KR20230006821A - Modified B cells and methods of use thereof - Google Patents

Abstract

The present invention relates to genetically modified B cells and their uses, such as for the treatment of various diseases and disorders including cancer, heart disease, inflammatory diseases, muscle wasting diseases, diseases of the nervous system, and the like. In certain embodiments, the invention relates to an isolated modified B cell ("CAR-B cell), which is capable of expressing a chimeric receptor ("CAR-B receptor"), wherein the chimeric receptor comprises (a) an extracellular domain. (b) a transmembrane domain; and (c) a cytoplasmic domain comprising at least one signaling domain. In various embodiments, the invention comprises an isolated modified B cell, wherein the B cell comprises a payload and the payload is not naturally expressed in B cells or is expressed at a higher level than is naturally expressed in B cells.In various embodiments, the payload is an antibody or fragment thereof.

Description

Modified B cells and methods of their use

Until now, most cellular immunotherapy has focused on T cells. For example, cancer immunotherapy mainly focuses on the modification and administration of T cells to enhance killer T cell responses to tumors. However, transforming B cells for the treatment of various diseases is a technique that has not been extensively studied despite the important role of B cells in the immune response.

B cells, also known as B lymphocytes, are a type of white blood cell that, among other things, helps the body resist infection and disease. They are part of our adaptive immune system and are capable of a variety of immune responses, such as secreting antibodies in response to recognized antigens. B cells can also present antigens and secrete cytokines.

Many B cells mature into plasma cells that produce antibodies (proteins) that can fight infection. Other B cells mature into memory B cells. All plasma cells that descend from a single B cell produce the same antibodies directed against the antigen that stimulated them to mature. The same principle applies to memory B cells. Thus, all plasma cells and memory cells “remember” the stimuli that led to their formation. B cells, or B lymphocytes, are short-lived and independent of the thymus and are responsible for the production of immunoglobulins. See, eg, https://www.medicinenet.com/script/main/art.asp?articlekey=2413. Thus, B cells are immunologically important cells.

B cells appear to be related to patient outcomes in cancer treatment. For example, the presence of tertiary lymphoid structures (TLS) is associated with better patient outcomes. See, for example, Helmink, B.A., et al., Nature, 2020, 577(7791), 549-555; See Petitprez F et al., Nature, 2020, 577(7791), 556-560. TLS is a collection of immune cells (mostly T and B cells) that develop in response to immunological stimuli. TLS surrounding tumor cells include B cells, but the role of B cells in the antitumor response is unclear. B cells found in tumors can produce suppressive factors that interfere with the function of immune cells. See, eg, Kessel, A., et al., Autoimmun Rev., 2012, 11(9), 670-677; See Khan, A.R., et al., Nature Commun., 2015, 6, 5997. In addition, current evidence indicates that B cells interfere with antitumor responses in most cancer mouse models. Affara, N.I., et al. Cancer Cell, 2014, 25(6), 809-821; Shalapour, S., et al., Nature, 2017, 551, 340-345; Ammirante, M. et al., Nature, 2010, 464, 302-305. However, the presence of B cells in TLS constructs correlates with a positive clinical outcome for cancer immunotherapy. Petitprez 2020. Intratumoral injection of LPS-activated splenocytes containing B cells together with checkpoint inhibitors has been shown to produce an antitumor response. Soldevilla et al., Oncoimmunology, 2018, 7:8, e1450711.

CD79 (also referred to as “Cluster of Differentiation 79”) is a transmembrane protein capable of forming a complex with the B cell receptor and generating a signal after antigen recognition by the B cell receptor. ¹ CD79 consists of two different chains known as CD79A and CD79B (also known as Igα and Igβ). Both CD79a and CD79b are members of the immunoglobulin superfamily. They form heterodimers on the surface of B cells stabilized by disulfide bonds. Both CD79 chains contain immunoreceptor tyrosine-based activation motifs (“ITAMs”) in their intracellular tail regions that propagate signals in B cells. ²

¹ Chu PG, Arber DA (June 2001); CD79: a review; See Applied Immunohistochemistry & Molecular Morphology. 9(2): 97-106. doi:10.1097/00022744-200106000-00001. PMID 11396639. See also https://en.wikipedia.org/wiki/CD79.

B, Cooper L, Terhorst C (Jan. 1995), Interplay between the human TCR/CD3 epsilon and the B-cell antigen receptor associated Ig-beta (B29); Immunology Letters. 44 (2-3): 97-103. doi:10.1016/0165-2478(94)00199-2. PMID 7541024를 참조한다. ²

B, Cooper L, Terhorst C (Jan. 1995), Interplay between the human TCR/CD3 epsilon and the B-cell antigen receptor associated Ig-beta (B29); Immunology Letters. 44 (2-3): 97-103. doi:10.1016/0165-2478(94)00199-2. See PMID 7541024.

Given the natural ability of B cells to present antigens and secrete proteins, they hold great potential as cell therapies to target specific diseased cell types and secrete therapeutic payloads. Therefore, there is a need for alternative therapies other than T cell therapy, such as engineered B cells, for the treatment of a variety of diseases and disorders, including cancer, heart disease, inflammatory diseases, muscle wasting diseases, nervous system diseases, and the like.

Summary of Invention

It has now been discovered that engineered B cells can be effective in the treatment of various diseases and disorders mentioned herein. Accordingly, the present invention relates to modified B cells.

It was also found that CD79a (immunoglobulin α) exhibits superior quality than CD79b (immunoglobulin β) when incorporated into the intracellular signaling domain of the CAR-B constructs of the present invention. Additionally, when used in the CAR-B constructs described herein, intracellular CD79b (immunoglobulin β) was further found to have no (or even negative effect) on efficacy. Accordingly, the present invention is particularly directed to CAR-B constructs comprising a CD79a intracellular signaling domain.

In certain embodiments, the invention relates to an isolated modified B cell, which is capable of expressing a chimeric receptor ("CAR-B receptor"), wherein the chimeric receptor comprises (a) an extracellular domain; (b) a transmembrane domain; and (c) a cytoplasmic domain comprising at least one signaling domain. The cytoplasmic domain preferably includes CD79a. In various embodiments, the extracellular domain comprises an extracellular binding domain and a hinge domain. In various embodiments, the extracellular binding domain recognizes at least one antigen or protein expressed on the surface of a target cell. In various embodiments, the target cell is selected from the group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells and endothelial cells. In various embodiments, the B cells express more than one CAR-B receptor construct. In various embodiments, the CAR-B receptor comprises more than one extracellular binding domain. In various embodiments, the extracellular binding domain is a single chain variable fragment (scFv), or an extracellular domain of a full-length antibody, or receptor or ligand. In various embodiments, the extracellular binding domain is capable of binding an antigen or protein selected from the group consisting of PSMA, GPC3, ASGR1, ASGR2, sarcoglycan, Corin, FAP (fibroblast activation protein) and Her2. In various embodiments, the hinge domain is from the group consisting of IgG, CD28 and CD8. In various embodiments, the hinge domain consists of a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 27, 29, 31. In various embodiments, the cytoplasmic domain comprises one or more signaling domains unique to the B cell receptor. In various embodiments, the cytoplasmic domain is CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ, and BLNK It includes a domain selected from the group consisting of. In various embodiments, the cytoplasmic domain further comprises a costimulatory domain.

In various embodiments, the invention provides an isolated modified B cell, wherein the B cell is capable of expressing and secreting a payload, wherein the payload is not naturally expressed in a B cell or is higher than that naturally expressed in a B cell. including those expressed at higher levels. In various embodiments, the payload is an antibody or fragment thereof. In various embodiments, the antibody is a secreted antibody and may include blocking antibodies (e.g., anti-PD-1) or agonist antibodies (anti-CD137, GITR, OX40) engineered to contain native or engineered Fc regions. and may be soluble or membrane-based. In various embodiments, the payload may be an immune modulator such as a chemokine or cytokine. . In various embodiments, the payload comprises IL-1, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, IL-21, interferon α, interferon β, Interferon γ, TSLP, CCL21, FLT3L, XCL1, LIGHT (TNFSF14), OX40L, CD137L, CD40L, ICOSL, anti-CD3 antibody, CD47, TIM4-FC, CXCL13, CCL21, CD80, CD40L, IFNα A2, LIGHT, 4- 1BBL, MDGF (C19orf10), FGF10, PDGF, Agrin, TNF-α, GM-CSF, anti-FAP antibody, anti-TGF-β antibody; TGF-β traps, decoys or other inhibitory molecules; anti-BMP antibodies; BMP traps, decoys or other inhibitory molecules. In various embodiments, a B cell may express more than one payload. In various embodiments, a B cell may express more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 payloads.

In various embodiments, the present invention relates to a method of treating a patient comprising administering a modified B cell of the present invention. In various embodiments, the modified B cells are administered intratumorally, intravenously, subcutaneously or intradermally. In various embodiments, the method further comprises administering a checkpoint inhibitor. In various embodiments, a checkpoint inhibitor for a checkpoint molecule selected from the group consisting of PD-1, PD-L1, CTLA-4, LAG3, TIM-3 and NKG2A proteins. In various embodiments, the checkpoint inhibitor is a monoclonal antibody.

In various embodiments, the invention relates to an isolated modified B cell capable of expressing a chimeric receptor, wherein the chimeric receptor comprises (a) an extracellular domain, the extracellular domain comprising an extracellular binding domain and a hinge domain. ; (b) a transmembrane domain; and (c) a cytoplasmic domain comprising at least one signaling domain, wherein the modified B cell is further capable of expressing a payload, wherein the payload is not naturally expressed on the surface of the cell. In various embodiments, the extracellular binding domain recognizes an antigen or protein expressed on the surface of a target cell. In various embodiments, the target cell is selected from the group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells and endothelial cells. In various embodiments, the B cells express more than one CAR-B receptor construct. In various embodiments, the CAR-B receptor comprises more than one extracellular binding domain. In various embodiments, the extracellular binding domain is a single chain variable fragment (scFv), antibody, or extracellular domain of a receptor or ligand. In various embodiments, the extracellular binding domain is capable of binding an antigen or protein selected from the group consisting of PSMA, GP3, ASGR1, ASGR2, sarcoglycan, Corin, FAP and Her2. In various embodiments, the hinge domain is from the group consisting of IgG, CD28 and CD8. In various embodiments, the hinge domain consists of a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 27, 29, and 31. In various embodiments, the cytoplasmic domain comprises at least one signaling domain unique to B cells. In various embodiments, the cytoplasmic domain is represented by CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ and BLNK. It includes a domain selected from the group consisting of In various embodiments, the cytoplasmic domain further comprises a costimulatory domain. In various embodiments, the payload is a secreted or membrane bound antibody or fragment thereof. In various embodiments, the payload comprises IL-1, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, IL-21, interferon α, interferon β, Interferon γ, TSLP, CCL21, FLT3L, XCL1, LIGHT (TNFSF14), OX40L, CD137L, CD40L, ICOSL, anti-CD3 antibody, CD47, TIM4-FC, CXCL13, CCL21, CD80, CD40L, IFNα A2, LIGHT, 4- 1BBL, MDGF (C19orf10), FGF10, PDGF, Agrin, TNF-α, GM-CSF, anti-FAP antibody, anti-TGF-β antibody; TGF-β traps, decoys or other inhibitory molecules; anti-BMP antibodies; BMP traps, decoys or other inhibitory molecules. In various embodiments, B cells may express more than one payload. In various embodiments, a B cell may express more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 payloads. In various embodiments, the modified B cell further encodes at least one protein selected from the group consisting of the cytoplasmic domains of CD79a, CD79b, CD40, CD19, CD137, Fcγr2a, CD3ζ and MyD88. In various embodiments, the intent is directed to a method of treating a patient comprising administering modified B cells. In various embodiments, the method further comprises administering a checkpoint inhibitor. In various embodiments, the checkpoint inhibitor is selected from inhibitors of one or more checkpoint molecules from the group consisting of PD-1, PD-L1, CTLA-4, LAG3, TIM-3 and NKG2A. In various embodiments, the checkpoint inhibitor is a monoclonal antibody. In various embodiments, the invention relates to an isolated modified B cell capable of expressing a chimeric receptor, wherein the chimeric receptor comprises an extracellular domain, wherein the extracellular domain comprises a hinge domain and an extracellular binding domain and the extracellular binding domain is not naturally expressed on B cells; The extracellular binding domain is capable of recognizing a target of interest. In various embodiments, the binding domain is a single chain variable fragment (scFv), antibody, ligand or receptor. In various embodiments, the binding domain is a scFv. In various embodiments, the binding domain is a receptor, ligand, or fragment thereof. In various embodiments, the B cell may further express a payload. In various embodiments, the invention includes a method of treating a patient comprising administering modified B cells to the patient.

In various embodiments, the invention comprises a nucleic acid capable of expressing a chimeric B cell receptor, wherein the chimeric receptor comprises (a) an extracellular domain, the extracellular domain comprising an extracellular binding domain and a hinge domain; (b) a transmembrane domain; and (c) a cytoplasmic domain comprising at least one signaling domain. In various embodiments, the extracellular binding domain recognizes an antigen or protein expressed on the surface of a target cell. In various embodiments, the extracellular binding domain is a single chain variable fragment (scFv), antibody, receptor or ligand. In various embodiments, the target cell is selected from the group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells and endothelial cells. In various embodiments, vectors express more than one CAR-B receptor. In various embodiments, the CAR-B receptor expresses more than one extracellular binding domain. In various embodiments, the extracellular binding domain binds an antigen or protein selected from the group consisting of PSMA, GP3, ASGR1, ASGR2, Sarcoglycan, Corin, Her2, FAP, MUC1, CEA153, JAM-1, and LFA-1. can do. In various embodiments, the hinge domain is from the group consisting of IgG, CD28 and CD8. In various embodiments, the hinge domain consists of a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 27, 29, and 31. In various embodiments, the cytoplasmic domain comprises at least one signaling domain specific to the B cell receptor. In various embodiments, the cytoplasmic domain is represented by CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ and BLNK. It includes a domain selected from the group consisting of In various embodiments, the cytoplasmic domain further comprises a costimulatory domain.

In various embodiments, the invention relates to a vector comprising a nucleic acid capable of expressing a chimeric B cell receptor, wherein the chimeric receptor comprises (a) an extracellular domain, the extracellular domain comprising an extracellular binding domain and a hinge domain. contains; (b) a transmembrane domain; and (c) a cytoplasmic domain comprising at least one signaling domain. In various embodiments, the extracellular binding domain recognizes an antigen or protein. In various embodiments, the target cell is selected from the group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells and endothelial cells. In various embodiments, vectors express more than one CAR-B receptor. In various embodiments, a CAR-B expresses more than one extracellular binding domain. In various embodiments, the extracellular binding domain is a single chain variable fragment (scFv), antibody, receptor or ligand. In various embodiments, the extracellular binding domain binds an antigen or protein selected from the group consisting of PSMA, GPC3, ASGR1, AGSR2, Sarcoglycan, Corin, Her2, FAP, MUC1, CEA153, JAM-1, and LFA-1. can do. In various embodiments, the hinge domain is from the group consisting of IgG, CD28 and CD8. In various embodiments, the hinge domain consists of a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 27, 29, and 31. In various embodiments, the cytoplasmic domain comprises one or more signaling domains unique to B cells. In various embodiments, the cytoplasmic domain is represented by CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ and BLNK. and a signaling domain selected from the group consisting of In various embodiments, the cytoplasmic domain further comprises a costimulatory domain. In various embodiments, the cytoplasmic region is composed of multiple, two or more domains that are identical or unique.

In various embodiments, the present invention provides an isolated modified B cell capable of expressing an integrin, homing antibody, protein, receptor, or combination thereof, wherein the integrin, homing antibody, protein, or receptor is not naturally expressed in the B cell. or is expressed at a higher level than is naturally expressed in B cells; The integrins, homing antibodies, proteins, receptors, or combinations thereof are attracted to a site or target of interest. In various embodiments, integrins, homing antibodies, proteins, and receptors are CLA (PSGL-1 glycotype), CLA (PSGL-1 glycotype), CCR10, CCR3, CCR4, CCR5, CCR6, CCR9, CD43E, CD44, c-Met , CXCR3, CXCR4, LFA-1, LFA-1 (αLβ2), selectin ligand, VLA-4, VLA-4 (α4β1), and α4β7, or combinations thereof. In various embodiments, the site of interest is a homing or target tissue, an inflammatory site in a specific site or tissue, or a tumor or tumor microenvironment in which delivery of a payload is desired. In various embodiments, the home or target tissue is skin, gastrointestinal (gut, colon, mesenteric lymph node (mLN), Peyer's Patch (PP), small intestine), liver, lung, bone marrow, heart, peripheral lymph node (LN), CNS, thymus and bone marrow. In various embodiments, the target of interest is CXCL16, CCL17, CCL17(22), CCL20 (MIP-3α), CCL21, CCL25, CCL27, CCL28, CCL4, CCL5, CD62E, CD62P, CXCL10, CXCL12, CXCL13, CXCL16, CXCL9/ CXCL10, CXCR3, E/P-selectin, E-selectin, GPR15L, HGF, hyaluronic acid, ICAM-1, CCR1, 2, 5, MAdCAM, MAdCAM-1, PNAd, VAP-1, VCAM, and VCAM-1 ligand for, or a combination thereof. In various embodiments, a method comprises treating a patient by administering an isolated modified B cell. In various embodiments, the method further comprises administering a compound or derivative thereof, wherein the compound or derivative thereof is capable of modulating the expression of integrins, homing antibodies, proteins, and receptors, or combinations thereof. In various embodiments, the compound or derivative thereof can alter the trafficking of B cells to a site or target of interest in a patient. In various embodiments, the compound is all-trans-retinoic acid (ATRA) or a derivative thereof.

