH17xCD3-IL18-proCCL21)

[0174] MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHGGGSGGGS GAP TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT LYCKK PAGRNTGPWLKKV LKCNTPDP SKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLNTDAYLSLQELQGQDP AS GSGATNFSLLKQAGDVEEN PGP QVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGS GGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELK PASS SGATNFSLLKQAGDVEEN PGP MEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED G GGTKTESSSRSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQAELCADPKELWVQQLMQHLDKTPSPQKPAQGCRKDRGASKTGKKGKGSKGCKRTERSQTPKGP Sequence Listing <110> Abeile Pharmaceutical Technology Co., Ltd. <120> Artificial immune surveillance chimeric antigen receptor (AI-CAR) and its expressing cells <130> ARTI917PCT <141> 2020-02-21 <150> 62 / 808,815 <151> 2019-02-21 <150> 62 / 808,823 <151> 2019-02-21 <150> 62 / 808,833 <151> 2019-02-21 <160> twenty one <170> SIPOSequenceListing 1.0 <210> 1 <211> 532 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 1 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 20 25 30 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Asp Phe Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 50 55 60 Glu Trp Met Gly Arg Val Asn Pro Ser Asn Gly Asp Thr Asn Tyr Asn 65 70 75 80 Gln Lys Phe Lys Gly Arg Val Thr Ser Thr Arg Asp Thr Ser Ile Ser 85 90 95 Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Glu Arg Ile Tyr Tyr Gly Ile Ser Trp Tyr Phe 115 120 125 Asp Val Trp Asp Thr Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 145 150 155 160 Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 165 170 175 Ile Thr Cys Arg Ala Ser Gly Asn Ile His Asn Tyr Leu Ala Trp Tyr 180 185 190 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu Tyr Asn Ala Lys 195 200 205 Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 210 215 220 Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala 225 230 235 240 Thr Tyr Tyr Cys His His Tyr Tyr Ser Thr Pro Pro Thr Phe Gly Gln 245 250 255 Gly Thr Lys Leu Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro 260 265 270 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 275 280 285 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 290 295 300 Gly Leu Asp Phe Ala Cys Asp Ala Val Val Ile Ser Val Gly Ser Met 305 310 315 320 Gly Leu Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr 325 330 335 Met Pro Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu 340 345 350 Tyr His Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala 355 360 365 Glu Ser Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu 370 375 380 Ile Pro Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro 385 390 395 400 Cys Asn Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys 405 410 415 Pro Glu Thr Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 420 425 430 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 435 440 445 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 450 455 460 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 465 470 475 480 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 485 490 495 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 500 505 510 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 515 520 525 Leu Pro Pro Arg 530 <210> 2 <211> 496 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 2 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 20 25 30 Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr 65 70 75 80 Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln 115 120 125 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Val Met Thr Gln Thr Pro 145 150 155 160 Leu Ser Leu Ser Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Arg 165 170 175 Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp 180 185 190 Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val 195 200 205 Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser 210 215 220 Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val 225 230 235 240 Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly 245 250 255 Ala Gly Thr Lys Leu Glu Leu Lys Gly Ala Pro Thr Thr Thr Pro Ala 260 265 270 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 275 280 285 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 290 295 300 Arg Gly Leu Asp Phe Ala Cys Asp Ile Pro Trp Leu Gly His Leu Leu 305 310 315 320 Val Gly Leu Ser Gly Ala Phe Gly Phe Ile Ile Leu Val Tyr Leu Leu 325 330 335 Ile Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys 340 345 350 Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His 355 360 365 Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser 370 375 380 Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu Glu Val Leu 385 390 395 400 Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Gln Gln Asp Lys Val Pro 405 410 415 Glu Pro Ala Ser Leu Ser Ser Asn His Ser Leu Thr Ser Cys Phe Thr 420 425 430 Asn Gln Gly Tyr Phe Phe Phe His Leu Pro Asp Ala Leu Glu Ile Glu 435 440 445 Ala Cys Gln Val Tyr Phe Arg Ser Lys Arg Ser Arg Gly Gly His Ser 450 455 460 Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His 465 470 475 480 Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Pro 485 490 495 <210> 3 <211> 530 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 3 Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp 1 5 10 15 Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu 35 40 45 Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu 50 55 60 Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser 65 70 75 80 Ala Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln 85 90 95 Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 100 105 110 Tyr Cys Ala Arg His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 145 150 155 160 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 165 170 175 Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln 180 185 190 Lys Pro Gly Gly Ala Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu 195 200 205 His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 210 215 220 Phe Thr Phe Thr Ile Ser Ser Leu Gln Gln Glu Asp Ile Ala Thr Tyr 225 230 235 240 Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr 245 250 255 Lys Val Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro 260 265 270 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 275 280 285 Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 290 295 300 Asp Phe Ala Ala Asp Ala Val Val Ile Ser Val Gly Ser Met Gly Leu 305 310 315 320 Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro 325 330 335 Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu Tyr His 340 345 350 Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala Glu Ser 355 360 365 Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro 370 375 380 Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro Cys Asn 385 390 395 400 Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu 405 410 415 Thr Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 420 425 430 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 435 440 445 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 450 455 460 Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 465 470 475 480 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 485 490 495 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 500 505 510 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 515 520 525 Pro Arg 530 <210> 4 <211> 528 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 4 Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp 1 5 10 15 Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Thr Phe 35 40 45 Thr Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Arg Gly Leu 50 55 60 