In various embodiments, the invention relates to an isolated modified B cell capable of expressing an immunosuppressive molecule, wherein the immunosuppressive molecule is not naturally expressed in the B cell or is higher than that naturally expressed in the B cell. expressed at the level of In various embodiments, the immune suppressive molecule is selected from IL-10, TGF-β, PD-L1, PD-L2, LAG-3, and TIM-3, or combinations thereof. In various embodiments, the immunosuppressive molecule is capable of reducing inflammatory and autoimmune activity of B cells at a site or target of interest in a patient. In various embodiments, the present invention relates to a method of treating a patient comprising administering an isolated modified B cell. In various embodiments, the immune inhibitory molecule is selected from IL-10, TGF-β, PD-L1, PD-L2, LAG-3, and TIM-3, or combinations thereof. In various embodiments, the immunosuppressive molecule is capable of reducing inflammatory and autoimmune activity of B cells at a site or target of interest in a patient. In various embodiments, the invention further comprises administering a compound or derivative thereof capable of increasing expression of an integrin, homing antibody, protein, receptor, or combination thereof in a B cell. In various embodiments, the compound or derivative thereof can alter the trafficking of B cells to a site or target of interest in a patient. In various embodiments, the compound is all-trans-retinoic acid (ATRA) or a derivative thereof. In various embodiments, the present invention relates to an isolated modified B cell, wherein the isolated modified B cell is treated with a compound or derivative thereof, wherein the compound or derivative thereof comprises an integrin, a homing antibody, a protein, a receptor, a or a combination thereof may be increased. In various embodiments, the compound or derivative thereof can alter the trafficking of B cells to a site or target of interest in a patient. In various embodiments, the compound is all-trans-retinoic acid (ATRA) or a derivative thereof. In various embodiments, the compound or derivative thereof is capable of (i) modulating the expression of an integrin, homing antibody, protein, receptor, or combination thereof in a B cell, and (ii) directing the migration of the B cell to a region of interest or can be changed to target. In various embodiments, the compound is all-trans-retinoic acid (ATRA) or a derivative thereof.

In various embodiments, the invention relates to an isolated modified B cell, which is capable of expressing one or more constitutively active toll-like receptors (TLRs), wherein the TLRs are not naturally expressed in B cells or are naturally expressed in B cells. is expressed at a higher level than that of In various embodiments, the TRL is selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. In various embodiments, the TLRs can enhance B cells to increase an immune response in a patient. In various embodiments, the TLRs are capable of generating potent effector B cells to increase a patient's immune response. In various embodiments, the immune suppressive molecule activates inflammatory and autoimmune activity of B cells at a site or target of interest in a patient. can reduce In various embodiments, the TLR is selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. In various embodiments, the TLRs are capable of (i) enhancing B cells and (ii) generating potent effector B cells to increase an immune response in a patient. In various embodiments, at least one of the TLR agonists is administered to the patient. In various embodiments, isolated modified B cells are treated with one or more TLR agonists. In various embodiments, the TLR agonist is capable of (i) enhancing B cells and (ii) generating potent effector B cells to increase an immune response in a patient. In various embodiments, the TLR agonist binds to one or more TLRs selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. In various embodiments, the TLR agonist is selected from CpG-rich oligonucleotides, double-stranded RNA mimics, polyinosinic acid:polycytidylic acid (poly-I:C). In various embodiments, the TLR agonist comprises a CpG oligonucleotide. In various embodiments, the TLR agonist is capable of (i) enhancing B cells and (ii) generating potent effector B cells to increase a patient's immune response. In various embodiments, the TLR agonist binds to one or more TLRs selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. In various embodiments, the TLR agonist is selected from CpG-rich oligonucleotides, double-stranded RNA mimics, polyinosinic acid:polycytidylic acid (poly-I:C). In various embodiments, the TLR agonist comprises a CpG oligonucleotide.

In various embodiments, the invention relates to an isolated modified B cell, wherein the B cell is electroporated with mRNA encoding one or more of the antigens fused to a targeting signal. In various embodiments, the antigen is (i) not naturally presented by B cells, (ii) not naturally presented by B cells simultaneously on both HLA class I and class II molecules, or (iii) naturally HLA Both class I and class II molecules are not presented by B cells with high efficiency. In various embodiments, the targeting signal is a targeting signal of a lysosomal protein. In various embodiments, the targeting signal is a targeting signal of lysosomal-associated membrane protein-1 (LAMP1). In various embodiments, the antigen can be targeted to lysosomes and can be efficiently presented on both HLA class I and class II molecules simultaneously. In various embodiments, the B cells are capable of increasing an antigen-specific immune response in a patient. In various embodiments, the antigen is (i) not naturally presented by B cells, (ii) not naturally presented by B cells simultaneously on both HLA class I and class II molecules, or (iii) naturally HLA Both class I and class II molecules are not presented by B cells with high efficiency. In various embodiments, the targeting signal is a targeting signal of a lysosomal protein. In various embodiments, the targeting signal is a targeting signal of lysosomal-associated membrane protein-1 (LAMP1). In various embodiments, the antigen can be targeted to lysosomes and can be efficiently presented on both HLA class I and class II molecules simultaneously. In various embodiments, the B cells are capable of increasing an antigen-specific immune response in a patient.

1 shows an example of a chimeric B cell receptor (CAR-B) of the present invention. In certain embodiments, a CAR-B construct will include an extracellular domain, a transmembrane domain and a cytoplasmic domain. As shown in Figure 1. An extracellular domain may include a binding domain and a hinge region in certain embodiments. In certain embodiments, the binding region may be an scFv. The CAR-B construct is cloned into a vector for expression.
2A-2C show examples of engineered B cells with homing domains. In various embodiments, an engineered B cell comprises (a) a scFv binding domain and an optional hinge region; (b) an scFv binding domain directly linked to the cell via a transmembrane domain, or (c) a ligand/receptor binding domain directly linked to the cell via a transmembrane domain.
3 shows examples of specific CAR-B constructs of the present invention. (A) CAR-B binding to GPC3. (B) CAR-B binding to PSMA.
4 shows examples of CAR-B receptors of the invention capable of binding (A) GPC3 and (B) PSMA. The "C" domain corresponds to the primary BCR C-terminus.
5 illustrates the expression of various anti-PSMA CARs on the surface of HEK-293 cells.
6A-6C present FACS plots illustrating interrogation of the binding of anti-PSMA CARs and anti-sarcoglycan CARs to PSMA. B cells expressing the anti-PSMA CAR-B constructs pWF396 and pWF397 bound PSMA, whereas B cells expressing pWF398 (anti-sarcoglycan CAR-B) did not bind PSMA.
7 illustrates the ability of adenovirus F35 encoding GFP to transduce human B cells. Human B cells were isolated from peripheral blood. B cells were infected with an adenovirus encoding GFP. 0, 1, 3, 10 ul, represents the microliter volume of adenovirus preparation used to infect human B cells. The titer of the adenovirus preparation was approximately 1 xe ¹² particles/ml.
Figure 8 illustrates an experiment in which BALB/c mice were injected with CT26 bilateral tumors on day 0. On days 12 and 16, tumor bearing mice were intratumorally injected with payload expressing cells in a volume of 10 ⁶ in 50 μL.
Figure 9 illustrates the effect of 12 different combinations of intratumoral injected payloads on tumor volume over 30-35 days compared to saline and 3T3 cells (no payload).
10 illustrates the effect of 12 different combinations of intratumoral injected payloads on tumor volume over 30-35 days compared to saline and 3T3 cells (no payload).
11A-11C illustrate the effect of the top three combinations of intratumoral injected payload on tumor volume over 30 days compared to saline and 3T3 cells (no payload).
12 illustrates the laparoscopic effect of intratumorally injected B cells. B cells were then either (i) fresh or (ii) first grown in growth medium containing 5 μg/ml lipopolysaccharide (RPMI, 10% FBS, 1% Pen/Strep, 5ng/ml recombinant mouse IL-4, 100uM beta-mercaptoethanol) for 16-24 hours. Then, 5X10 ⁶ B cells were intratumorally injected into the CT26 mouse model and the antitumor response was measured in the distal (peritoneal) tumor. Tumors were implanted on day 0, and a palpable tumor mass was observed on day 6. Treatment was started on day 6 intratumorally.
13A-13C illustrate the expression of three CAR-B receptors (also referred to as CAR-B receptors) in mouse B cells 24 hours after transfection.
14 illustrates the efficacy of PSMA-specific CAR engineered murine B cells on tumor volume and survival in BALB/c mice bearing CT26-PSMA tumors.
15 illustrates the efficacy of PSMA-specific CAR engineered allogeneic B cells on tumor volume and survival in BALB/c mice bearing CT26-PSMA tumors.
16 illustrates the efficacy of PSMA-specific CAR engineered murine B cells against immunocompromised BALB/c mice bearing CT26-PSMA tumors.
17 illustrates the efficacy of murine B cells on tumor volume and survival in C57B1/6 mice bearing HEPA 1-6 GPC3 tumors.
18 illustrates NFKb signaling in luciferase reporter cells in B cells engineered with four different CAR constructs recognizing GPC3, using GFP as a control.
19 illustrates basal or tonic NFKb activity in the absence of cognate target antigen in a CAR construct expressed in a human B cell reporter line.
20 illustrates the efficacy of murine B cells electroporated with anti-GPC3CAR-CD79a and CD80 payload mRNA in syngeneic C57B1/6 mice bearing HEPA1-6GPC3 tumors.
21A-21C illustrates the response of saline control, anti-GPC3CAR-CD79a, and anti-GPC3CAR-CD79a plus CD80 Combo B cell populations.
22A-22C illustrates the expression of GPC3 CARs after electroporation using FACS plots.

The invention disclosed herein relates to several embodiments of engineered or modified B cells:

One. modified B cells homing to a site/target of interest using a binding domain such as, for example, a scFv, antibody, ligand, receptor or fragment thereof;

2. a B cell modified with a homing domain further comprising activation, and optionally a costimulatory domain, wherein the B cell is capable of homing and activating upon interaction with a desired target;

3. B cells engineered to make desired protein payloads such as antibodies, therapeutic proteins, polypeptides, nucleic acid sequences (eg, RNAi), and the like;

4. engineered B cells further engineered to express homing/binding domains, activation domains, selective costimulatory domains, and desired protein payloads such as antibodies, therapeutic proteins, polypeptides, nucleic acid sequences (eg, RNAi), and the like;

5. An integrin, homing antibody, protein, or B cell is modified to express a receptor that causes it to be attracted to a particular ligand, chemokine, or attractant at a particular site/target (eg, homing tissue) of interest, e.g., carrying a desired payload. B cells that can migrate to the site/target of interest for delivery;

6. B cells modified to express immunosuppressive molecules such that inflammation and autoimmune activity of B cells confined to the region/target of interest are reduced leading to a positive therapeutic response;

7. B cells treated with compounds or derivatives thereof such that trafficking of B cells is altered by expression of specific B cell integrins and/or homing receptors;

8. (i) treated with a toll-like receptor (TLR) agonist and/or (ii) expressing a constitutively active TLR to enhance B cells and/or generate potent effector B cells to increase an immune response in a subject. B cells engineered to;

9. B cells electroporated with mRNA encoding a specific antigen of interest fused to a targeting signal of a lysosomal protein so that B cells can simultaneously and efficiently present the specific antigen of interest and/or antigen-derived epitope on both HLA class I and class II molecules. cell.

10. B cells electroporated with self-amplifying RNA encoding all items mentioned so far in 1-9 above.

The various embodiments of the engineered or modified B cells of the present application are not mutually exclusive and, unless expressly indicated, are combined with one another in any way and without any limitation to facilitate any outcome and/or therapeutic response contemplated herein. It is understood that it can be

tumor antigen. In certain embodiments, the site/target of interest is a tumor antigen. The choice of antigen binding domain (moiety) of the invention will depend on the particular type of cancer being treated. Some tumor antigens may be membrane bound, while others may be secreted. For example, a tumor antigen may be secreted and accumulated in the extracellular matrix, or a tumor antigen may be expressed as part of an MHC complex. Tumor antigens are well known in the art and include, for example, CD19, KRAS, HGF, CLL, glioma-associated antigen, carcinoembryonic antigen (CEA); β-human chorionic gonadotropin, alphafetoprotein (AFP), lectin-responsive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxyl esterase , mut hsp70-2, M-CSF, prostate, prostate specific antigen (PSA), PAP, NY-ESO-1, LAGE-1a, p53, protein, PSMA, Her2/neu, survivin and telomerase, prostate Carcinoma Tumor Antigen-1 (PCTA-1), MAGE, ELF2M, Neutrophil Elastase, EphrinB2, CD22, Insulin Growth Factor (IGF)-I, IGF-II, IGF-I Receptor, Mesothelin, EGFR, BCMA, KIT and IL-13.

infectious disease antigens. In certain embodiments, the site/target of interest is an infectious disease antigen for which an immune response may be sought. Infectious disease antigens are well known in the art and may include, but may include, parasitic antigens such as viruses, bacteria, protists, parasites, molds, yeasts, mycoplasmas, viral proteins, bacterial proteins and carbohydrates, and fungal proteins and carbohydrates. Not limited. In addition, the type of infectious disease of the infectious disease antigen is not particularly limited, and among viral infectious diseases such as AIDS, hepatitis B, Epstein Barr virus (EBV) infection, HPV infection, HCV infection, SARS, SARS-CoV2, etc. It may include, but is not limited to. Parasitic antigens may include, but are not limited to, malaria parasite sporozooid proteins.

In certain embodiments the modified B cell expresses an engineered B cell receptor (CAR-B) comprising an extracellular domain, a transmembrane domain and an intracellular domain. In certain embodiments, the extracellular domain comprises a binding domain and a hinge domain. In certain embodiments, the extracellular domain comprises a binding domain, such as a scFv, ligand, antibody, receptor, or fragment thereof, which allows the modified B cell to bind to a protein expressed on the surface of a specific target cell, thereby targeting it. to target. In certain embodiments, the transformed tumor cells target and bind to proteins/antigens expressed on the surface of the tumor cells. In certain embodiments, the modified B cell further expresses a payload. In certain embodiments, the payload may increase the number of cross-presenting antigens or antigenic fragments to dendritic cells (DCs) in a tumor or lymph node. In certain embodiments, the payload is capable of activating and attracting T cells into a tumor. In certain embodiments, the payload can promote the formation of tertiary lymphoid structures (TLS) in a tumor. In certain embodiments of the invention, the modified B cell expresses both a CAR-B and a payload. In certain embodiments, a CAR-B comprises a stimulatory domain that activates expression of a payload when bound to an antigen or protein expressed on the surface of a tumor cell.

One. Design and domain orientation of chimeric antigen receptor (CAR-B) in B cells

In various embodiments, the present invention provides a chimeric B cell receptor (CAR-B). It will be appreciated that a chimeric B cell receptor (CAR-B) is a genetically engineered receptor. These engineered receptors can be readily inserted into and expressed by B cells according to techniques known in the art. With CAR-B, a single receptor can be programmed to recognize a specific protein or antigen expressed on tumor cells and, when bound to that protein or antigen, can induce an anti-tumor response. In various embodiments, CAR-Bs act in part as a homing mechanism for the delivery of B cells to a target tissue.

Compared to cells containing the receptor, the chimeric B cell receptor of the present invention has an extracellular domain (including an antigen binding domain and may include an extracellular signaling domain and/or a hinge domain), a transmembrane domain, and an intracellular domain. It will be appreciated that this will include domains. The intracellular domain preferably comprises at least an activation domain consisting of CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, CD3ζ Fcγr2a and/or MyD88. It will be further understood that an antigen-binding domain is engineered to be located in the extracellular portion of a molecule/construct so that it can recognize and bind its target or targets.

Structurally, it will be understood that these domains correspond to locations on immune cells. Exemplary CAR-B constructs according to the invention are set forth in Table 1:

construct name extracellular domain hinge TM signal 1 signal 2 pWF-82 Anti-PSMA CD8 CD28 hCD19 pWF-83 Anti-PSMA CD8 CD28 hCD40 pWF-84 Anti-PSMA CD8 CD28 hCD40 CD79b pWF-85 Anti-PSMA CD8 CD28 hCD40 CD137 pWF-86 Anti-PSMA CD8 CD28 hCD40 Fcγr2a pWF-87 Anti-PSMA CD8 CD28 hMyd88 hCD40 pWF-88 Anti-PSMA CD8 CD28 CD79a pWF-89 Anti-PSMA CD8 CD28 CD79b pWF-391 Anti-PSMA 3x Strep II Tags CD28 CD79b pWF-394 anti-sarcoglycan 3x Strep II Tags CD28 CD79b pWF-396 anti-GPC-3 CD8 CD28 CD79a pWF-397 anti-GPC-3 CD8 CD28 CD79b pWF-460 anti-GPC-3 Human IgG1 Fc CD28 CD79a pWF428 anti-GPC-3 human lambda invariant domain human lambda invariant domain pWF429 anti-GPC-3 Human IgG1 Fc Human IgG1 Fc pWF-521 anti-GPC3 vL-hclambda constant region-linker-vH-hcH1-cH2-cH3 Human IgG1 Fc human IgG1 endogenous BCR complex pWF-533 anti-GPC3-vL-hcH1 Human IgG1 (complex with pWF534) endogenous BCR complex pWF-534 anti-GPC3-vH-hcKappa-hcH2-cH3 Human IgG1 Fc human IgG1 endogenous BCR complex

In various embodiments, the chimeric B cell receptor consists of an extracellular domain, a transmembrane domain and a cytoplasmic domain. In various embodiments, the cytoplasmic domain comprises an activation domain. In various embodiments, the cytoplasmic domain may also include a co-stimulatory domain. In various embodiments, the extracellular domain comprises an antigen binding domain. In various embodiments, the extracellular domain further comprises a hinge region between the antigen binding domain and the transmembrane domain. 1 provides a schematic diagram of chimeric B cell receptors of various embodiments of the present invention.

extracellular domain. A number of extracellular domains can be used with the present invention. In various embodiments, the extracellular domain comprises an antigen binding domain. In various embodiments, an extracellular domain may also include a hinge region and/or a signaling domain. In various embodiments, the extracellular domain containing the IgG1 constant domains may also include either an IgG1 (pore) or an IgG1 (knob) to facilitate directed CAR-B formation.

Antigen-binding domain and binding domain. “Antigen binding domain”, “antigen-binding domain” or “binding domain” as used herein refers to a portion of a CAR-B capable of binding an antigen or protein expressed on a cell surface. In some embodiments, the antigen binding domain binds an antigen or protein on a cell involved in a hyperproliferative disorder. In a preferred embodiment, the antigen binding domain binds an antigen or protein expressed on the surface of a tumor cell. Antigen binding molecules will be further understood with reference to the following definitions and descriptions.

An antigen binding domain is said to “specifically bind” a target antigen or protein when its dissociation constant (K _d ) is 1×10 ⁻⁷ M. The antigen binding domain specifically binds antigen with “high affinity” when the K _d is 1-5×10 ⁻⁹ M and with “very high affinity” when the K _d is 1-5× ^{10 −10} M. In one embodiment, the antigen binding domain has a K _d of 10 ⁻⁹ M. In one embodiment, the off rate is <1×10 ⁻⁵ . In another embodiment, the antigen binding domain will bind an antigen or protein with a K _d of between about 10 ⁻⁷ M and 10 ⁻¹³ M, and in another embodiment the antigen-binding domain will bind with a K _d 1.0-5.0× ¹⁰ something to do.

An antigen-binding domain is said to be “selective” when it binds to one target more tightly than it does to a second target.

The term "neutralizing" refers to an antigen binding domain that binds a ligand and prevents or reduces the biological effect of that ligand. This can be done, for example, by directly blocking the ligand's binding site or by altering the ability of the ligand to bind to the ligand and bind through indirect means (eg, structural or energetic alteration of the ligand). In some embodiments, the term may also refer to an antigen-binding domain that prevents the protein to which it binds from performing a biological function.

The term “target” or “antigen” refers to a molecule or part of a molecule capable of being bound by an antigen binding molecule. In certain embodiments, a target may have more than one epitope.

The term "antibody" refers to Y-shaped proteins known as immunoglobulins that are produced by the immune system to recognize specific antigens. The term “antibody fragment” refers to antigen-binding fragments and Fc fragments of antibodies. Types of antigen-binding fragments include F(ab')2, Fab, Fab' and scFv molecules. Fc fragments are produced entirely from the heavy chain constant regions of immunoglobulins.

extracellular signaling domain. The extracellular domain is beneficial for signal transduction and efficient response of lymphocytes to antigens. Extracellular domains of particular use in the present invention include CD28, CD28T (see, eg, US patent application US2017/0283500Al), OX40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death- 1 (PD-1), inducible T cell costimulator (ICOS), lymphocyte function-related antigen-1 (LFA-1, CD1-1a/CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7 -H3), LIGHT, (TNFSF14), NKG2C, CD79a (immunoglobulin α), CD79b (immunoglobulin β), DAP-10, Fc gamma receptor, MHC class 1 molecule, TNF receptor protein, immunoglobulin protein, cytokine receptor , integrin, signaling lymphocyte activation molecule (SLAM protein), activated NK cell receptor, BTLA, toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2 , SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL-2Rbeta, IL-2Rgamma, IL-7Ralpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D , ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D , TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3 ), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds to CD83, or any combination thereof (i.e. , including). Extracellular domains may be derived from natural or synthetic sources.

hinge domain. As described herein, extracellular domains often include a hinge portion. It is part of the extracellular domain adjacent to the cell membrane. The extracellular domain may further include a spacer region. A variety of hinges may be used in accordance with the present invention, including immunoglobulin (Ig) sequences, 3X strep II spacers or other suitable molecules to achieve a particular desired distance from a target cell. In some embodiments, the hinge region comprises CD28 as described herein, or an extracellular domain of CD8 or a portion thereof.

transmembrane domain. A CAR-B can be designed to include a transmembrane domain fused to or otherwise linked to the extracellular domain of the CAR-BB. similarly fused to the intracellular domain of CAR-B. In one embodiment, a transmembrane domain naturally associated with one of the domains of CAR-B is used. In some cases, transmembrane domains may be selected or modified by amino acid substitutions to avoid binding of these domains to transmembrane domains of the same or different surface membrane proteins in order to minimize interactions with other members of the receptor complex. . Transmembrane domains can be from natural or synthetic sources. When the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. The transmembrane regions of particular use in the present invention are CD28, CD28T, OX-40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD-1), inducible T cell costimulatory (ICOS), lymphocyte function-associated antigen-1 (LFA-1, CD1-1a/CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, CD79a (immunoglobulin α), CD79b (immunoglobulin β), DAP-10, Fc gamma receptor, MHC class 1 molecule, TNF receptor protein, immunoglobulin protein, cytokine receptor, integrin, signaling lymphocyte activation molecule (SLAM protein), Active NK Cell Receptor, BTLA, Toll Ligand Receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46 , CD19, CD4, CD8alpha, CD8beta, IL-2Rbeta, IL-2Rgamma, IL-7Ralpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1 , CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds to CD83, or any combination thereof.

Optionally, a short linker may form a link between any or part of the extracellular, transmembrane and intracellular domains of CAR-B.

In certain embodiments, the transmembrane domain within a CAR-B of the invention is a CD28 transmembrane domain. In one embodiment, the CD28 transmembrane domain comprises the nucleic acid sequence of SEQ ID NO: 1. In one embodiment, the CD28 transmembrane domain comprises a nucleic acid sequence encoding the amino acid sequence of SEQ ID NO:2. In one embodiment, the CD28 transmembrane domain comprises the nucleic acid sequence of SEQ ID NO:3. In another embodiment, the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO:4.

In one embodiment, the transmembrane domain in a CAR-B of the invention is a CD8 transmembrane domain.

intracellular (cytoplasmic) domain. The intracellular (IC, or cytoplasmic) domain of a CAR-B receptor of the present invention may provide activation of at least one of the normal effector functions of an immune cell.

It will be appreciated that suitable intracellular molecules include, but are not limited to, CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a CD3ζ and MyD88. Intracellular molecules include CD28, CD28T, OX-40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD-1), inducible T cell costimulator (ICOS), lymphocyte Function-related antigen-1 (LFA-1, CD1-1a/CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, CD79a (immunoglobulin α), CD79b (immunoglobulin β), DAP-10, Fc gamma receptor, MHC class 1 molecule, TNF receptor protein, immunoglobulin protein, cytokine receptor, integrin, signaling lymphocyte activation molecule (SLAM protein), activated NK cell receptor, BTLA , toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8 Alpha, CD8beta, IL-2R beta, IL-2R gamma, IL-7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3) , BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP- 76, PAG/Cbp, CD19a, a ligand that specifically binds to CD83, or any combination thereof. The cytoplasmic signaling sequences within the cytoplasmic signaling portion of the CAR-B of the present invention may be linked to each other in random or specific order.

As used herein, the term "co-stimulatory" domain or molecule refers to a heterogeneous group of cell surface molecules that act to amplify or counteract the initial activation signals of a cell.

In a preferred embodiment, the cytoplasmic domain is designed to include the signaling domain of hCD19, said hCD19 domain comprising the nucleic acid sequence set forth in SEQ ID NO:5. In another embodiment, the cytoplasmic domain is designed to include the signaling domain of hCD40, wherein the hCD40 domain comprises the nucleic acid sequence set forth in SEQ ID NO:7. In another embodiment, the cytoplasmic domain is designed to include the signaling domains of hCD40 and hCD79b, wherein the hCD40 domain comprises the nucleic acid sequence set forth in SEQ ID NO:7 and the hCD79b domain comprises the nucleic acid sequence set forth in SEQ ID NO:25. do. In another embodiment, the cytoplasmic domain is designed to include the signaling domains of hCD40 and hCD137, wherein the hCD40 domain comprises the nucleic acid sequence set forth in SEQ ID NO:7 and the hCD137 domain comprises the nucleic acid sequence set forth in SEQ ID NO:13. do. In another embodiment, the cytoplasmic domain is designed to include hCD40 and the signaling domain of hFcγr2a, wherein the hCD40 domain comprises the nucleic acid sequence set forth in SEQ ID NO: 7 and the hFcγr2a domain comprises the nucleic acid sequence set forth in SEQ ID NO: 17 do. In another embodiment, the cytoplasmic domain is designed to include the signaling domains of hCD40 and hMyd88, wherein the hCD40 domain comprises the nucleic acid sequence set forth in SEQ ID NO:7 and the hMyd88 domain comprises the nucleic acid sequence set forth in SEQ ID NO:21 do. In another embodiment, the cytoplasmic domain is designed to include the signaling domain of hCD79a, wherein the hCD79a domain comprises the nucleic acid sequence set forth in SEQ ID NO:12. In another embodiment, the cytoplasmic domain is designed to include the signaling domain of hCD79b, wherein the hCD79b domain comprises the nucleic acid sequence set forth in SEQ ID NO:25. These embodiments are preferably of human origin but may be from other species. In various embodiments the signaling domain comprises both hCD79a together with hCD79b or another hCD79a domain. In various embodiments the signaling domain comprises both hCD79b along with hCD79a or another hCD79b domain.

2. transforming B cells

Modified B cells expressing the payload. In various embodiments of the invention, modified B cells capable of expressing a payload are provided. As used herein, the term "payload" refers to an amino acid sequence, a nucleic acid sequence encoding a peptide or protein, or an RNA molecule for use as a therapeutic agent. In certain embodiments the payload is for delivery to a tumor or tumor microenvironment or draining lymph node. In certain embodiments, B cells preferably deliver payloads to the tumor or tumor microenvironment or draining lymph nodes that can, for example, increase the number of cross-presenting dendritic cells (DCs) in the tumor. Cross-presenting DCs will allow for improved presentation of tumor antigens. In various embodiments, the payload can activate and attract T cells into a tumor. Activating more T cells in the tumor complements cross-presenting DCs and reshapes the tumor environment to have stronger anti-tumor immune function. The payload may also promote the formation of tertiary lymphoid structures (TLS) in tumors. Clinical studies have demonstrated a relationship between B cells, TLS, and response to immune checkpoint blockade.

Non-exclusive examples of payloads of the invention include IL-1, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, IL-21, interferon α, Interferon β, Interferon γ, TSLP, CCL21, FLT3L, XCL1, LIGHT (TNFSF14), OX40L, CD137L, CD40L, ICOSL, anti-CD3 antibody, CD47, TIM4-FC, CXCL13, CCL21, CD80, CD40L, IFNα A2, LIGHT , 4-1BBL, MDGF (C19orf10), FGF10, PDGF, Agrin, TNF-α, GM-CSF, anti-FAP antibody, anti-TGF-β antibody; TGF-β traps, decoys or other inhibitory molecules; anti-BMP antibodies; BMP traps, decoys or other inhibitory molecules.

Signaling for payload presentation. In various embodiments of the invention, the payload is expressed in transformed B cells as a DNA construct under the control of an activated transcriptional pathway. In certain embodiments, expression of the payload is controlled by the nuclear factor of activated T cells ("NFAT") pathway. The NFAT pathway is a transcription factor pathway that is activated during the immune response and is activated by NFκΒ. In various embodiments, the modified B cell expresses both payload and CAR-B. In various embodiments, where the transformed B cell expresses both a payload and a CAR-B, the CAR-B may further encode a signaling molecule leading to activation of the NFκΒ pathway. Such molecules include, but are not limited to, CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, CD3ζ and MyD88.

In various embodiments, the invention relates to an isolated B cell expressing at least one payload. In various embodiments, the invention relates to isolated B cells expressing more than one payload. In various embodiments, the invention relates to isolated B cells expressing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 different payloads.

Modification of B cells for homing . In various embodiments of the invention, a modified B cell can be modified with a homing domain such that the B cell can be located at a site/target of interest and activated upon interaction with the target (eg, as shown in FIG. 2 ). In addition, B cell homing receptors expressed on B cell membranes that recognize addresses and ligands on target tissues, compounds or derivatives thereof that alter trafficking of B cells to specific sites, and inhibit inflammation and autoimmune activity of B cells. The molecule may play a role in B cell homing and development of specific immune responses.

Transformed B cells expressing the integrin of interest. The major homing receptors expressed by lymphocytes are integrins, a large class of molecules characterized by a heterodimeric structure of α and β chains. In general, the specific pair of α and β chains of an integrin determines the type of homing receptor. For example, the pair of α4 and β7 chains expresses mucosal address cell adhesion molecule 1 (MAdCAM-1) expressed in Peyer's Patch (PP) and high endothelial venules (HEV) of the gastrointestinal (GI) lamina propria endothelial vein (LPV). ) characterizes the key integrin molecule (α4β7) responsible for lymphocyte binding to. Similarly, a pair of α4 and β1 chains characterizes the homing receptor for skin (α4β1).

In various embodiments of the invention, B cells to be modified may be pre-selected for specific traits that mediate preferred localization. For example, memory B cells expressing CXCR3 can be enriched and then engineered. CXCR3 cells can be attracted to ligands expressed at sites of inflammation. As such, modified B cells may preferentially localize to such sites.

In various embodiments of the invention, modified B cells expressing the α4 and β7 chains of integrins are provided. Expression of α4β7 integrin is preferred to promote homing of transformed B cells to the colon. In various embodiments, modified B cells expressing the α4 and β1 chains of integrins are provided. Expression of α4β1 integrin preferably promotes homing of transformed B cells to the skin. In various embodiments, modified B cells expressing a desired pair of α and β chains of integrins are provided such that the expressed integrin facilitates homing of the modified B cell to a desired region/target of interest. Thus, in various embodiments, any desired combination of α and β chains of integrins is contemplated for expression in B cells, such that modified B cells expressing a particular integrin target a desired region/target of interest.

Modified B cells expressing the homing receptor of interest. B cells have the ability to homing to inflamed tissues, and altering homing receptor expression can compensate for the original homing tendency. B cell localization is also driven by the expression of decoy molecules (eg, targets such as ligands and chemokines) at specific locations or sites of inflammation in a tissue. Such molecules may also include antibodies such as the MECA79 antibody that target cells to peripheral node addressing (PNAd). Bahmani et al., J Clin Invest. 2018;128(11):4770-4786; Azzi et al., Cell Rep. 2016;15(6):1202-13. Thus, B cells can be engineered to express specific antibodies, proteins and receptors that promote B cell homing to the site/target of interest and interaction of such B cells with the desired target. In certain instances, expression of such receptors redirects B cells to a tissue of interest.

In various embodiments of the invention, modified B cells capable of expressing a homing antibody, protein or receptor are provided, the expression of which can direct the B cell to a specific site/target of interest. Examples of homing of T cells to specific homing tissues (target tissues) using specific homing receptor/ligand pairs are shown in Table 2. The same specific homing receptor/ligand pair can also promote homing of B cells to specific homing tissues (target tissues). Thus, in various embodiments of the present invention, homing of modified B cells to exemplary homing tissues (target tissues) is facilitated using the corresponding homing receptor/ligand pairs listed in Table 2.