Glu Trp Ile Gly Val Met Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala 65 70 75 80 Ala Phe Met Ser Arg Val Thr Met Leu Val Asp Thr Ser Lys Asn Gln 85 90 95 Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 100 105 110 Tyr Cys Ala Lys Ser Met Ile Thr Thr Gly Phe Val Met Asp Ser Trp 115 120 125 Gly Gln Gly Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 145 150 155 160 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 165 170 175 Lys Ala Ser Glu Asp Ile Tyr Asn Arg Leu Thr Trp Tyr Gln Gln Lys 180 185 190 Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser Gly Ala Thr Ser Leu Glu 195 200 205 Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 210 215 220 Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr 225 230 235 240 Cys Gln Gln Tyr Trp Ser Asn Pro Tyr Thr Phe Gly Gln Gly Thr Lys 245 250 255 Val Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro 260 265 270 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 275 280 285 Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 290 295 300 Phe Ala Ala Asp Pro Ile Leu Leu Thr Ile Ser Ile Leu Ser Phe Phe 305 310 315 320 Ser Val Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp Lys Lys Arg 325 330 335 Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu 340 345 350 Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn 355 360 365 Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln 370 375 380 Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp Thr Phe Pro Gln Gln 385 390 395 400 Leu Glu Glu Ser Glu Lys Gln Arg Leu Gly Gly Asp Val Gln Ser Pro 405 410 415 Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg 420 425 430 Asp Ser Ser Leu Thr Cys Leu Ala Gly Asn Val Ser Ala Cys Asp Ala 435 440 445 Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys 450 455 460 Asn Gly Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr 465 470 475 480 Asn Ser Thr Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly Ile Leu Thr 485 490 495 Leu Asn Pro Val Ala Gln Gly Gln Pro Ile Leu Thr Ser Leu Gly Ser 500 505 510 Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln 515 520 525 <210> 5 <211> 533 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 5 Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp 1 5 10 15 Val Leu Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 20 25 30 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Ser Ser Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu 50 55 60 Glu Trp Met Gly Arg Ile Tyr Ser Gly Asp Gly Asp Ala Ile Tyr Asn 65 70 75 80 Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser 85 90 95 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Glu Gly Lys Thr Gly Asp Leu Leu Leu Arg Ser 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln 145 150 155 160 Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn 165 170 175 Cys Arg Ala Ser Lys Ser Val Ser Thr Ser Ile Tyr Ser Tyr Met His 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Tyr 195 200 205 Ala Ser Tyr Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly 210 215 220 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp 225 230 235 240 Val Ala Val Tyr Tyr Cys Glu His Ser Arg Glu Phe Pro Phe Thr Phe 245 250 255 Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro 260 265 270 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 275 280 285 Ser Leu Arg Pro Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His 290 295 300 Thr Arg Gly Leu Asp Phe Ala Ala Asp Pro Ile Leu Leu Thr Ile Ser 305 310 315 320 Ile Leu Ser Phe Phe Ser Val Ala Leu Leu Val Ile Leu Ala Cys Val 325 330 335 Leu Trp Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp 340 345 350 His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu 355 360 365 Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg 370 375 380 Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp 385 390 395 400 Thr Phe Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln Arg Leu Gly Gly 405 410 415 Asp Val Gln Ser Pro Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro 420 425 430 Glu Ser Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu Ala Gly Asn Val 435 440 445 Ser Ala Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys 450 455 460 Arg Glu Ser Gly Lys Asn Gly Pro His Val Tyr Gln Asp Leu Leu Leu 465 470 475 480 Ser Leu Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro Phe Ser Leu Gln 485 490 495 Ser Gly Ile Leu Thr Leu Asn Pro Val Ala Gln Gly Gln Pro Ile Leu 500 505 510 Thr Ser Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser 515 520 525 Phe Tyr Gln Asn Gln 530 <210> 6 <211> 495 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 6 Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp 1 5 10 15 Val Leu Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe 35 40 45 Ser Ile Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg His Ser Gly Tyr Gly Ser Ser Tyr Gly Val Leu 115 120 125 Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 145 150 155 160 Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 165 170 175 Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr 180 185 190 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser 195 200 205 Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 210 215 220 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Gln Glu Asp Ile Ala 225 230 235 240 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gly 245 250 255 Gly Thr Lys Val Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro 260 265 270 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 275 280 285 Arg Pro Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 290 295 300 Gly Leu Asp Phe Ala Ala Asp Ile Pro Trp Leu Gly His Leu Leu Val 305 310 315 320 Gly Leu Ser Gly Ala Phe Gly Phe Ile Ile Leu Val Tyr Leu Leu Ile 325 330 335 Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn 340 345 350 Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His Gly 355 360 365 Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe 370 375 380 Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu Glu Val Leu Glu 385 390 395 400 Arg Asp Lys Val Thr Gln Leu Leu Leu Gln Gln Asp Lys Val Pro Glu 405 410 415 Pro Ala Ser Leu Ser Ser Asn His Ser Leu Thr Ser Cys Phe Thr Asn 420 425 430 Gln Gly Tyr Phe Phe Phe His Leu Pro Asp Ala Leu Glu Ile Glu Ala 435 440 445 Cys Gln Val Tyr Phe Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp 450 455 460 Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr 465 470 475 480 Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Pro 485 490 495 <210> 7 <211> 581 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 7 Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp 1 5 10 15 Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu 35 40 45 Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu 50 55 60 Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser 65 70 75 80 Ala Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln 85 90 95 Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 100 105 110 Tyr Cys Ala Arg His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln 145 150 155 160 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 165 170 175 Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln 180 185 190 Lys Pro Gly Gly Ala Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu 195 200 205 His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 210 215 220 Phe Thr Phe Thr Ile Ser Ser Leu Gln Gln Glu Asp Ile Ala Thr Tyr 225 230 235 240 Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr 245 250 255 Lys Val Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro 260 265 270 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 275 280 285 Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 