T _eff Cell homing receptors and cognate ligands that mediate organic targeting
Home organization type T _eff cell homing receptor cognate ligand skin CLA (PSGL-1 glycoform) E/P-selectin CD43E E-selectin VLA-4 (α ₄ β ₁ ) VCAM-1 LFA-1 (α _L β ₂ ) ICAM-1 CCR4 CCL17 CCR10 CCL27 Gastrointestinal (gut, colon, mLN, PP) α ₄ β ₇ MAdCAM-1 CCR9 ^{a CCL25a} CXCR4 CXCL12 selectin ligand ^b E/P-selectin ^b VLA- ^4b VCAM- ^1b LFA- ^1b ICAM- ^{1b CCR6b} CCL20 (MIP-3α) ^b liver CD44 hyaluronic acid VLA-4 VCAM-1 CCR5 CCL5 VAP-1 selectin ligand ^b E/P-selectin α ₄ β ₇ ^b MAdCAM- ^1b lung LFA-1 ICAM-1 CCR3 CCL28 CCR4 CCL17 CXCR4 CXCL12 selectin ligand ^b E/P-selectin ^b VLA- ^4b VCAM- ^1b LFA- ^1b ICAM- ^1b marrow CLA (PSGL-1 glycoform) E/P-selectin CD43E E-selectin VLA-4 VCAM-1 LFA-1 ICAM-1 CXCR4 CXCL12 α ₄ β ₇ ^b MAdCAM- ^1b Heart CCR5 CCL4, CCL5 CCR4 ? CXCR3 CXCL10 c-Met HGF brain VLA- ^4b VCAM- ^1b LFA- ^1b ICAM- ^1b CXCR3 ^b CXCL9/ ^CXCL10b peripheral LN ^c selectin ligand ^b E/P-selectin ^b LFA- ^1b ICAM- ^1b CXCR3 ^b CXCL9/ ^{CXCL10b a} Involves T _eff cells that return to the gut but not to the colon.
^b Inflammatory response, tissue damage.
^c Under non-inflammatory steady-state conditions, T _eff cells normally lose L-selectin and CCR7 expression and can enter during the inflammatory response (b) as shown, but LN access is severely restricted. In contrast, both native T cells and T _cm cells express L-selectin, CCR7 and CXCR4 and are involved in PNAd, CCL19/CCL21 and CXCL12, respectively, resulting in T-cell rolling and LFA-1/ICAM-1/2-mediated adhesion. and migration to the LN.

Exemplary homing tissue (target tissue) types and ligands or chemokines that enable tissue-restricted B cell homing in accordance with the present invention are shown in Table 3.

Home organization type Ligands/chemokines CNS Ligand for VCAM-1, CD62P, CCR1,2,5, CXCR3 liver CD62P, VAP-1, CXCL16 Intestine MAdCAM, CD62P, CCL25 colon MAdCAM, CD62P, CCL20, GPR15L skin CD62E, CD62P, CCL17(22), ICAM-1 thymus VCAM, CD62P, CCL25 peripheral lymph nodes PNAd, CCL21, ICAM-1 Peyer's Patch MAdCAM, CCL21, CXCL13 marrow VCAM, CD62P, CXCL12, ICAM-1

In various embodiments of the invention, specific homing receptor/ligand pairs as set forth in Table 2 are used to express one or more antibodies, proteins, or receptors that promote homing of modified B cells to exemplary target/homing tissues. Modified B cells are provided. In various embodiments of the invention, modified B cells expressing one or more of the homing receptors that promote homing of modified B cells to exemplary target/homing tissues using the ligands or chemokines set forth in Tables 2 and/or 3 are Provided. As used herein, the term “B cell homing” refers to a B cell of the present application to a site/target of interest, e.g., a homing or target tissue, an inflammatory site in a specific location or tissue, or where delivery of a therapeutic payload is desired. It means localizing, targeting, trafficking, directing or redirecting to a tumor or tumor microenvironment. As used in the context of B cell homing, the terms "antibody", "protein" or "receptor" refer to a nucleic acid sequence encoding an amino acid sequence, peptide or protein, or RNA molecule for use as a therapeutic agent, which is When expressed in a modified B cell of the invention, it will direct the B cell to the region/target of interest.

In certain embodiments, the homing antibody, protein or receptor molecule is for homing/targeting modified B cells expressing such molecules to a site/target of interest. In certain embodiments, the homing antibody, protein or receptor molecule is for homing/targeting modified B cells expressing such molecules to a specific location or site of inflammation in a tissue. In certain embodiments, the homing antibody, protein or receptor is for targeting B cells to a tumor or tumor microenvironment and tumor draining lymph nodes. In certain embodiments, an engineered or modified B cell of the invention is capable of delivering a therapeutic payload to a desired location of interest, e.g., a homing or target tissue, a specific location or site of inflammation in a tissue, or a tumor or tumor microenvironment. It is desirable to target B cells to specific locations. Thus, in certain embodiments, it is preferred that the B cells are homing to a site/target of interest, including, e.g., a tumor or tumor microenvironment and a tumor draining lymph node, e.g., at a site/target of interest (e.g. Delivering a payload to a region/target of interest that can increase the number of cross-presenting dendritic cells (DCs) (eg, in a tumor).

In various embodiments, the homing antibody, protein, or receptor is expressed in modified or engineered B cells as a DNA construct. In various embodiments, the homing antibody, protein or receptor is expressed in transformed B cells as a DNA construct under the control of a constitutively activated transcriptional pathway. In various embodiments, the homing antibody, protein or receptor involved in B cell homing/targeting is not naturally expressed on B cells or is expressed at a higher level than is naturally expressed on B cells. Examples of homing of modified B cells to specific homing/target tissues using specific homing receptor/ligand pairs according to the present invention are shown in Table 4. Notwithstanding the exemplary homing tissue, homing receptor and ligand pairs set forth in Table 4, the modified B cells of the present invention can be engineered to express any homing antibody, protein or receptor (e.g., all set forth in Table 2). homing receptors), the modified B cells can be directed to specific sites/targets of interest.

Homing organization type homing receptor Ligands/chemokines liver CXCR6 CXCL16 Intestine CCR9 CCL25 large intestine (colon) CCR6 CCL20 lymph nodes CCR7 CCL21 marrow CXCR4 CXCL12 Peyer's Patch CCR7 and CXCR5 CCL21 and CXCL13, respectively skin CCR4 CCL17(22)

Non-exclusive examples of homing (target) tissue types for certain homing receptor/ligand pairs of the present invention are skin, gastrointestinal (gut, colon, mesenteric lymph node (mLN), Peyer's Patch (PP), small intestine), liver, lung, bone marrow. , heart, peripheral lymph nodes (LN), CNS, thymus and bone marrow.

Non-exclusive examples of homing receptors that can be paired with a particular or corresponding attractant/ligand/chemokine of the present invention are CLA (PSGL-1 glycoform), CLA (PSGL-1 glycotype), CCR10, CCR3, CCR4, CCR5 , CCR6, CCR9, CD43E, CD44, c-Met, CXCR3, CXCR4, LFA-1, LFA-1 (αLβ2), selectin ligands, VLA-4, VLA-4 (α4β1), and α4β7.

Non-exclusive examples of ligands/chemokines capable of pairing with specific or corresponding homing receptors of the present invention are CXCL16, CCL17, CCL17(22), CCL20 (MIP-3α), CCL21, CCL25, CCL27, CCL28, CCL4, CCL5 , CD62E, CD62P, CXCL10, CXCL12, CXCL13, CXCL16, CXCL9/CXCL10, CXCR3, E/P-selectin, E-selectin, GPR15L, HGF, ligand for hyaluronic acid, ICAM-1, CCR1,2,5, MAdCAM , MAdCAM-1, PNAd, VAP-1, VCAM, and VCAM-1.

In certain embodiments of the present invention, modified B cells are provided that express or have increased expression of an exemplary B cell homing receptor (eg, as set forth in Table 2), wherein the modified B cell is a corresponding ligand/chemokine to be targeted to the corresponding homing tissue of interest expressing (eg, as described in Tables 2 and/or 3). In certain embodiments of the invention, modified B cells co-expressing integrins with specific α and β chain pairs and specific B cell homing receptors (eg, as described in Tables 2 and/or 3) are provided. expression of the integrins and/or homing receptors promotes or facilitates the homing/targeting of the modified B cells to the site/target of interest. In some embodiments, modified B cells co-expressing α4β7 integrin and CCR9 are provided. Co-expression of α4β7 and CCR9 preferably promotes small intestine homing of the modified B cells of the present invention. In some embodiments, modified B cells co-expressing α4β1 integrin and CCR4 are provided. Co-expression of α4β1 and CCR4 preferably promotes small intestine homing of the modified B cells of the present invention.

Modified B cells expressing immunosuppressive molecules. B cells are a major cause of many autoimmune diseases. However, B cells can be used therapeutically to antagonize autoimmunity. Specifically, B cells can be engineered to express one or more immunosuppressive molecules that can reduce the autoimmune activity of B cells and thereby reduce autoimmune diseases. Immunosuppressive molecules are well known in the art. Such inhibitory molecules may include, but are not limited to, IL-10, TGF-β, PD-L1, PD-L2, LAG-3 and TIM-3. In certain embodiments of the invention, engineered to express at least one of the inhibitory molecules selected from IL-10, TGF-β, PD-L1, PD-L2, LAG-3 and TIM-3, or any combination thereof. Modified B cells are provided, and inflammation at the site and autoimmune activity of B cells confined to the site are reduced, resulting in a positive therapeutic response.

Compounds that alter B cell trafficking. In certain embodiments of the invention, modified B cells are provided that are treated with at least one compound or derivative thereof that alters the trafficking of B cells by inducing expression of specific B cell integrins and/or homing receptors. Compounds or derivatives thereof that alter B cell trafficking are well known in the art. In certain embodiments, modified B cells treated with all-trans-retinoic acid (ATRA) or a derivative thereof that promote B cell homing to the stomach (small intestine) due to increased expression of α4β7 integrin and CCR9 homing receptor are provided. . As used herein, the term “compound” refers to a chemical, drug, therapeutic or derivative thereof that alters the trafficking of B cells in a desired manner.

In various embodiments of the invention, modified B cells engineered to co-express specific integrins (eg, specific α and β chain pairings) and specific B cell homing receptors of interest alter trafficking of the modified B cell and Treatment with one or more compounds or derivatives thereof that promote cellular homing receptors to specific sites/targets of interest due to increased expression of specific integrins and/or homing. In various embodiments, the modified B cell and the specific B cell homing receptor further express at least one or more immunosuppressive molecules so as to co-express integrins having specific α and β chain pairs, and variant B targeting specific sites of inflammation. The autoimmune activity of cells is reduced, allowing autoimmune diseases to be reduced. In some embodiments, modified B cells engineered to express one or more immune suppressive molecules, such as IL-10, TGF-β, PD-L1, PD-L2, LAG-3 and TIM-3, or combinations thereof. treatment with ATRA or expression of α4β7 integrin and CCR9 homing receptors is induced to promote B cell homing to a specific site/target of interest (e.g., the stomach), but B cells restricted to that site are inflammatory and autoimmune. activity is reduced, resulting in a positive therapeutic response. In one embodiment, modified B cells engineered to express one or more immune suppressive molecules, e.g., IL-10, TGF-β, or a combination thereof, express α4β7 integrin and the CCR9 homing receptor to a specific region/target of interest ( Although induced to promote B cell homing to the stomach (eg, the stomach), inflammation in that area and autoimmune activity of B cells confined to that area are reduced, leading to a positive therapeutic response.

Any B cell of the invention that has been modified to co-express a specific B cell integrin and a homing receptor that targets the B cell to a specific homing/target tissue of interest may further reduce the inflammatory and autoimmune activity of site-restricted B cells. It is understood that it can be engineered to express one or more immunosuppressive molecules for the immune system and/or can be treated with compounds that alter the homing/targeting of modified B cells by inducing expression of specific B cell integrins and/or homing receptors.

Activation of B cells by TLR agonists and TLRs. B cells have a natural ability to take up and present antigens recognized by specific B cell receptors (BCRs). B cells activated by toll-like receptors (TLRs) generate potent effector B cells that defend the body from an immune response. Expression or increase of TLRs in B cells may provide a mechanism to enrich B cells for innate signals that regulate the adaptive immune response.

Activation of B cells by TLR agonists. In various embodiments of the invention, B cells are provided wherein the B cells are treated with one or more TLR agonists in vitro. In various embodiments, a TLR can be TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and/or TLR13. In various embodiments, the TLR agonist preferentially binds to one or more TLRs selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. TLR agonists are well known in the art and may include, but are not limited to, CpG-rich oligonucleotides and double-stranded RNA mimetics, polyinosinic acid:polycytidylic acid (poly-I:C). In various embodiments, a TLR agonist can be a CpG oligonucleotide.

In various embodiments, each B cell can be treated with one TLR agonist. In various embodiments, each B cell can be treated with more than one TLR agonist. For example, each B cell can be treated with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 different TLR agonists. Alternatively, the patient can be administered a heterogeneous population of B cells, and each B cell is treated with a unique TLR agonist or combination of TLR agonists. In some embodiments, a B cell for use with a therapeutic agent is treated with one or more TLR agonists prior to or concurrently with administration of the B cell to a subject or patient in need thereof. In certain embodiments, treatment with one or more TLR agonists can generate more potent effector B cells to defend the body from an immune response. In certain embodiments, treatment with one or more TLR agonists can enhance B cells for an immune response. In some embodiments, treatment of a B cell of the invention with one or more TLR agonists induces expression or activation of one or more TLRs.

Activation of B cells by TLR expression. In various embodiments of the invention, modified B cells capable of expressing constitutively active TLRs are provided. In various embodiments, TLRs are expressed in modified or engineered B cells as DNA constructs under the control of a constitutively activated transcriptional pathway. In various embodiments, the TLRs are not naturally expressed in B cells or are expressed at higher levels than are naturally expressed in B cells. In various embodiments, a TLR can be TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and/or TLR13.

In various embodiments, each B cell can express more than one constitutively active TLR. For example, each B cell may express 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 different constitutively active TLRs. Alternatively, the patient may receive a heterogeneous population of B cells, each B cell capable of expressing and/or secreting a unique constitutively active TLR or combination of TLRs. In various embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 different constitutively active TLRs are transferred to a subject or patient via a heterogeneous population of B cells. can be administered.

In certain embodiments of the invention, the B cell is a modified B cell expressing at least one constitutively active TLR. In certain embodiments, modified B cells expressing one or more constitutively active TLRs are treated with one or more TLR agonists. In certain embodiments, expression of constitutively active TLRs can generate more potent effector B cells to defend the body from an immune response. In certain embodiments, expression of constitutively active TLRs can enhance B cells for an immune response. In certain embodiments, the modified B cell expresses both a constitutively active TLR and any CAR-B of the present application. In various embodiments, modified B cells that express constitutively active TLRs and/or CAR-Bs are further treated with one or more TLR agonists prior to or concurrently with administration of the modified B cells to a subject or patient in need thereof. do. In certain embodiments, B cells can be engineered to express payloads and modifiers such as TLRs in the absence of CAR-B for intratumoral administration.

Transformed B cells present antigen simultaneously on HLA class I and class II molecules. In addition to their antibody-producing function, B cells can express high levels of human leukocyte antigen (HLA) class II molecules and present antigens to CD4+ T cells (Hong et al., 2018, Immunity 49, 695-708). In various embodiments of the present invention, modified B cells capable of simultaneously presenting specific antigens such as tumor antigens or infectious disease antigens and/or epitopes from antigens of interest on both HLA class I and class II molecules are provided. Tumor antigens and infectious disease antigens are well known in the art and are described in the section above. In certain embodiments, a specific antigen of interest, e.g., a tumor antigen or an infectious disease antigen, is fused to a targeting signal of a lysosomal protein that targets the antigen to the lysosome and presents the antigen simultaneously and efficiently on both HLA class I and class II molecules. do. In some embodiments, the targeting signal is a targeting signal of lysosomal-associated membrane protein-1 (LAMP1). In some embodiments, the targeting signal may enter an endosomal recycling compartment. The c-terminal sequence of Clec9A is such a targeting moiety. As used herein, a specific tumor antigen or infectious disease antigen fused to a targeting signal is a nucleic acid sequence encoding an amino acid sequence, a peptide or protein, or an RNA molecule (eg, an mRNA molecule) for use as a therapeutic agent. refers to In one embodiment, a specific tumor antigen or infectious disease antigen fused to a targeting signal refers to an mRNA molecule for use as a therapeutic agent. In certain embodiments, specific tumor antigens and/or infectious disease antigens fused to a targeting signal, such as that of LAMP1 or Clec9A, are targeted to lysosomes or endosomes and presented simultaneously and efficiently on both HLA class I and class II molecules. desirable. In certain embodiments, electroporation of B cells (eg, human B cells) before or after maturation with mRNA encoding specific tumor antigens and/or infectious disease antigens of interest is targeted, such as LAMP1 or a targeting signal of LAMP1. Preferably fused to a signal Clec9A can efficiently present specific antigens and/or antigen-derived epitopes simultaneously and efficiently on both HLA class I and class II molecules. In various embodiments, the particular tumor antigen and/or infectious disease antigen of interest is not naturally presented by B cells, is not naturally presented simultaneously by B cells on both HLA class I and class II molecules, or is not naturally presented by HLA class I and class II molecules are not naturally presented by B cells with high efficiency. Introduction of such electroporated B cells into a subject, eg, a human host, allows the development of an antigen-specific immune response by presenting a specific antigen of interest and/or antigen-derived epitope simultaneously and efficiently on HLA class I and class II molecules. It is thought to promote or strengthen.