290 295 300 Asp Phe Ala Ala Asp Trp Leu Ile Phe Phe Ala Ser Leu Gly Ser Phe 305 310 315 320 Leu Ser Ile Leu Leu Val Gly Val Leu Gly Tyr Leu Gly Leu Asn Arg 325 330 335 Ala Ala Arg His Leu Cys Pro Pro Leu Pro Thr Pro Cys Ala Ser Ser 340 345 350 Ala Ile Glu Phe Pro Gly Gly Lys Glu Thr Trp Gln Trp Ile Asn Pro 355 360 365 Val Asp Phe Gln Glu Glu Ala Ser Leu Gln Glu Ala Leu Val Val Glu 370 375 380 Met Ser Trp Asp Lys Gly Glu Arg Thr Glu Pro Leu Glu Lys Thr Glu 385 390 395 400 Leu Pro Glu Gly Ala Pro Glu Leu Ala Leu Asp Thr Glu Leu Ser Leu 405 410 415 Glu Asp Gly Asp Arg Cys Lys Ala Lys Met Lys Arg Gly Arg Lys Lys 420 425 430 Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr 435 440 445 Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly 450 455 460 Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 465 470 475 480 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 485 490 495 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 500 505 510 Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr 515 520 525 Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 530 535 540 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln 545 550 555 560 Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln 565 570 575 Ala Leu Pro Pro Arg 580 <210> 8 <211> 548 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 8 Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp 1 5 10 15 Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Thr Phe 35 40 45 Thr Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Arg Gly Leu 50 55 60 Glu Trp Ile Gly Val Met Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala 65 70 75 80 Ala Phe Met Ser Arg Val Thr Met Leu Val Asp Thr Ser Lys Asn Gln 85 90 95 Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 100 105 110 Tyr Cys Ala Lys Ser Met Ile Thr Thr Gly Phe Val Met Asp Ser Trp 115 120 125 Gly Gln Gly Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 145 150 155 160 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 165 170 175 Lys Ala Ser Glu Asp Ile Tyr Asn Arg Leu Thr Trp Tyr Gln Gln Lys 180 185 190 Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser Gly Ala Thr Ser Leu Glu 195 200 205 Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 210 215 220 Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr 225 230 235 240 Cys Gln Gln Tyr Trp Ser Asn Pro Tyr Thr Phe Gly Gln Gly Thr Lys 245 250 255 Val Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro 260 265 270 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 275 280 285 Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 290 295 300 Phe Ala Ala Asp Trp Met Ala Phe Val Ala Pro Ser Ile Cys Ile Ala 305 310 315 320 Ile Ile Met Val Gly Ile Phe Ser Thr His Tyr Phe Gln Gln Lys Val 325 330 335 Phe Val Leu Leu Ala Ala Leu Arg Pro Gln Trp Cys Ser Arg Glu Ile 340 345 350 Pro Asp Pro Ala Asn Ser Thr Cys Ala Lys Lys Tyr Pro Ile Ala Glu 355 360 365 Glu Lys Thr Gln Leu Pro Leu Asp Arg Leu Leu Ile Asp Trp Pro Thr 370 375 380 Pro Glu Asp Pro Glu Pro Leu Val Ile Ser Glu Val Leu His Gln Val 385 390 395 400 Thr Pro Val Phe Arg His Pro Pro Cys Ser Asn Trp Pro Gln Arg Glu 405 410 415 Lys Gly Ile Gln Gly His Gln Ala Ser Glu Lys Asp Met Met His Ser 420 425 430 Ala Ser Ser Pro Pro Pro Pro Arg Ala Leu Gln Ala Glu Ser Arg Gln 435 440 445 Leu Val Asp Leu Tyr Lys Val Leu Glu Ser Arg Gly Ser Asp Pro Lys 450 455 460 Pro Glu Asn Pro Ala Cys Pro Trp Thr Val Leu Pro Ala Gly Asp Leu 465 470 475 480 Pro Thr His Asp Gly Tyr Leu Pro Ser Asn Ile Asp Asp Leu Pro Ser 485 490 495 His Glu Ala Pro Leu Ala Asp Ser Leu Glu Glu Leu Glu Pro Gln His 500 505 510 Ile Ser Leu Ser Val Phe Pro Ser Ser Ser Leu His Pro Leu Thr Phe 515 520 525 Ser Cys Gly Asp Lys Leu Thr Leu Asp Gln Leu Lys Met Arg Cys Asp 530 535 540 Ser Leu Met Leu 545 <210> 9 <211> 572 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 9 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 20 25 30 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Ala Tyr Ala Phe 35 40 45 Ser Ser Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Met Gly Arg Ile Tyr Pro Arg Asp Gly Asp Thr Asn Tyr Asn 65 70 75 80 Gly Lys Phe Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp 85 90 95 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Glu Gly Asp Gly Tyr Tyr Trp Tyr Phe Asp Val 115 120 125 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln 145 150 155 160 Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser 165 170 175 Cys Arg Ala Ser Gln Ser Ile Arg Asn Tyr Leu His Trp Tyr Gln Gln 180 185 190 Lys Pro Gly Glu Ala Pro Arg Leu Leu Ile Tyr Tyr Ala Ser Gln Ser 195 200 205 Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 210 215 220 Phe Thr Leu Thr Ile Ser Ser Leu Glu Thr Glu Asp Phe Ala Met Tyr 225 230 235 240 Tyr Cys Gln His Ser Asn Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr 245 250 255 Lys Leu Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro 260 265 270 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 275 280 285 Glu Ala Ser Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 290 295 300 Asp Phe Ala Ala Asp Ala Val Val Ile Ser Val Gly Ser Met Gly Leu 305 310 315 320 Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro 325 330 335 Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu Tyr His 340 345 350 Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala Glu Ser 355 360 365 Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro 370 375 380 Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro Cys Asn 385 390 395 400 Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu 405 410 415 Thr Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe 420 425 430 Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg 435 440 445 Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser 450 455 460 Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr 465 470 475 480 Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys 485 490 495 Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys 500 505 510 Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala 515 520 525 Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys 530 535 540 Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr 545 550 555 560 Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 565 570 <210> 10 <211> 526 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 10 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 145 150 155 160 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 165 170 175 Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly 180 185 190 Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val 195 200 205 Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 225 230 235 240 Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 245 250 255 Lys Gly Ala Pro Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro 260 265 270 Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ser 275 280 285 Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala 290 295 300 Ala Asp Pro Ile Leu Leu Thr Ile Ser Ile Leu Ser Phe Phe Ser Val 305 310 315 320 Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp Lys Lys Arg Ile Lys 325 330 335 Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His 340 345 350 Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu 355 360 365 Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg 370 375 380 Asp Glu Val Glu Gly Phe Leu Gln Asp Thr Phe Pro Gln Gln Leu Glu 385 390 395 400 Glu Ser Glu Lys Gln Arg Leu Gly Gly Asp Val Gln Ser Pro Asn Cys 405 410 415 Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg Asp Ser 420 425 430 Ser Leu Thr Cys Leu Ala Gly Asn Val Ser Ala Cys Asp Ala Pro Ile 435 440 445 Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly 450 455 460 Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser 465 470 475 480 Thr Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly Ile Leu Thr Leu Asn 485 490 495 Pro Val Ala Gln Gly Gln Pro Ile Leu Thr Ser Leu Gly Ser Asn Gln 500 505 510 Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln 515 520 525 <210> 11 <211> 684 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 11 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 145 150 155 160 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 165 170 175 Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly 180 185 190 Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val 195 200 205 Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 225 230 235 240 Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 245 250 255 Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 260 265 270 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 275 280 285 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 290 295 300 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 305 310 315 320 Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu 325 330 335 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 340 345 350 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 355 360 365 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 370 375 380 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 385 390 395 400 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 405 410 415 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 420 425 430 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 435 440 445 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 450 455 460 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 465 470 475 480 Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 485 490 495 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly 500 505 510 Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr 515 520 525 Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp 530 535 540 Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met 545 550 555 560 Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile 565 570 575 Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser 580 585 590 Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile 595 600 605 Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys Ser 610 615 620 Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met 625 630 635 640 Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys 645 650 655 Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly 660 665 670 Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 675 680 <210> 12 <211> 670 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 12 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 145 150 155 160 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 165 170 175 Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly 180 185 190 Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val 195 200 205 Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 225 230 235 240 Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 245 250 255 Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 260 265 270 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 275 280 285 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 290 295 300 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 305 310 315 320 Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu 325 330 335 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 340 345 350 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 355 360 365 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 370 375 380 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 385 390 395 400 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 405 410 415 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 420 425 430 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 435 440 445 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 450 455 460 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 465 470 475 480 Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 485 490 495 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Lys His Leu 500 505 510 Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp Val Leu Ser Gln 515 520 525 Asp Pro Tyr Val Lys Glu Ala Glu Asn Leu Lys Lys Tyr Phe Asn Ala 530 535 540 Gly His Ser Asp Val Ala Asp Asn Gly Thr Leu Phe Leu Gly Ile Leu 545 550 555 560 Lys Asn Trp Lys Glu Glu Ser Asp Arg Lys Ile Met Gln Ser Gln Ile 565 570 575 Val Ser Phe Tyr Phe Lys Leu Phe Lys Asn Phe Lys Asp Asp Gln Ser 580 585 590 Ile Gln Lys Ser Val Glu Thr Ile Lys Glu Asp Met Asn Val Lys Phe 595 600 605 Phe Asn Ser Asn Lys Lys Lys Arg Asp Asp Phe Glu Lys Leu Thr Asn 610 615 620 Tyr Ser Val Thr Asp Leu Asn Val Gln Arg Lys Ala Ile His Glu Leu 625 630 635 640 Ile Gln Val Met Ala Glu Leu Ser Pro Ala Ala Lys Thr Gly Lys Arg 645 650 655 Lys Arg Ser Gln Met Leu Phe Arg Gly Arg Arg Ala Ser Gln 660 665 670 <210> 13 <211> 808 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 13 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 145 150 155 160 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 165 170 175 Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly 180 185 190 Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val 195 200 205 Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 225 230 235 240 Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 245 250 255 Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 260 265 270 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 275 280 285 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 290 295 300 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 305 310 315 320 Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu 325 330 335 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 340 345 350 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 355 360 365 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 370 375 380 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 385 390 395 400 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 405 410 415 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 420 425 430 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 435 440 445 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 450 455 460 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 465 470 475 480 Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 485 490 495 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly 500 505 510 Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr 515 520 525 Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp 530 535 540 Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met 545 550 555 560 Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile 565 570 575 Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser 580 585 590 Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile 595 600 605 Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys Ser 610 615 620 Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met 625 630 635 640 Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys 645 650 655 Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly 660 665 670 Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp Pro Ala Gly Gly 675 680 685 Gly Thr Lys Thr Glu Ser Ser Ser Arg Ser Asp Gly Gly Ala Gln Asp 690 695 700 Cys Cys Leu Lys Tyr Ser Gln Arg Lys Ile Pro Ala Lys Val Val Arg 705 710 715 720 Ser Tyr Arg Lys Gln Glu Pro Ser Leu Gly Cys Ser Ile Pro Ala Ile 725 730 735 Leu Phe Leu Pro Arg Lys Arg Ser Gln Ala Glu Leu Cys Ala Asp Pro 740 745 750 Lys Glu Leu Trp Val Gln Gln Leu Met