In various embodiments, the invention provides, e.g., an mRNA sequence encoding at least one specific antigen of interest, e.g., a tumor antigen or infectious disease antigen, both HLA class I and class II molecules fused to a targeting signal. to a nucleic acid sequence, such as a targeting signal of LAMP1 for use as a therapeutic agent in electroporation of B cells for the simultaneous and efficient presentation of specific antigens and/or antigen-derived epitopes in In various embodiments, the invention provides an infectious disease antigen of interest and/or more than one (e.g., 1, 2, 3, 4, 5, or more) specific tumor antigens encoding fused to a targeting signal. It relates to nucleic acid sequences, such as mRNA sequences. In various embodiments, the present invention provides pools of different mRNA sequences, e.g., for use as therapeutics in the electroporation of B cells as described above, each pool encoding at least one particular antigen of interest, e.g. , a pool of different nucleic acid sequences of tumor antigens or infectious disease antigens fused to different targeting signals than other pools of mRNA sequences. Thus, in some embodiments, a subject can be administered a homogeneous population of B cells, each of which is electroporated with mRNA encoding at least one specific antigen of interest fused to a targeting signal. In some embodiments, a subject can be administered a homogeneous population of B cells, each of which is electroporated with mRNA encoding one or more specific antigens of interest fused to a targeting signal. In some embodiments, a subject may be administered a heterogeneous population of B cells, each of which is electroporated with a combination of mRNAs each encoding at least one specific antigen of interest fused to a different targeting signal.

In some embodiments, a B cell for use in electroporation as described above may be any modified B cell of the present application. In some embodiments, the modified B cell comprises a Chimeric Antigen Receptor for B Cell (CAR-B). In various embodiments, the modified B cells are capable of expressing CAR-B and efficiently presenting specific antigens of interest and/or antigen-derived epitopes on both HLA class I and class II molecules simultaneously and efficiently.

In various embodiments, the invention relates to methods of administering isolated B cells to a patient in need thereof. In various embodiments, a B cell population can be administered to a patient. In various embodiments, each B cell may express more than one payload peptide or protein. For example, each B cell can express 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 different payloads. Alternatively, the patient may be administered a heterogeneous B cell population in which each B cell is capable of expressing and/or secreting a unique payload or combination of payloads. In various embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 different payloads may be administered to a patient via a heterogeneous population of B cells.

3. treatment method

Thus, in some aspects, the invention includes a method of treating or preventing a tumor or cancerous tissue, the method comprising administering to a patient in need thereof an effective amount of at least one CAR-B disclosed herein. .

A method for treating a disease or disorder, including cancer, is provided. In some embodiments, the invention relates to generating a B cell-mediated immune response in a subject comprising administering to the subject an effective amount of an engineered immune cell of the present application. In some embodiments, the B cell-mediated immune response is directed against a target cell or cells. In some embodiments, the engineered immune cell comprises a Chimeric Antigen Receptor for B Cell (CAR-B). In some embodiments, the target cell is a tumor cell. In some aspects, the invention includes a method of treating or preventing a malignancy, comprising administering to a subject in need thereof an effective amount of one or more isolated antigen-binding molecules described herein. In some aspects, the invention includes a method of treating or preventing a malignancy comprising administering to a subject in need thereof an effective amount of at least one immune cell, wherein the immune cell is at least one Includes chimeric antigen receptors.

In some aspects, the invention includes pharmaceutical compositions comprising one or more antigen-binding molecules as described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises an additional active agent.

In some embodiments, the subject is diagnosed with liver-limited metastatic disease. In another embodiment, the metastatic disease is cancer. In another embodiment, the cancer has metastasized from a primary tumor of the breast, colon, rectum, esophagus, lung, pancreas, and/or stomach. In another embodiment, the subject is diagnosed with an unresectable metastatic liver tumor. In another embodiment, the subject is diagnosed with an unresectable metastatic liver tumor from primary colorectal cancer. In some embodiments, the subject is diagnosed with hepatocellular carcinoma.

It will be appreciated that the target dose for modified B cells may range from 1 x 10 ⁶ -2 x 10 ¹⁰ cells/kg, preferably 2 x 10 ⁶ cells/kg, more preferably. It will be appreciated that doses above and below this range may be appropriate for a particular subject and that appropriate dosage levels can be determined by a health care provider as needed. Additionally, multiple doses of cells may be provided according to the present invention.

Also provided is a method of reducing the size of a tumor in a subject, comprising administering to the subject a modified B cell of the invention, wherein the cell is sensitive to antigens of the tumor, the payload or both the CAR-B and the payload. A CAR-B receptor comprising an antigen binding domain that binds. In some embodiments, the subject has a solid tumor or a hematological malignancy such as lymphoma or leukemia. In some embodiments, modified B cells are delivered to a tumor bed. In some embodiments, the cancer is present in the subject's bone marrow.

Also provided is a method of homing a B cell to a site/target of interest in a subject comprising administering to the subject a modified B cell of the invention, wherein the cell is directed to a ligand, chemokine, or attractant at the site/target of interest. Includes integrins that are attracted, homing antibodies, proteins, or receptors. In some embodiments, the site/target of interest is, for example, a homing or target tissue, an inflammatory site in a particular location or tissue, or a tumor or tumor microenvironment in which delivery of a therapeutic payload is desired.

Also provided is a method of reducing inflammation and autoimmune activity of B cells in a region/target of interest in a subject comprising administering to the subject a modified B cell of the present invention, wherein the cells comprise an immunosuppressive molecule. do. In some embodiments, the site/target of interest is, for example, a homing or target tissue, an inflammatory site in a particular location or tissue, or a tumor or tumor microenvironment in which delivery of a therapeutic payload is desired.

Also of interest in a subject of B cells comprising treating a B cell of the present invention with a compound or derivative thereof suitable for altering B cell trafficking, and administering the treated B cell to a subject in need thereof. A method for altering trafficking to a site/target is provided. In some instances, the compound or derivative thereof alters B cell trafficking by increasing expression of integrins, homing antibodies, proteins, receptors, or combinations thereof expressed by B cells.

Also, enhancing and/or potent effector of the B cells to increase the immune response in a subject comprising treating a B cell of the present invention with one or more TLR agonists and administering the treated B cell to a subject in need thereof. Methods of producing B cells are provided. In some embodiments, treatment of a B cell of the invention with one or more TLR agonists induces expression or activation of one or more TLRs. In some embodiments, the B cells are enhanced and/or potent to increase the immune response in the subject, further comprising administering to the subject a modified B cell of the invention that expresses at least one constitutively active TLR. Methods of producing effector B cells, also provided are methods of enhancing B cells and/or producing potent effector B cells to increase an immune response in a subject comprising administering to the subject a modified B cell of the present invention. wherein the cell expresses an antigen on the tumor, a constitutively active TLR or a CAR-B receptor comprising an antigen binding domain that binds to both the CAR-B and the constitutively active TLR, and the cell is The cells are treated with one or more TLR agonists prior to or concurrently with administration.

Also provided is a method of increasing an antigen-specific immune response in a subject, comprising administering to the subject a modified B cell of the present invention, wherein the cell contains a specific antigen and/or antigen in both HLA class I and class II molecules. It is electroporated with a nucleic acid sequence, eg mRNA, encoding a specific tumor antigen and/or infectious disease antigen fused to a targeting signal, such as that of LAMP1 or Clec9A, for simultaneous and efficient presentation of antigen-derived epitopes. In some embodiments, the subject has a solid tumor or a hematological malignancy such as lymphoma or leukemia.

The various embodiments of the methods of treatment using engineered or modified B cells of the present application are not mutually exclusive to facilitate any outcome and/or therapeutic response contemplated herein, and may in no way be used unless expressly indicated. It is understood that they can be combined with each other without any limitation.

In some embodiments, the modified B cell is an autologous B cell. In some embodiments, the modified B cell is an allogeneic B cell. In some embodiments, the modified B cell is a heterologous B cell. In some embodiments, the modified B cells of the present application are transfected or transduced in vivo. In another embodiment, the engineered cells are transfected or transduced ex vivo.

As used herein, the term “subject” or “patient” refers to an individual. In some aspects, the subject is a mammal, such as a human. In some aspects, the subject may be a non-human primate. Non-human primates include marmosets, monkeys, chimpanzees, gorillas, orangutans, and gibbons. The term "subject" includes cats, dogs, etc., livestock (eg, llamas, horses, cows), wild animals (eg, deer, elk, moose, etc.), laboratory animals (eg, mice, rabbits, Domestic animals such as mice, gerbils, guinea pigs, etc.) and bird species (eg chickens, turkeys, ducks, etc.) are also included. Preferably, the subject is a human subject. More preferably, the subject is a human patient.

The method may further comprise administering one or more chemotherapeutic agents. In certain embodiments, the chemotherapeutic agent is a lymphdepleting (pretreatment) chemotherapeutic agent. Beneficial preconditioning treatment regimens with correlated beneficial biomarkers are described in US Provisional Patent Application Nos. 62/262,143 and 62/167,750, which are incorporated herein by reference in their entirety. These include, for example, certain beneficial doses of cyclophosphamide (200 mg/m ² /day to 2000 mg/m ² /day) and certain doses of fludarabine (20 mg/m ² /day to 900 mg/m 2 /day) to the patient. m ² /day), a method for controlling a patient in need of T cell therapy is described. A preferred dosing regimen is to administer about 500 mg/m ² /day of cyclophosphamide and about 60 mg/m ² /day of fludarabine to the patient daily for 3 days prior to administration of a therapeutically effective amount of engineered B cells to the patient. and treating a patient comprising administering.

In another embodiment, the antigen-binding molecule, transduced (or otherwise engineered) cell (eg, CAR), and chemotherapeutic agent are each administered in an amount effective to treat a disease or condition in a subject.

In certain embodiments, a composition comprising a CAR-expressing immune effector cell disclosed herein may be administered with any number of chemotherapeutic agents. Examples of chemotherapeutic agents include thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimine and methylamelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamin; Chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novenvicine, fenesterine, prednimustine, trophosphamide , nitrogen mustards such as uracil mustard; nitrureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; Aclasinomycin, Actinomycin, Autramycin, Azaserin, Bleomycin, Cactinomycin, Calicheamicin, Carabicin, Carminomycin, Carzinophylline, Chromomycin, Dactinomycin, Daunorubicin, Detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olibomycin, fe antibiotics such as phlomycin, potpyromycin, puromycin, que-ramycin, rodrubicin, streptonigryn, streptozocin, tubersidin, ubenimex, ginostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacytidine, 6-azauridine, carmopur, cytarabine, dideoxyuridine, doxifuridine, enocitabine, floxuridine, 5-FU; androgens such as calosterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, trirostane; folic acid supplements such as proline acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defamine; demecolsine; diaziquone; elformitin; elliptinium acetate; Etogluside; gallium nitrate; hydroxyurea; lentinan; Ronidamine; mitoguazone; mitoxantrone; furdamole; nitrate; pentostatin; penamet; pirarubicin; pophyllic acid; 2-ethylhydrazide; procarbazine; PSK®; Razoxic acid; sizopyran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gastosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids such as paclitaxel (Taxol®, Bristol-Myers Squibb) and docetaxel (Taxotere®, Rhone-Poulenc Rorer); chlorambucil; gemcitabine; 6-thioguanine mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navel Vin; Novantrone; Teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS2000; Difluoromethylomithine (DMFO); Targretin ^™ (bexarotene ), retinoic acid derivatives such as Panretin ^™ (allitretinoin); Ontak ^™ (denylleukin diptitox); esperamicin; capecitabine; Also included in this definition are antiestrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above; These include antihormonal drugs that act to modulate or inhibit hormonal action on: CHOP when appropriate, namely cyclophosphamide (Cytoxan®) doxorubicin (hydroxydoxorubicin), fludarabine, vincristine (Oncovin®) and prednisone Combinations of chemotherapeutic agents, including but not limited to, are also administered.

In some embodiments, the chemotherapeutic agent is administered concurrently with or within 1 week of administration of the engineered cells or nucleic acids. In other embodiments, the chemotherapeutic agent is administered 1 to 4 weeks or 1 week to 1 month, 1 week to 2 months, 1 week to 3 months, 1 week to 6 months, 1 week to 9 months after administration of the engineered cell or nucleic acid. , or for 1 week to 12 months. In another embodiment, the chemotherapeutic agent is administered at least 1 month prior to administration of the cells or nucleic acids. In some embodiments, the method further comprises administering two or more chemotherapeutic agents.

A variety of additional therapeutic agents can be used with the compositions described herein. For example, potentially useful additional therapeutic agents include PD-1 (or PD-L1) such as nivolumab ( ^Opdivo® ), pembrolizumab (Keytruda®), pembrolizumab, pidilizumab, and atezolizumab (Tecentriq®). ) inhibitors. Other additional therapeutic agents include anti-CTLA-4 antibodies (eg ipilimumab®), anti-LAG-3 antibodies (eg relatlimab, BMS) alone or in combination with PD-1 and/or PD-1 It is combined with an L1 inhibitor.

Additional therapeutic agents suitable for use with the present invention include ibrutinib (Imbruvica®), ofatumumab (Arzerra®), rituximab (Rituxan®), bevacizumab (Avastin®), trastuzumab (Herceptin®) , trastuzumab emtansine (KADCYLA®), imatinib (Gleevec®), cetuximab (Erbitux®), panitumumab (Vectibix®), catumaxomab, ibritumomab, ofatumumab, tositumomab, Brentuximab, alemtuzumab, gemtuzumab, erlotinib, gefitinib, vandetanib, afatinib, lapatinib, neratinib, axitinib, mastinib, pazopanib, sunitinib, Sora Fenib, toceranib, restaurtinib, axitinib, cediranib, lenvatinib, nintedanib, pazopanib, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib , vandetanib, entrectinib, cabozantinib, imatinib, dasatinib, nilotinib, ponatinib, radotinib, bosutinib, lestaurtinib, ruxolitinib, pacritinib, cobimetinib, selumeti nip, trametinib, binimetinib, alectinib, ceritinib, crizotinib, aflibercept, adipotide, denileukin diptitox, mTOR inhibitors such as everolimus and temsirolimus, sonidegib and hedgehog inhibitors such as vismodegib, CDK inhibitors such as CDK inhibitors (palbociclib), but are not limited thereto.

In a further embodiment, a composition comprising a CAR-containing B cell may be administered with an anti-inflammatory agent. Anti-inflammatory drugs or drugs include steroids and glucocorticoids (including betamethasone, budesonide, dexamethasone, hydrocortisone acetate, hydrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone), aspirin, ibuprofen, naproxen, methotrexate, sulfasalazine, leflunomide , anti-TNF drugs, non-steroidal anti-inflammatory drugs (NSAIDS) including cyclophosphamide and mycophenolate. Exemplary NSAIDs include ibuprofen, naproxen, naproxen sodium, Cox-2 inhibitors, and sialylates. Exemplary analgesics include tramadol in acetaminophen, oxycodone, proporcipene hydrochloride. Exemplary glucocorticoids include cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone or prednisone. Exemplary biological response modifiers are cell surface markers (eg, CD4, CD5, etc.), TNF antagonists (eg, etanercept (ENBREL®), adalimumab (HUMIRA®) and infliximab (REMICADE®)) , molecules directed against cytokine inhibitors such as chemokine inhibitors and adhesion molecule inhibitors. Exemplary DMARDs include azathioprine, cyclophosphamide, cyclosporine, methotrexate, penicillamine, leflunomide, sulfasalazine, hydroxychloroquine, gold (oral (Auranofin) and intramuscular) and minocycline.

In certain embodiments, a composition described herein is administered in conjunction with a cytokine. As used herein, “cytokine” is meant to refer to proteins released by one cell population that act on other cells as intercellular mediators. Examples of cytokines are lymphokines, monokines and traditional polypeptide hormones. Cytokines include human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); liver growth factor (HGF); fibroblast growth factor (FGF); prolactin; placental lactogen; Muller-inhibiting substances; mouse gonadotropin-related peptide; inhibin; activin; vascular endothelial growth factor; integrins; thrombopoietin (TPO); nerve growth factors (NGF) such as NGF-beta; platelet growth factor; transforming growth factors (TGFs) such as TGF-alpha and TGF-beta; insulin-like growth factors-I and -II; erythropoietin (EPO); osteoinductive factor; interferons such as interferon-alpha, beta and -gamma; colony stimulating factors (CSF) such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (G-CSF); Interleukins (ILs), such as IL-1, IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10 , IL-11, IL-12; tumor necrosis factors such as IL-15, TNF-alpha or TNF-beta; and growth hormones such as LIF and other polypeptide factors including kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture, and biologically active equivalents of the native sequence cytokines.