Gln His Leu Asp Lys Thr Pro 755 760 765 Ser Pro Gln Lys Pro Ala Gln Gly Cys Arg Lys Asp Arg Gly Ala Ser 770 775 780 Lys Thr Gly Lys Lys Gly Lys Gly Ser Lys Gly Cys Lys Arg Thr Glu 785 790 795 800 Arg Ser Gln Thr Pro Lys Gly Pro 805 <210> 14 <211> 1119 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 14 Tyr Tyr Pro Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp 35 40 45 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly 50 55 60 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 65 70 75 80 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 85 90 95 Arg Ala Ser Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys 100 105 110 Pro Gly Gly Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp 115 120 125 Ser Gly Val Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 130 135 140 Thr Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr 145 150 155 160 Cys Leu Gln Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys 165 170 175 Val Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro 180 185 190 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 195 200 205 Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 210 215 220 Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly 225 230 235 240 Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg 245 250 255 Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln 260 265 270 Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu 275 280 285 Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 290 295 300 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 305 310 315 320 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 325 330 335 Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly 340 345 350 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 355 360 365 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 370 375 380 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 385 390 395 400 Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe 405 410 415 Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met 420 425 430 Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val 435 440 445 Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 450 455 460 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 465 470 475 480 Thr Tyr Thr Met Ser Trp Val Arg Gln Thr Pro Ala Lys Gly Leu Val 485 490 495 Trp Val Ser Thr Ile Asn Ser Asp Gly Tyr Asn Ile Tyr Tyr Ser Asp 500 505 510 Ser Met Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Tyr Thr 515 520 525 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr 530 535 540 Tyr Cys Ala Arg Cys Ser Tyr Tyr Ser Tyr Asp Tyr Phe Asp Tyr Trp 545 550 555 560 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 565 570 575 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 580 585 590 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 595 600 605 Arg Ala Ser Glu Asn Ile Asp Asn Tyr Leu Ala Trp Tyr Gln Gln Lys 610 615 620 Gln Gly Lys Val Pro Lys Leu Leu Ile Tyr Ala Ala Thr Asn Leu Ala 625 630 635 640 Asp Gly Met Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 645 650 655 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr 660 665 670 Cys Gln His Tyr Tyr Ser Asn Gln Leu Thr Phe Gly Gln Gly Thr Lys 675 680 685 Leu Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro 690 695 700 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 705 710 715 720 Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 725 730 735 Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly 740 745 750 Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg 755 760 765 Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln 770 775 780 Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu 785 790 795 800 Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 805 810 815 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 820 825 830 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 835 840 845 Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly 850 855 860 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 865 870 875 880 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 885 890 895 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 900 905 910 Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe 915 920 925 Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met 930 935 940 Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val 945 950 955 960 Gln Cys Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn 965 970 975 Leu Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe 980 985 990 Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile 995 1000 1005 Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val 1010 1015 1020 Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn 1025 1030 1035 1040 Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp 1045 1050 1055 Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp 1060 1065 1070 Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala 1075 1080 1085 Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp 1090 1095 1100 Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 1105 1110 1115 <210> 15 <211> 1024 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 15 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 145 150 155 160 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 165 170 175 Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly 180 185 190 Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val 195 200 205 Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 225 230 235 240 Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 245 250 255 Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 260 265 270 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 275 280 285 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 290 295 300 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 305 310 315 320 Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu 325 330 335 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 340 345 350 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 355 360 365 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 370 375 380 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 385 390 395 400 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 405 410 415 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 420 425 430 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 435 440 445 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 450 455 460 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 465 470 475 480 Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 485 490 495 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly 500 505 510 Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Gln 515 520 525 Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 530 535 540 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr 545 550 555 560 Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 565 570 575 Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr Asp Arg Val Lys 580 585 590 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 595 600 605 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 610 615 620 Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val 625 630 635 640 Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 645 650 655 Gly Gly Ser Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser 660 665 670 Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser 675 680 685 Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys 690 695 700 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe 705 710 715 720 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 725 730 735 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 740 745 750 Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys 755 760 765 Leu Glu Leu Lys Pro Ala Gly Gly Gly Gly Gly Ser Glu Val Gln Leu 770 775 780 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu 785 790 795 800 Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 805 810 815 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Leu Ile Asn 820 825 830 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe 835 840 845 Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn 850 855 860 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly 865 870 875 880 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 885 890 895 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 900 905 910 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 915 920 925 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 930 935 940 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 945 950 955 960 Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro 965 970 975 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile 980 985 990 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly 995 1000 1005 Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1010 1015 1020 <210> 16 <211> 1195 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 16 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 145 150 155 160 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 165 170 175 Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly 180 185 190 Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val 195 200 205 Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 225 230 235 240 Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 245 250 255 Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 260 265 270 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 275 280 285 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 290 295 300 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 305 310 315 320 Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu 325 330 335 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 340 345 350 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 355 360 365 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 370 375 380 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 385 390 395 400 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 405 410 415 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 420 425 430 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 435 440 445 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 450 455 460 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 465 470 475 480 Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 485 490 495 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly 500 505 510 Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Gln 515 520 525 Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 530 535 540 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr 545 550 555 560 Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 565 570 575 Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr Asp Arg Val Lys 580 585 590 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 595 600 605 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 610 615 620 Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val 625 630 635 640 Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 645 650 655 Gly Gly Ser Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser 660 665 670 Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser 675 680 685 Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys 690 695 700 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe 705 710 715 720 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 725 730 735 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 740 745 750 Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys 755 760 765 Leu Glu Leu Lys Pro Ala Gly Gly Gly Gly Gly Ser Glu Val Gln Leu 770 775 780 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu 785 790 795 800 Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 805 810 815 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Leu Ile Asn 820 825 830 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe 835 840 845 Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn 850 855 860 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly 865 870 875 880 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 885 890 895 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 900 905 910 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 915 920 925 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 930 935 940 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 945 950 955 960 Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro 965 970 975 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile 980 985 990 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly 995 1000 1005 Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1010 1015 1020 Pro Ala Gly Gly Gly Thr Lys Thr Glu Ser Ser Ser Arg Gly Tyr Phe 1025 1030 1035 1040 Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp Gln 1045 1050 1055 Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met Thr 1060 1065 1070 Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile Ser 1075 1080 1085 Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser Val 1090 1095 1100 Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser 1105 1110 1115 1120 Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys Ser Asp 1125 1130 1135 Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met Gln 1140 1145 1150 Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys Glu 1155 1160 1165 Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly Asp 1170 1175 1180 Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 1185 1190 1195 <210> 17 <211> 1301 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 17 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly 115 120 125 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 145 150 155 160 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 165 170 175 Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly 180 185 190 Ala Ile Lys Arg Leu Ile Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val 195 200 205 Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 225 230 235 240 Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 245 250 255 Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 260 265 270 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 275 280 285 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 290 295 300 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 305 310 315 320 Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu 325 330 335 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 340 345 350 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 355 360 365 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 370 375 380 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 385 390 395 400 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 405 410 415 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 420 425 430 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 435 440 445 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 450 455 460 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 465 470 475 480 Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 485 490 495 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly 500 505 510 Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Gln 515 520 525 Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 530 535 540 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr 545 