4. manufacturing method

Various known techniques can be used to prepare polynucleotides, polypeptides, vectors, antigen-binding molecules, immune cells, compositions and the like according to the present invention.

Prior to in vitro manipulation or genetic modification of the immune cells described herein, the cells can be obtained from a subject. In some embodiments, immune cells include B cells. B cells can be obtained from several sources, including peripheral blood mononuclear cells (PBMCs), bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments, B cells can be obtained from units of blood collected from a subject using any number of techniques known to those of skill in the art, such as FICOLL™ isolation. Cells can be obtained from the circulating blood of a subject, preferably by apheresis. Apheresis products typically contain T cells, monocytes, granulocytes, B cells, other nucleated leukocytes, and lymphocytes, including red blood cells and platelets. In certain embodiments, cells collected by apheresis can be washed to remove the plasma fraction and placed in an appropriate buffer or medium for subsequent processing. Cells can be washed with PBS. As will be appreciated, a wash step can be used using a semi-automated perfusion centrifuge, such as the Cobe™ 2991 Cell Handler, Baxter Cyto-Mate™, and the like. After washing, cells can be resuspended in various biocompatible buffers or other saline solutions with or without buffer. In certain embodiments, unwanted constituents of an apheresis sample may be removed.

Immune cells, such as B cells, can be genetically modified after isolation using known methods, or immune cells can be activated and expanded (or differentiated in the case of progenitor cells) in vitro before being genetically modified. In another embodiment, an immune cell, such as a B cell, is genetically modified with a chimeric B cell receptor described herein (e.g., transduced with a viral vector comprising one or more nucleotide sequences encoding CAR-B). is then activated and/or expanded in vitro. Methods of activating and expanding B cells are known in the art and are described in, for example, U.S. Patent Nos. 6,905,874; 6,867,041; 6,797,514; and PCT WO 2012/079000, the contents of which are incorporated herein by reference in their entirety. Generally, these methods involve contacting PBMCs or isolated B cells with stimulatory and costimulatory agents, usually attached to beads or other surfaces, in a culture medium in the presence of an appropriate cytokine such as IL-2.

In another embodiment, the B cell is described in U.S. Patent No. 6,040,177; 5,827,642; and WO/2012129514, the contents of which are incorporated herein by reference in their entirety.

Certain methods for making constructs and engineered immune cells of the invention are described in PCT application PCT/US2015/14520, the contents of which are incorporated herein by reference in their entirety. Additional methods of making constructs and cells can be found in US Provisional Patent Application No. 62/244,036, the contents of which are incorporated herein by reference in their entirety.

For cloning of a polynucleotide, the vector may be introduced into a host cell (an isolated host cell) to allow replication of the vector itself, thereby amplifying copies of the polynucleotide contained therein. Cloning vectors may generally contain sequence components including, but not limited to, origins of replication, promoter sequences, transcription initiation sequences, enhancer sequences and selectable markers. These elements can be appropriately selected by a person skilled in the art. For example, the origin of replication can be selected to promote autonomous replication of the vector in the host cell.

In certain embodiments, the present disclosure provides isolated host cells containing vectors provided herein. Host cells containing the vectors may be useful for expressing or cloning polynucleotides contained in the vectors. Suitable host cells may include, without limitation, prokaryotic cells, fungal cells, yeast cells, or higher eukaryotic cells such as mammalian cells. Prokaryotic cells suitable for this purpose include, without limitation, fungi such as gram-negative or gram-positive organisms, eg Enterobacteriaceae such as Escherichia , eg E. coli , Enterobacter , Erwinia , Klebsi. Ella , Proteus , Salmonella , e.g. Salmonella typhimurium , Serratia , e.g. Serratia mark-eskans and Shigella , as well as bacilli such as B. subtilis and B. licheniformis; Pseudomonas such as P. aeruginosa and Streptomyces .

Vectors include DEAE-dextran-mediated delivery, calcium phosphate precipitation, cationic lipid-mediated delivery, liposome-mediated transfection, electroporation, microprojectile bombardment, receptor-mediated gene delivery, delivery by polylysine, histones, chitosan, and peptides. It can be introduced into a host cell using any suitable method known in the art, including but not limited to. Standard methods for transfection and transformation of cells for expression of a vector of interest are well known in the art. In a further embodiment, a mixture of different expression vectors can be used to genetically modify a donor population of immune effector cells, each vector encoding a different CAR-B as disclosed herein. The resulting transduced immune effector cells form a mixed population of engineered cells with a proportion of engineered cells expressing one or more different CAR-Bs.

In one embodiment, the present invention provides a method of storing a genetically engineered cell expressing a CAR-B targeting protein. This includes cryopreservation of immune cells so that the cells remain viable upon thawing. The fraction of immune cells that express CAR-B can be cryopreserved by methods known in the art to provide a permanent source of these cells for future treatment of patients suffering from malignancies. If necessary, cryopreserved transformed immune cells can be thawed, grown and expanded for more such cells.

As used herein, “cryopreservation” means preserving cells by cooling to sub-zero temperatures, for example (typically) 77 Kelvin or 196° C. (the boiling point of liquid nitrogen). Cryoprotectants are often used at sub-zero temperatures to prevent damage to cells by freezing at low temperatures or warming to room temperature. Cryopreservatives and optimal cooling rates can protect cells from damage. A cryoprotectant that may be used according to the present invention is dimethyl sulfoxide (DMSO) (Lovelock & Bishop, Nature, 1959, 183, 1394-1395; Ashwood-Smith, Nature, 1961, 190, 1204-1205), glycerol, polyvinyl pyrrolidine (Rinfret, Ann. N.Y. Acad. Sci., 1960, 85, 576) and polyethylene glycol (Sloviter & Ravdin, Nature, 1962, 196, 48). A preferred cooling rate is 1-3° C./min.

The term "substantially pure" is used to indicate that a given component is present at high levels. The ingredient is preferably the predominant ingredient present in the composition. Preferably present at a level greater than 30%, greater than 50%, greater than 75%, greater than 90%, or even greater than 95%, the level being determined on a dry weight/dry weight basis for the total composition under consideration. At very high levels (eg, greater than 90%, greater than 95% or greater than 99%) a component may be considered "in pure form". Biologically active substances (including polypeptides, nucleic acid molecules, antigen binding molecules, moieties) of the present invention may be provided in a form in which the substance is substantially free of one or more contaminants to which it may otherwise be associated. When a composition is substantially free of a given contaminant, the contaminant will be at a low level (eg, at a level of less than 10%, less than 5% or less than 1% on a dry weight/dry weight basis specified above).

In some embodiments, cells are formulated by first harvesting the cells from their culture medium, then washing and concentrating the cells in a medium and container system ("pharmaceutically acceptable" carrier) suitable for administration of a therapeutically effective amount. A suitable infusion medium can be any isotonic medium formulation, usually physiological saline, Normosol ^™ R (Abbott) or Plasma-Lyte ^™ A (Baxter), but water or 5% dextrose in Ringer's lactate may also be used. The infusion medium may be supplemented with human serum albumin.

The desired throughput of cells in the composition is generally at least 2 cells or more typically greater than 10 ² cells, and may be greater than 10 ¹⁰ cells, including up to 10 ⁶ , up to 10 ⁸ or 10 ⁹ cells. The number of cells will depend on the desired use for which the composition is intended and the types of cells included therein. The desired cell density is typically 10 ⁶ cells/ml or more, typically 10 ⁷ cells/ml or more, typically 10 ⁸ cells/ml or more. Clinically relevant immune cell numbers can be divided into multiple injections equal to or greater than a cumulative 10 ⁵ , 10 ⁶ , 10 ⁷ , 10 ⁸ , 10 ⁹ , 10 ¹⁰ , 10 ¹¹ , or 10 ¹² cells. In some aspects of the invention, fewer cells may be administered, in the range of 10 ⁶ /kg (10 ⁶ -10 ¹¹ per patient), particularly since all injected cells will be redirected to a specific target antigen. CAR-B treatment can be administered multiple times with doses within these ranges. The cells may be autologous, allogeneic or xenogeneic to the patient receiving treatment. In some aspects, different CAR-B cells are found in a single product. A composition can be 2, 3, 4, 5, 6, 7, 8, 9 or up to 10 different CAR-B cells. They may consist of cells expressing the chimeric CAR protein and B cells expressing a different CAR and/or payload.

The B cells of the present invention can be administered as a pharmaceutical composition, alone or in combination with diluents and/or other components such as IL-2 or other cytokines or cell populations. A pharmaceutical composition of the present invention may comprise a CAR-B expressing cell population, such as a B cell as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions include neutral buffered saline, phosphate buffered saline, and the like; carbohydrates such as glucose, mannose, sucrose or dextran, mannitol; protein; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (eg aluminum hydroxide); and buffers such as preservatives. Compositions of the present invention are preferably formulated for intravenous administration. Treatment may include treatment with one or more corticosteroids such as dexamethasone and/or methylprednisolone.

A composition of the present application may include, consist essentially of, or consist of the disclosed ingredients.

A pharmaceutical composition (solution, suspension, etc.) of the present invention may contain one or more of the following: a sterile diluent such as water for injection, saline, preferably physiological saline, Ringer's solution, isotonic sodium chloride, a solvent or suspension medium, fixed oils such as polyethylene glycol, glycerin, propylene glycol or other synthetic mono- or diglycerides that can act as solvents; antibacterial agents such as benzyl alcohol and methyl paraben; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylene-diaminetetraacetic acid; buffers such as acetate, citrate or phosphate and tonicity regulators such as sodium chloride or dextrose. Parenteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Injectable pharmaceutical compositions are preferably sterile.

It will be appreciated that adverse events can be minimized by transducing immune cells (containing one or more CAR-Bs) with a suicide gene. It may be desirable to incorporate an inducible "on" or "accelerator" switch into immune cells. These techniques may employ the use of dimerization domains and selective activators of dimerization of these domains. Such techniques include, for example, the technique described by Wu et al., Science 2014, 350(6258), which utilizes the FKBP/Rapalog dimerization system in certain cells, the contents of which are incorporated herein by reference in their entirety. . Additional dimerization techniques are described, for example, in Fegan et al. Chem. Rev. 2010, 110, 3315-3336 and US Patent Nos. 5,830,462; 5,834,266; 5,869,337; and 6,165,787, the contents of which are also incorporated herein by reference in their entirety. Additional dimerization pairs may include cyclosporine-A/cyclophylline receptors, estrogen/estrogen receptors (optionally with tamoxifen), glucocorticoid/glucocorticoid receptors, tetracycline/tetracycline receptors, vitamin D/vitamin D receptors. Further examples of dimerization techniques are described in, for example, WO 2014/127261, WO 2015/090229, US 2014/0286987, US 2015/0266973, US 2016/0046700, US Patent No. 8,486,693, US 2014/0171649, and US 2012/ 0130076, the contents of which are further incorporated herein by reference in their entirety.

Suitable techniques include the use of inducible caspase-9 (U.S. Application Publication No. 2011/0286980) or thymidine kinase before, after, or simultaneously with cells being transduced with the CAR-B constructs of the present invention. Additional methods for introducing suicide genes and/or "on" switches include CRISPR, TALENS, MEGATALEN, zinc finger, RNAi, siRNA, shRNA, antisense technologies, and other technologies known in the art.

Anti-CD20 or anti-CD19 represents an additional means to reduce or eliminate engineered B cells when engineered B cells are responsible for side effects or pathology.

It is to be understood that the description herein is illustrative and explanatory only and does not limit the invention as claimed. The use of the singular in this application includes the plural unless specifically stated otherwise.

Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books and monographs, are expressly incorporated by reference in their entirety for all purposes. As used in accordance with this disclosure, the following terms should be understood to have the following meanings unless otherwise indicated:

The use of "or" in this application means "and/or" unless specified otherwise. Also, the use of the term "comprising" and other forms such as "comprising" and "including" is not limiting. Also, terms such as "element" or "component" include both elements and components comprising one unit and elements and components comprising one or more subunits unless specifically stated otherwise.

The term "polynucleotide", "nucleotide" or "nucleic acid" includes both single-stranded and double-stranded nucleotide polymers. Nucleotides comprising polynucleotides may be ribonucleotides or deoxyribonucleotides or modified forms of both types of nucleotides. These modifications include base modifications such as bromoridine and inosine derivatives, ribose modifications such as 2',3'-dideoxyribose, and phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphoro-di internucleotidic linkage modifications such as selenoate, phosphoro-anilothioate, phosphoraniladate and phosphoroamidate.

The term "oligonucleotide" refers to a polynucleotide comprising 200 or fewer nucleotides. Oligonucleotides can be single-stranded or double-stranded, for example for use in the construction of mutant genes. Oligonucleotides can be sense or antisense oligonucleotides. Oligonucleotides may contain labels including radioactive labels, fluorescent labels, haptens or antigen labels for detection assays. Oligonucleotides can be used, for example, as PCR primers, cloning primers or hybridization probes.

The term “control sequence” refers to polynucleotide sequences capable of affecting the expression and processing of ligated coding sequences. The nature of such regulatory sequences may vary depending on the host organism. In certain embodiments, control sequences for prokaryotes may include promoters, ribosome binding sites, and transcription termination sequences. For example, control sequences for eukaryotes can include a promoter comprising one or a plurality of recognition sites for transcription factors, transcription enhancer sequences, and transcription termination sequences. A "control sequence" may include a leader sequence (signal peptide) and/or a fusion partner sequence.

As used herein, "operably linked" means that the components to which the term applies are in a relationship that enables them to perform their respective functions under appropriate conditions.

The term “vector” refers to any molecule or entity (eg, nucleic acid, plasmid, bacteriophage or virus) used to transfer protein-coding information into a host cell. The term “expression vector” or “expression construct” refers to a nucleic acid sequence that is suitable for transformation of a host cell and that directs and/or controls (with the host cell) the expression of one or more heterologous coding regions operably linked thereto. refers to a vector. Expression constructs can include, but are not limited to, sequences that affect or control transcription, translation, and, if present, introns, which can affect RNA splicing of coding regions operably linked thereto. .

The term "host cell" refers to a cell that has been or can be transformed with a nucleic acid sequence to express a gene of interest. The term includes the progeny of the parent cell, regardless of whether or not the progeny are identical in morphology or genetic makeup to the original parent cell as long as the gene of interest is present.

The term "transformation" refers to a change in the genetic properties of a cell and refers to a cell that has been modified to contain new DNA or RNA. For example, cells are transformed where they are genetically modified from their native state by introducing new genetic material through transfection, transduction or other techniques. After transformation or transduction, the transforming DNA is physically integrated into the cell's chromosome and can be recombined with the cell's DNA, or it can remain unreplicated and transiently as an episomal element, or it can be independently replicated as a plasmid. there is. A cell is considered "stably transformed" when the transforming DNA replicates with cell division.

The term "transfection" refers to uptake of foreign or exogenous DNA by a cell. A number of transfection techniques are well known in the art and are disclosed herein. See, for example, Graham et al. , Virology, 1973, 52:456; Sambrook et al., Molecular Cloning: A Laboratory Manual, 2001, supra; Davis et al., Basic Methods in Molecu-lar Biology, 1986, Elsevier; See Chu et al., Gene, 1981, 13:197.

The term “transduction” refers to the process by which foreign DNA is introduced into a cell via a viral vector. See, eg, Jones et al., Genetics: principles and analysis, 1998, Boston: Jones & Bartlett Publ.

The term "polypeptide" or "protein" refers to a macromolecule having the amino acid sequence of a protein comprising deletions, additions and/or substitutions from one or more amino acids of the native sequence. The terms "polypeptide" and "protein" specifically include antigen-binding molecules, antibodies, or sequences having deletions, additions and/or substitutions from one or more amino acids of an antigen-binding protein. The term "polypeptide fragment" refers to a polypeptide having amino terminal deletions, carboxyl terminal deletions and/or internal deletions compared to the full length native protein. Such fragments may also contain modified amino acids compared to native proteins. Useful polypeptide fragments include immunologically functional fragments of antigen binding molecules.

The term “isolated” means (i) is free of at least some other protein as commonly found, (ii) is essentially free of other proteins of the same source, e.g., the same species, or (iii) is a polynucleotide, lipid, carbohydrate or natural protein. is separated from at least about 50% of other substances associated with (iv) is operably associated (by covalent or non-covalent interactions) with a polypeptide that is not associated with it in nature, or (v) does not occur in nature.

A "variant" of a polypeptide (eg, an antigen binding molecule) includes an amino acid sequence in which one or more amino acid residues are inserted, deleted and/or substituted into an amino acid sequence relative to another polypeptide sequence. Variants include fusion proteins.

The term "identity" refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. "Percent identity" means the percentage of identical residues between amino acids or nucleotides in the molecules being compared, calculated based on the size of the smallest of the molecules being compared. For such calculations, the spacing of alignments (if any) is preferably processed by a particular mathematical model or computer program (ie, an "algorithm").

To calculate percent identity, the sequences being compared are generally aligned in a way that provides the greatest match between sequences. One example of a computer program that can be used to determine percent identity is the GCG program package that includes GAP (Devereux et al., Nucl. Acid Res., 1984, 12, 387; Genetics Computer Group, University of Wisconsin, Madison, Wis. .). The computer algorithm GAP is used to align two polypeptides or polynucleotides for which percent sequence identity is to be determined. Sequences are aligned for optimal matching of each amino acid or nucleotide ("matched range" determined by an algorithm). In certain embodiments, a standard comparison matrix (eg, Dayhoff et al., 1978, Atlas of Protein Sequence and Structure, 1978, 5:345-352 for the PAM 250 comparison matrix; Henikoff et al., Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 10915-10919 for the BLO-SUM 62 comparison matrix) is also used by the algorithm.

As used herein, the 20 common (eg, naturally occurring) amino acids and their abbreviations follow conventional usage. See Immunology A Synthesis (2nd Edition, Golub and Green, Eds., Sinauer Assoc., Sunderland, Mass. (1991)), which is incorporated herein by reference for any purpose. Non-natural amino acids such as stereoisomers of the 20 common amino acids (e.g., D-amino acids), alpha-, alpha-disubstituted amino acids, N-alkyl amino acids, lactic acid and other unconventional amino acids are also suitable for the polypeptides of the present invention. may be an ingredient. Examples of non-traditional amino acids include: 4-hydroxyproline, .gamma.-carboxy-glutamate, epsilon-N,N,N-trimethyllysine, e-N-acetyllysine, 0-phosphoserine, N-acetylserine. , N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, .sigma.-N-methylarginine, and other similar amino acids and imino acids (eg, 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino-terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.

Conservative amino acid substitutions may include non-natural amino acid residues that are typically incorporated by chemical peptide synthesis rather than synthesis in biological systems. This includes peptidomimetics and other amino acid moieties in inverted or inverted form. Naturally occurring residues can be classified according to common side chain properties.

a) Hydrophobicity: Norleucine, Met, Ala, Val, Leu, Ile;

b) neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

c) acidic: Asp, Glu;

d) basicity: His, Lys, Arg;

e) residues that influence chain orientation: Gly, Pro; and

f) Aromatic: Trp, Tyr, Phe.

For example, non-conservative substitutions may involve exchanging a member of one of these classes for a member of another class.

In altering an antigen-binding molecule, costimulatory or activation domain of an engineered T cell, according to certain embodiments, the hydropathic index of an amino acid may be considered. Each amino acid was assigned a hydrophobicity index based on its hydrophobicity and charge characteristics. It is isoleucine (+4.5); Valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); Tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); Lysine (-3.9); and arginine (−4.5). See, for example, Kyte et al., J. Mol. Biol., 1982, 157, 105-131. It is known that certain amino acids can be substituted with other amino acids having similar hydrophobicity indexes or scores and still retain similar biological activity. Substitution of like amino acids can be effected on the basis of hydrophilicity and is also understood in the art, especially when the resulting biologically functional protein or peptide is intended for use in immunological embodiments, as in the present case. Exemplary amino acid substitutions are shown in Table 5.

original residue Exemplary Substitution preferred substitution Ala Val, Leu, Ile Val Arg Lys, Gin, Asn Lys Asn Gln Gln Asp Glu Glu Cys Ser, Ala Ser Gln Asn Asn Glu Asp Asp Gly Pro, Ala Ala His Asn, Gln, Lys, Arg Arg Ile Leu, Val, Met, Ala, Phe, Norleucine Leu Leu Norleucine, Ile, Va, Met, Ala, Phe Ile Lys Arg, 1, 4 diamino-butyric acid, Gin, Asn Arg Met Leu, Phe, Ile Leu Phe Leu, Val, Ile, Ala, Tyr Leu Pro Ala Gly Ser Thr, Ala, Cys Thr Thr Ser Ser Trp Tyr, Phe Tyr Tyr Trp, Phe, Thr, Ser Phe Val Ile, Met, Leu, Phe, Ala, norleucine Leu

The term “derivative” refers to a molecule that contains chemical modifications other than insertions, deletions or substitutions of amino acids (or nucleic acids). In certain embodiments, derivatives include covalent modifications, including but not limited to chemical linkages with polymers, lipids, or other organic or inorganic moieties. In certain embodiments, a chemically modified antigen-binding molecule may have a greater half-life in circulation than a chemically unmodified antigen-binding molecule. In some embodiments, the derivative antigen-binding molecule is covalently modified to include one or more water soluble polymer attachments, including but not limited to polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol.

Peptide analogues are commonly used in the pharmaceutical industry as non-peptide drugs with similar properties to the template peptide. Non-peptide compounds of this type are referred to as "peptidomimetics" or "peptidomimetics". Fauchere, J. L., Adv. Drug Res., 1986, 15, 29; Veber, D. F. & Freidinger, R. M., Trends in Neuroscience, 1985, 8, 392-396; and Evans, B. E., et al., J. Med. Chem., 1987, 30, 1229-1239, incorporated herein by reference for any purpose.

The term “therapeutically effective amount” refers to the amount of CAR-B cells determined to produce a therapeutic response in a mammal. Such therapeutically effective amounts are readily ascertained by one skilled in the art.

The terms "patient" and "subject" are used interchangeably, and include both human and non-human animal subjects, as well as subjects with an officially diagnosed disorder, subjects without an officially recognized disorder, subjects undergoing treatment, and the onset of a disorder, etc. Include subjects at risk.

The terms “treat” and “treatment” include therapeutic treatment, prophylactic treatment, and applications that reduce the risk that a subject will develop a disorder or other risk factor. Treatment does not require complete cure of the disorder and includes embodiments that reduce symptoms or underlying risk factors. The term "prevention" does not require 100% elimination of the possibility of an event. Rather, it indicates that the probability of occurrence of an event is reduced in the presence of the compound or method.

Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, tissue culture and transformation (eg, electroporation, lipofection). Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may generally be performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, eg, Sambrook et al., Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), incorporated herein by reference for any purpose.

5. order

The following sequences will further illustrate the present invention:

CD28 transmembrane domain - mouse

(SEQ ID NO: 1)

TTCTGGGCCCTTGTGGTGGTTGCCGGAGTGCTGTTTTGCTATGGGCTCCTGGTTACCGTTGCCCTTTGTGTGATTTGGACC

CD28 transmembrane domain - mouse

(SEQ ID NO: 2)

FWALVVVAGVLFCYGLLVTVALCVIWT

CD28 transmembrane domain - human

(SEQ ID NO: 3)

TTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTG

CD28 transmembrane domain - human

(SEQ ID NO: 4)

FWVLVVVGGVLACYSLLVTVAFIIFWV

CD19 cytoplasmic domain - human

(SEQ ID NO: 5)

CAGCGGGCTTTAGTCTTGCGGCGTAAACGTAAAAGAATGACAGATCCAACTCGCAGGTTCTTCAAAGTGACCCCCCCACCTGGGTCCGGACCGCAGAACCAATATGGGAATGTCCTGTCTCTGCCTACGCCTACAAGTGGACTGGGTAGGGCTCAGAGGTGGGCTGCCGGTCTCGGCGGAACTGCGCCATCTTACGGAAATCCCTCCTCCGACGTTCAGGCAGACGGGGCCCTGGGGTCTCGATCCCCGCCTGGTGTTGGACCAGAAGAGGAAGAGGGCGAGGGCTACGAAGAGCCCGACTCCGAAGAGGACAGTGAGTTTTACGAGAACGACAGCAACCTGGGGCAGGATCAGCTGTCACAGGATGGCTCAGGATATGAAAACCCTGAGGACGAGCCTTTGGGGCCTGAAGATGAGGACTCCTTTTCTAATGCAGAGTCATATGAGAATGAGGACGAAGAATTGACTCAACCCGTGGCAAGAACAATGGATTTCCTCAGTCCACACGGGAGTGCATGGGACCCCTCCAGAGAGGCTACTAGCCTCGGTTCTCAAAGCTATGAGGACATGAGGGGTATTCTGTACGCAGCGCCTCAGTTGAGGTCCATCCGCGGCCAGCCAGGCCCAAACCATGAGGAAGATGCCGATTCTTACGAAAACATGGACAACCCCGATGGTCCTGACCCCGCATGGGGGGGCGGCGGGAGGATGGGCACCTGGTCTACTCGC

CD19 cytoplasmic domain - human

(SEQ ID NO: 6)

QRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYGGEDMRGILYAAPQLRSIRGQPGPGPTSMGEEDADWSAD

CD40 cytoplasmic domain - human

(SEQ ID NO: 7)

AAGAAGGTTGCAAAAAAACCTACTAATAAGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAG

CD40 cytoplasmic domain - human

(SEQ ID NO: 8)

KKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ

CD40 + CD79b cytoplasmic domain - human

(SEQ ID NO: 9)

AAGAAGGTTGCAAAAAAACCTACTAATAAGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAGGACAAGGACGATAGTAAAGCAGGGATGGAGGAGGACCATACATACGAGGGACTGGATATCGATCAGACAGCCACGTACGAAGACATTGTGACACTGAGAACTGGCGAGGTGAAGTGGTCAGTGGGAGAACATCCGGGGCAGGAA

CD40 + CD79b cytoplasmic domain - human

(SEQ ID NO: 10)

KKVAKKPTNK APHPKQEPQE INFPDDLPGS NTAAPVQETL HGCQPVTQED GKESRISVQE RQDKDDSKAG MEEDHTYEGL DIDQTATYED IVTLRTGEVK WSVGEHPGQE

CD40 + CD137 cytoplasmic domain - human

(SEQ ID NO: 11)

AAGAAGGTTGCAAAAAAACCTACTAATAAGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAGAAAAGAGGCCGAAAAAAGCTGCTGTACATCTTCAAACAACCCTTCATGCGACCTGTTCAGACGACACAGGAGGAGGACGGCTGCAGCTGTAGGTTTCCCGAAGAAGAGGAGGGAGGATGCGAACTT

CD40 + CD137 cytoplasmic domain - human

(SEQ ID NO: 12)

KKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

CD137 cytoplasmic domain - human

(SEQ ID NO: 13)

AAAAGAGGCCGAAAAAAGCTGCTGTACATCTTCAAACAACCCTTCATGCGACCTGTTCAGACGACACAGGAGGAGGACGGCTGCAGCTGTAGGTTTCCCGAAGAAGAGGAGGGAGGATGCGAACTT

CD137 cytoplasmic domain - human

(SEQ ID NO: 14)

KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

CD40 and Fc gamma receptor 2a cytoplasmic domain - human

(SEQ ID NO: 15)

AAGAAGGTTGCAAAAAAACCTACTAATAAGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAGCGCAAAAAACGTATAAGCGCAAACTCTACAGATCCAGTAAAAGCCGCGCAATTCGAGCCTCCCGGCCGCCAGATGATTGCAATACGGAAACGTCAACTGGAGGAAACTAATAATGACTATGAGACGGCCGACGGTGGATACATGACCCTTAATCCCCGCGCGCCAACCGACGATGATAAGAACATATATCTGACGCTCCCCCCTAACGATCACGTTAACAGTAATAAT

CD40 and Fc gamma receptor 2a cytoplasmic domain - human

(SEQ ID NO: 16)

KKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQRKKRISANSTDPVKAAQFEPPGRQMIAIRKRQLEETNNDYETADGGYMTLNPRAPTDDDKNIYLTLPPNDHVNSNN

Fc gamma receptor 2a cytoplasmic domain - human

(SEQ ID NO: 17)

CGCAAAAAACGTATAAGCGCAAACTCTACAGATCCAGTAAAAGCCGCGCAATTCGAGCCTCCCGGCCGCCAGATGATTGCAATACGGAAACGTCAACTGGAGGAAACTAATAATGACTATGAGACGGCCGACGGTGGATACATGACCCTTAATCCCCGCGCGCCAACCGACGATGATAAGAACATATATCTGACGCTCCCCCTAACGATCACGTTAACAGTAATAAT

Fc gamma receptor 2a cytoplasmic domain - human

(SEQ ID NO: 18)

RKKRISANSTDPVKAAQFEPPGRQMIAIRKRQLEETNNDYETADGGYMTLNPRAPTDDDKNIYLTLPPNDHVNSNN

Myd88 + CD40 cytoplasmic domain - human

(SEQ ID NO: 19)

ATGGCGGCGGGCGGGCCCGGCGCCGGAAGCGCCGCGCCAGTCTCATCTACGTCCAGTCTGCCACTGGCTGCCCTGAACATGAGAGTGAGACGCCGTTTATCCCTCTTCCTGAATGTGCGGACCCAGGTCGCCGCTGATTGGACCGCCCTGGCCGAAGAGATGGACTTTGAATACTTGGAAATCAGACAGCTGGAAACACAGGCAGACCCAACCGGGAGACTGCTTGACGCCTGGCAGGGACGCCCAGGGGCAAGTGTTGGTCGGTTACTGGAGCTTTTAACTAAGTTGGGCCGCGATGACGTGCTGTTGGAGTTAGGACCCAGTATCGAGGAGGATTGTCAGAAATACATCTTGAAACAGCAGCAGGAGGAGGCGGAAAAGCCCCTGCAGGTGGCGGCCGTTGACAGCAGTGTACCCAGAACAGCTGAGCTGGCCGGCATCACAACCCTGGATGATCCCCTGGGCCACATGCCTGAGAGGTTCGACGCTTTCATAAAGAAGGTTGCAAAAAAACCTACTAATAAGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAG

Myd88 + CD40 cytoplasmic domain - human

(SEQ ID NO: 20)

MAAGGPGAGSAAPVSSTSSLPLAALNMRVRRRLSLFLNVRTQVAADWTALAEEMDFEYLEIRQLETQADPTGRLLDAWQGRPGASVGRLLELLTKLGRDDVLLELGPSIEEDCQKYILKQQQEEAEKPLQVAAVDSSVPRTAELAGITTLDDPLGHMPERFDAFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHHGCKESVQEDG

Myd88 cytoplasmic domain - human

(SEQ ID NO: 21)

ATGGCGGCGGGCGGGCCCGGCGCCGGAAGCGCCGCGCCAGTCTCATCTACGTCCAGTCTGCCACTGGCTGCCCTGAACATGAGAGTGAGACGCCGTTTATCCCTCTTCCTGAATGTGCGGACCCAGGTCGCCGCTGATTGGACCGCCCTGGCCGAAGAGATGGACTTTGAATACTTGGAAATCAGACAGCTGGAAACACAGGCAGACCCAACCGGGAGACTGCTTGACGCCTGGCAGGGACGCCCAGGGGCAAGTGTTGGTCGGTTACTGGAGCTTTTAACTAAGTTGGGCCGCGATGACGTGCTGTTGGAGTTAGGACCCAGTATCGAGGAGGATTGTCAGAAATACATCTTGAAACAGCAGCAGGAGGAGGCGGAAAAGCCCCTGCAGGTGGCGGCCGTTGACAGCAGTGTACCCAGAACAGCTGAGCTGGCCGGCATCACAACCCTGGATGATCCCCTGGGCCACATGCCTGAGAGGTTCGACGCTTTCATA

Myd88 cytoplasmic domain - human

(SEQ ID NO: 22)

MAAGGPGAGSAAPVSSTSSLPLAALNMRVRRRLSLFLNVRTQVAADWTALAEEMDFEYLEIRQLETQADPTGRLLDAWQGRPGASVGRLLELLTKLGRDDVLLELGPSIEEDCQKYILKQQQEEAEKPLQVAAVDSSVPRTAELAGITTLDDPLGHMPERFDAFI

CD79a cytoplasmic domain - human

(SEQ ID NO: 23)

AGGAAACGATGGCAGAACGAGAAGCTCGGGTTGGATGCCGGGGATGAATATGAAGATGAAAACCTTTATGAAGGCCTGAACCTGGACGACTGCTCCATGTATGAGGACATCTCCCGGGGCCTCCAGGGCACCTACCAGGATGTGGGCAGCCTCAACATAGGAGATGTCCAGCTGGAGAAGCCG

CD79a cytoplasmic domain - human

(SEQ ID NO: 24)

RKRWQNEKLGLDAGDEYEDENLYEGLNLDDCSMYEDISRGLQGTYQDVGSLNIGDVQLEKP

CD79b cytoplasmic domain - human

(SEQ ID NO: 25)

CTGGACAAGGATGACAGCAAGGCTGGCATGGAGGAAGATCACACCTACGAGGGCCTGGACATTGACCAGACAGCCACCTATGAGGACATAGTGACGCTGCGGACAGGGGAAGTGAAGTGGTCTGTAGGTGAGCACCCAGGCCAGGAG

CD79b cytoplasmic domain - human

(SEQ ID NO: 26)

LDKDDSKAGMEEDHTYEGLDIDQTATYEDIVTLRTGEVKWSVGEHPGQE

CD8 hinge domain - human

(SEQ ID NO: 27)

TTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGAC

CD8 hinge domain - human

(SEQ ID NO: 28)

FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD

Spacer with 3X strep II tag

(SEQ ID NO: 29)