550 555 560 Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 565 570 575 Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr Asp Arg Val Lys 580 585 590 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 595 600 605 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 610 615 620 Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val 625 630 635 640 Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 645 650 655 Gly Gly Ser Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser 660 665 670 Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser 675 680 685 Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys 690 695 700 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe 705 710 715 720 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 725 730 735 Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 740 745 750 Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys 755 760 765 Leu Glu Leu Lys Pro Ala Gly Gly Gly Gly Gly Ser Glu Val Gln Leu 770 775 780 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu 785 790 795 800 Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp 805 810 815 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Leu Ile Asn 820 825 830 Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe 835 840 845 Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn 850 855 860 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly 865 870 875 880 Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 885 890 895 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 900 905 910 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 915 920 925 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 930 935 940 Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 945 950 955 960 Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro 965 970 975 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile 980 985 990 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly 995 1000 1005 Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1010 1015 1020 Pro Ala Gly Gly Gly Thr Lys Thr Glu Ser Ser Ser Arg Gly Tyr Phe 1025 1030 1035 1040 Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp Gln 1045 1050 1055 Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met Thr 1060 1065 1070 Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile Ser 1075 1080 1085 Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser Val 1090 1095 1100 Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser 1105 1110 1115 1120 Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys Ser Asp 1125 1130 1135 Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met Gln 1140 1145 1150 Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys Glu 1155 1160 1165 Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly Asp 1170 1175 1180 Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp Ser Gly Gly Gly Thr 1185 1190 1195 1200 Lys Thr Glu Ser Ser Ser Arg Gly Val Gly Ser Glu Val Ser Asp Lys 1205 1210 1215 Arg Thr Cys Val Ser Leu Thr Thr Gln Arg Leu Pro Val Ser Arg Ile 1220 1225 1230 Lys Thr Tyr Thr Ile Thr Glu Gly Ser Leu Arg Ala Val Ile Phe Ile 1235 1240 1245 Thr Lys Arg Gly Leu Lys Val Cys Ala Asp Pro Gln Ala Thr Trp Val 1250 1255 1260 Arg Asp Val Val Arg Ser Met Asp Arg Lys Ser Asn Thr Arg Asn Asn 1265 1270 1275 1280 Met Ile Gln Thr Lys Pro Thr Gly Thr Gln Gln Ser Thr Asn Thr Ala 1285 1290 1295 Val Thr Leu Thr Gly 1300 <210> 18 <211> 716 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 18 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 20 25 30 Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr 65 70 75 80 Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln 115 120 125 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Val Met Thr Gln Thr Pro 145 150 155 160 Leu Ser Leu Ser Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Arg 165 170 175 Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp 180 185 190 Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val 195 200 205 Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser 210 215 220 Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val 225 230 235 240 Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly 245 250 255 Ala Gly Thr Lys Leu Glu Leu Lys Pro Ala Gly Gly Gly Gly Gly Ser 260 265 270 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 275 280 285 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 290 295 300 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 305 310 315 320 Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe 325 330 335 Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr 340 345 350 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 355 360 365 Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 370 375 380 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 385 390 395 400 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 405 410 415 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 420 425 430 Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys 435 440 445 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu 450 455 460 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr 465 470 475 480 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 485 490 495 Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys 500 505 510 Val Glu Ile Lys Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu 515 520 525 Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly 530 535 540 Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr 545 550 555 560 Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp 565 570 575 Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met 580 585 590 Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile 595 600 605 Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser 610 615 620 Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile 625 630 635 640 Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys Ser 645 650 655 Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met 660 665 670 Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys 675 680 685 Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly 690 695 700 Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 705 710 715 <210> 19 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 19 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His Gly Gly Gly Ser Gly Gly Gly Ser Gly Ala Pro Thr Thr Thr Pro 180 185 190 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 195 200 205 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 210 215 220 Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu 225 230 235 240 Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr 245 250 255 Cys Lys Lys Pro Ala Gly Arg Asn Thr Gly Pro Trp Leu Lys Lys Val 260 265 270 Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser 275 280 285 Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro 290 295 300 Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu 305 310 315 320 Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Asn Thr Asp 325 330 335 Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro 340 345 <210> 20 <211> 818 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 20 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His Gly Gly Gly Ser Gly Gly Gly Ser Gly Ala Pro Thr Thr Thr Pro 180 185 190 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 195 200 205 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 210 215 220 Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu 225 230 235 240 Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr 245 250 255 Cys Lys Lys Pro Ala Gly Arg Asn Thr Gly Pro Trp Leu Lys Lys Val 260 265 270 Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser 275 280 285 Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro 290 295 300 Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu 305 310 315 320 Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Asn Thr Asp 325 330 335 Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Ala Ser Gly 340 345 350 Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu 355 360 365 Glu Asn Pro Gly Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val 370 375 380 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 385 390 395 400 Thr Phe Ser Asp Tyr Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys 405 410 415 Gly Leu Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr 420 425 430 Tyr Thr Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 435 440 445 Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr 450 455 460 Ala Val Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp 465 470 475 480 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly 485 490 495 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Val Met Thr Gln 500 505 510 Thr Pro Leu Ser Leu Ser Val Thr Pro Gly Gln Pro Ala Ser Ile Ser 515 520 525 Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu 530 535 540 Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr 545 550 555 560 Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 565 570 575 Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu 580 585 590 Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr 595 600 605 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Pro Ala Gly Ser Gly Ala 610 615 620 Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro 625 630 635 640 Gly Pro Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu 645 650 655 Arg Gly Val Gln Cys Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val 660 665 670 Ile Arg Asn Leu Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg 675 680 685 Pro Leu Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro 690 695 700 Arg Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly 705 710 715 720 Met Ala Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser 725 730 735 Cys Glu Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn 740 745 750 Ile Lys Asp Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro 755 760 765 Gly His Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr 770 775 780 Phe Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys 785 790 795 800 Lys Glu Asp Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn 805 810 815 Glu Asp <210> 21 <211> 940 <212> PRT <213> Artificial Sequence <220> <223> synthesized <400> 21 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His Gly Gly Gly Ser Gly Gly Gly Ser Gly Ala Pro Thr Thr Thr Pro 180 185 190 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 195 200 205 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 210 215 220 Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu 225 230 235 240 Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr 245 250 255 Cys Lys Lys Pro Ala Gly Arg Asn Thr Gly Pro Trp Leu Lys Lys Val 260 265 270 Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser 275 280 285 Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro 290 295 300 Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu 305 310 315 320 Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Asn Thr Asp 325 330 335 Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Ala Ser Gly 340 345 350 Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu 355 360 365 Glu Asn Pro Gly Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val 370 375 380 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 385 390 395 400 Thr Phe Ser Asp Tyr Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys 405 410 415 Gly Leu Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr 420 425 430 Tyr Thr Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 435 440 445 Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr 450 455 460 Ala Val Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp 465 470 475 480 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly 485 490 495 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Val Met Thr Gln 500 505 510 Thr Pro Leu Ser Leu Ser Val Thr Pro Gly Gln Pro Ala Ser Ile Ser 515 520 525 Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu 530 535 540 Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr 545 550 555 560 Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 565 570 575 Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu 580 585 590 Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr 595 600 605 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Pro Ala Gly Ser Gly Ala 610 615 620 Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro 625 630 635 640 Gly Pro Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu 645 650 655 Arg Gly Val Gln Cys Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val 660 665 670 Ile Arg Asn Leu Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg 675 680 685 Pro Leu Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro 690 695 700 Arg Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly 705 710 715 720 Met Ala Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser 725 730 735 Cys Glu Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn 740 745 750 Ile Lys Asp Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro 755 760 765 Gly His Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr 770 775 780 Phe Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys 785 790 795 800 Lys Glu Asp Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn 805 810 815 Glu Asp Gly Gly Gly Thr Lys Thr Glu Ser Ser Ser Arg Ser Asp Gly 820 825 830 Gly Ala Gln Asp Cys Cys Leu Lys Tyr Ser Gln Arg Lys Ile Pro Ala 835 840 845 Lys Val Val Arg Ser Tyr Arg Lys Gln Glu Pro Ser Leu Gly Cys Ser 850 855 860 Ile Pro Ala Ile Leu Phe Leu Pro Arg Lys Arg Ser Gln Ala Glu Leu 865 870 875 880 Cys Ala Asp Pro Lys Glu Leu Trp Val Gln Gln Leu Met Gln His Leu 885 890 895 Asp Lys Thr Pro Ser Pro Gln Lys Pro Ala Gln Gly Cys Arg Lys Asp 900 905 910 Arg Gly Ala Ser Lys Thr Gly Lys Lys Gly Lys Gly Ser Lys Gly Cys 915 920 925 Lys Arg Thr Glu Arg Ser Gln Thr Pro Lys Gly Pro 930 935 940

Claims

1. A chimeric antigen receptor complex comprising: a first protein comprising a first extracellular domain connected to a first intercellular domain by a first linker, wherein the first extracellular domain comprises a first scFv having affinity for a first tumor epitope, and wherein the first intercellular domain comprises a JAK1 binding domain, and a second protein comprising a second extracellular domain connected to a second intercellular domain by a second linker, wherein the second extracellular domain comprises a second scFv having affinity for a second tumor epitope, and wherein the second intercellular domain comprises a JAK3 binding domain; wherein the first tumor epitope is on a first tumor antigen, and wherein the second tumor epitope is on a second tumor antigen, wherein the first intracellular domain further comprises a first cytotoxic signaling domain connected to a JAK1 binding domain, the second intracellular domain further comprises a second cytotoxic signaling domain connected to a JAK3 binding domain, the first intracellular domain is configured to dimerize with the second intracellular domain, wherein the amino acid sequence of the chimeric antigen receptor is as shown in SEQ ID NO: 1 and SEQ ID NO:

2.

2. A biomolecule complex comprising the chimeric antigen receptor complex of claim 1, and First tumor antigen, and Second tumor antigen.

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