GGCGCTGGTAGTGGCGGTAACTGGAGCCACCCTCAATTTGAGAAGGGCGGGTCAGGCGGATCAGGTGGTAGTGGTGGGTCCAACTGGAGCCATCCGCAATTTGAAAAGGGCGGAAGCGGCGGTTCCGGCGGTTCAGGCGGTAGCAACTGGTCACATCCGCAATTTGAGAAAGGCGGGTCAGGCGGCGGG

Spacer with 3X strep II tag

(SEQ ID NO: 30)

GAGSGGNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGG

Human IgG1 Fc (transmembrane)

(SEQ ID NO: 31)

CCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGAGCTGCAACTGGAGGAGAGCTGTGCGGAGGCGCAGGACGGGGAGCTGGACGGGCTGTGGACGACCATCACCATCTTCATCACACTCTTCCTGTTAAGCGTGTGCTACAGTGCCACCGTCACCTTCTTCAAGGTGAAGTGGATCTTCTCCTCGGTGGTGGACCTGAAGCAGACCATCATCCCCGACTACAGGAACATGATCGGACAGGGGGCCTGA

Human IgG1 Fc (transmembrane)

(SEQ ID NO: 32)

PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFKVKWIFSSVVDLKQTIIPDYRNMIGQGA

anti-huPSMA scFv

(SEQ ID NO: 33)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAA

anti-huPSMA scFv

(SEQ ID NO: 34)

EVQLVQSGAE VKKPGASVKV SCKTSGYTFT EYTIHWVRQA PGQSLEWMGN INPNNGGTTY NQKFQGRVTI TVDKSTSTAY MELSSLRSED TAVYYCAAGW NFDYWGQGTL VTVSSGKPGS GKPGSGKPGS GKPGSDIVMT QSPDSLAVSL GERATLSCRA SQDVGTAVDW YQQKPDQSPK LLIYWASTRH TGVPDRFTGS GSGTDFTLTI SSLQAEDVAV YFCQQYNSYP LTFGAGTKVE IK

Anti-sarcoglycan scFv

(SEQ ID NO: 35)

GAAGTCCAATTGGTTGAAAGCGGTGGTGGACTCGTCAAACCTGGCGGTAGCCTTAAACTTTCATGTGCCGCAAGCGGCTTCACGTTTAGTAACTATGCTATGAGTTGGGTCCGCCAAAGTCCAGAAAAGCGCCTCGAATGGGTGGCGGAGATCTCTGGAGGAGGAACATATACATATTATCCAGACACCATGACCGGTAGGTTTACAATCTCAAGAGACAACGCTAAGAACACCCTGTACCTGGAAATGTCAAGCCTGAGATCAGAAGATACGGCCATGTATTATTGTACGCGCCTACTCGACTATTGGGGTCAAGGAACTTCCGTGACGGTGTCAAGCGGAGGAGGTGGGAGCGGAGGAGGCGGAAGTGGCGGTGGTGGCTCTGGTGGCGGTGGAAGTGATATAGTGATGACGCAAGCTGCCTTTTCAAACCCTGTTACTTTGGGGACTAGCGCATCAATCTCCTGTAGGTCCAGCAAATCTTTGCTGCACAGTAATGGAATCACCTATCTTTTCTGGTATTTGCAAAAGCCTGGGCAGAGCCCGCAACTGCTGATCTATCAAATGTCAAATCTTGCTTCCGGAGTTCCAGACCGCTTCTCAAGTTCCGGGTCCGGCACTGATTTTACCTTGAGAATTTCTAGGGTCGAAGCTGAAGACGTCGGTGTCTATTATTGCGCGCAAAACCTTGAGCTTCCATACACCTTCGGGGGGGGCACAAAACTTGAGATCAAG

Anti-sarcoglycan scFv

(SEQ ID NO: 36)

EVQLVESGGGLVKPGGSLKLSCAASGFTFSNYAMSWVRQSPEKRLEWVAEISGGGTYTYYPDTMTGRFTISRDNAKNTLYLEMSSLRSEDTAMYYCTRLLDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQAAFSNPVTLGTSASISCRSSKSLLTFHSNGITYLFWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSYGTDFTLGRISRVEAPY

anti-hu GPC3 scFv

(SEQ ID NO: 37)

CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCGCTGCA

anti-hu GPC3 scFv

(SEQ ID NO: 38)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSAAA

pWF-82

(SEQ ID NO: 39)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGCAGCGGGCTTTAGTCTTGCGGCGTAAAC GTAAAAGAATGACAGATCCAACTCGCAGGTTCTTCAAAGTGACCCCCCCACCTGGGTCCGGACCGCAGAACCAATATGGGAATGTCCTGTCTCTGCCTACGCCTACAAGTGGACTGGGTAGGGCTCAGAGGTGGGCTGCCGGTCTCGGCGGAACTGCGCCATCTTACGGAAATCCCTCCTCCGACGTTCAGGCAGACGGGGCCCTGGGGTCTCGATCCCCGCCTGGTGTTGGACCAGAAGAGGAAGAGGGCGAGGGCTACGAAGAGCCCGACTCCGAAGAGGACAGTGAGTTTTACGAGAACGACAGCAACCTGGGGCAGGATCAGCTGTCACAGGATGGCTCAGGATATGAAAACCCTGAGGACGAGCCTTTGGGGCCTGAAGATGAGGACTCCTTTTCTAATGCAGAGTCATATGAGAATGAGGACGAAGAATTGACTCAACCCGTGGCAAGAACAATGGATTTCCTCAGTCCACACGGGAGTGCATGGGACCCCTCCAGAGAGGCTACTAGCCTCGGTTCTCAAAGCTATGAGGACATGAGGGGTATTCTGTACGCAGCGCCTCAGTTGAGGTCCATCCGCGGCCAGCCAGGCCCAAACCATGAGGAAGATGCCGATTCTTACGAAAACATGGACAACCCCGATGGTCCTGACCCCGCATGGGGGGGCGGCGGGAGGATGGGCACCTGGTCTACTCGCTAG

pWF-82

(SEQ ID NO: 40)

EVQLVQSGAE VKKPGASVKV SCKTSGYTFT EYTIHWVRQA PGQSLEWMGN INPNNGGTTY NQKFQGRVTI TVDKSTSTAY MELSSLRSED TAVYYCAAGW NFDYWGQGTL VTVSSGKPGS GKPGSGKPGS GKPGSDIVMT QSPDSLAVSL GERATLSCRA SQDVGTAVDW YQQKPDQSPK LLIYWASTRH TGVPDRFTGS GSGTDFTLTI SSLQAEDVAV YFCQQYNSYP LTFGAGTKVE IKFVPVFLPA KPTTTPAPRP PTPAPTIASQ PLSLRPEACR PAAGGAVHTR GLDFACDFWV LVVVGGVLAC YSLLVTVAFI IFWVQRALVL RRKRKRMTDP TRRFFKVTPP PGSGPQNQYG NVLSLPTPTS GLGRAQRWAA GLGGTAPSYG NPSSDVQADG ALGSRSPPGV GPEEEEGEGY EEPDSEEDSE FYENDSNLGQ DQLSQDGSGY ENPEDEPLGP EDEDSFSNAE SYENEDEELT QPVARTMDFL SPHGSAWDPS REATSLGSQS YEDMRGILYA APQLRSIRGQ PGPNHEEDAD SYENMDNPDG PDPAWGGGGR MGTWSTR-

pWF-83

(SEQ ID NO: 41)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGCTGGACAAGGATGACAGCAAGGCTGGCA TGGAGGAAGATCACACCTACGAGGGCCTGGACATTGACCAGACAGCCACCTATGAGGACATAGTGACGCTGCGGACAGGGGAAGTGAAGTGGTCTGTAGGTGAGCACCCAGGCCAGGAGTGA

pWF-83

(SEQ ID NO: 42)

EVQLVQSGAE VKKPGASVKV SCKTSGYTFT EYTIHWVRQA PGQSLEWMGN INPNNGGTTY NQKFQGRVTI TVDKSTSTAY MELSSLRSED TAVYYCAAGW NFDYWGQGTL VTVSSGKPGS GKPGSGKPGS GKPGSDIVMT QSPDSLAVSL GERATLSCRA SQDVGTAVDW YQQKPDQSPK LLIYWASTRH TGVPDRFTGS GSGTDFTLTI SSLQAEDVAV YFCQQYNSYP LTFGAGTKVE IKFVPVFLPA KPTTTPAPRP PTPAPTIASQ PLSLRPEACR PAAGGAVHTR GLDFACDFWV LVVVGGVLAC YSLLVTVAFI IFWVLDKDDS KAGMEEDHTY EGLDIDQTAT YEDIVTLRTG EVKWSVGEHP GQE-

pWF-84:

(SEQ ID NO: 43)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGAAGAAGGTTGCAAAAAAACCTACTAATA AGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAGGACAAGGACGATAGTAAAGCAGGGATGGAGGAGGACCATACATACGAGGGACTGGATATCGATCAGACAGCCACGTACGAAGACATTGTGACACTGAGAACTGGCGAGGTGAAGTGGTCAGTGGGAGAACATCCGGGGCAGGAATAA

pWF-84:

(SEQ ID NO: 44)

EVQLVQSGAE VKKPGASVKV SCKTSGYTFT EYTIHWVRQA PGQSLEWMGN INPNNGGTTY NQKFQGRVTI TVDKSTSTAY MELSSLRSED TAVYYCAAGW NFDYWGQGTL VTVSSGKPGS GKPGSGKPGS GKPGSDIVMT QSPDSLAVSL GERATLSCRA SQDVGTAVDW YQQKPDQSPK LLIYWASTRH TGVPDRFTGS GSGTDFTLTI SSLQAEDVAV YFCQQYNSYP LTFGAGTKVE IKFVPVFLPA KPTTTPAPRP PTPAPTIASQ PLSLRPEACR PAAGGAVHTR GLDFACDFWV LVVVGGVLAC YSLLVTVAFI IFWVKKVAKK PTNKAPHPKQ EPQEINFPDD LPGSNTAAPV QETLHGCQPV TQEDGKESRI SVQERQDKDD SKAGMEEDHT YEGLDIDQTA TYEDIVTLRT GEVKWSVGEH PGQE-

pWF-85:

(SEQ ID NO: 45)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGAAGAAGGTTGCAAAAAAACCTACTAATA AGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAGAAAAGAGGCCGAAAAAAGCTGCTGTACATCTTCAAACAACCCTTCATGCGACCTGGGTTCAGACGACAGAGAGGATGGACGGTAAGTTGCAGGAGCAGGACCGAGAGAGGATAGTTGCAGGATCGAACT

pWF-85:

(SEQ ID NO: 46)

EVQLVQSGAE VKKPGASVKV SCKTSGYTFT EYTIHWVRQA PGQSLEWMGN INPNNGGTTY NQKFQGRVTI TVDKSTSTAY MELSSLRSED TAVYYCAAGW NFDYWGQGTL VTVSSGKPGS GKPGSGKPGS GKPGSDIVMT QSPDSLAVSL GERATLSCRA SQDVGTAVDW YQQKPDQSPK LLIYWASTRH TGVPDRFTGS GSGTDFTLTI SSLQAEDVAV YFCQQYNSYP LTFGAGTKVE IKFVPVFLPA KPTTTPAPRP PTPAPTIASQ PLSLRPEACR PAAGGAVHTR GLDFACDFWV

LVVVGGVLAC YSLLVTVAFI IFWVKKVAKK PTNKAPHPKQ EPQEINFPDD LPGSNTAAPV QETLHGCQPV TQEDGKESRI SVQERQKRGR KKLLYIFKQP FMRPVQTTQE EDGCSCRFPE EEEGGCEL-

pWF-86

(SEQ ID NO: 150)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGAAGAAGGTTGCAAAAAAACCTACTAATA AGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAGCGCAAAAAACGTATAAGCGCAAACTCTACAGATCCAGTAAAAGCCGCGCAATTCGAGCCTCCCGGCCGCCAGATGATTGCAATACGGAAACGTCAACTGGAGGAAACTAATAATGACTATGAGACGGCCGACGGTGGATACATGACCCTTAATCCCCGCGCGCCAACCGACGATGATAAGAACATATATCTGACGCTCCCCCCTAACGATCACGTTAACAGTAATAATTAA

pWF-86:

(SEQ ID NO: 47)

EVQLVQSGAE VKKPGASVKV SCKTSGYTFT EYTIHWVRQA PGQSLEWMGN INPNNGGTTY NQKFQGRVTI TVDKSTSTAY MELSSLRSED TAVYYCAAGW NFDYWGQGTL VTVSSGKPGS GKPGSGKPGS GKPGSDIVMT QSPDSLAVSL GERATLSCRA SQDVGTAVDW YQQKPDQSPK LLIYWASTRH TGVPDRFTGS GSGTDFTLTI SSLQAEDVAV YFCQQYNSYP LTFGAGTKVE IKFVPVFLPA KPTTTPAPRP PTPAPTIASQ PLSLRPEACR PAAGGAVHTR GLDFACDFWV LVVVGGVLAC YSLLVTVAFI IFWVKKVAKK PTNKAPHPKQ EPQEINFPDD LPGSNTAAPV QETLHGCQPV TQEDGKESRI SVQERQRKKR ISANSTDPVK AAQFEPPGRQ MIAIRKRQLE ETNNDYETAD GGYMTLNPRA PTDDDKNIYL TLPPNDHVNS NN-

pWF-87:

(SEQ ID NO: 48)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGATGGCGGCGGGCGGGCCCGGCGCCGGAA GCGCCGCGCCAGTCTCATCTACGTCCAGTCTGCCACTGGCTGCCCTGAACATGAGAGTGAGACGCCGTTTATCCCTCTTCCTGAATGTGCGGACCCAGGTCGCCGCTGATTGGACCGCCCTGGCCGAAGAGATGGACTTTGAATACTTGGAAATCAGACAGCTGGAAACACAGGCAGACCCAACCGGGAGACTGCTTGACGCCTGGCAGGGACGCCCAGGGGCAAGTGTTGGTCGGTTACTGGAGCTTTTAACTAAGTTGGGCCGCGATGACGTGCTGTTGGAGTTAGGACCCAGTATCGAGGAGGATTGTCAGAAATACATCTTGAAACAGCAGCAGGAGGAGGCGGAAAAGCCCCTGCAGGTGGCGGCCGTTGACAGCAGTGTACCCAGAACAGCTGAGCTGGCCGGCATCACAACCCTGGATGATCCCCTGGGCCACATGCCTGAGAGGTTCGACGCTTTCATAAAGAAGGTTGCAAAAAAACCTACTAATAAGGCTCCCCATCCTAAGCAAGAGCCCCAAGAAATTAACTTTCCCGATGATCTTCCGGGTTCTAACACGGCAGCCCCGGTGCAGGAGACCCTGCATGGTTGTCAACCCGTCACTCAGGAGGACGGGAAAGAGTCTCGTATCTCCGTCCAGGAGAGACAGTGA

pWF-87:

(SEQ ID NO: 49)

EVQLVQSGAEVKKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWMGNINPNNGGTTYNQKFQGRVTITVDKSTSTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSDIVMTQSPDSLAVSLGERATLSCRASQDVGTAVDWYQQKPDQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQYNSYPLTFGAGTKVEIKFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVMAAGGPGAGSAAPVSSTSSLPLAALNMRVRRRLSLFLNVRTQVAADWTALAEEMDFEYLEIRQLETQADPTGRLLDAWQGRPGASVGRLLELLTKLGRDDVLLELGPSIEEDCQKYILKQQQEEAEKPLQVAAVDSSVPRTAELAGITTLDDPLGHMPERFDAFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ-

pWF-88:

(SEQ ID NO: 50)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGAGGAAACGATGGCAGAACGAGAAGCTCG GGTTGGATGCCGGGGATGAATATGAAGATGAAAACCTTTATGAAGGCCTGAACCTGGACGACTGCTCCATGTATGAGGACATCTCCCGGGGCCTCCAGGGCACCTACCAGGATGTGGGCAGCCTCAACATAGGAGATGTCCAGCTGGAGAAGCCGTGA

pWF-88:

(SEQ ID NO: 51)

EVQLVQSGAEVKKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWMGNINPNNGGTTYNQKFQGRVTITVDKSTSTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSDIVMTQSPDSLAVSLGERATLSCRASQDVGTAVDWYQQKPDQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQYNSYPLTFGAGTKVEIKFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVRKRWQNEKLGLDAGDEYEDENLYEGLNLDDCSMYEDISRGLQGTYQDVGSLNIGDVQLEKP-

pWF-89:

(SEQ ID NO: 52)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGCTGGACAAGGATGACAGCAAGGCTGGCA TGGAGGAAGATCACACCTACGAGGGCCTGGACATTGACCAGACAGCCACCTATGAGGACATAGTGACGCTGCGGACAGGGGAAGTGAAGTGGTCTGTAGGTGAGCACCCAGGCCAGGAGTGA

pWF-89:

(SEQ ID NO: 53)

EVQLVQSGAEVKKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWMGNINPNNGGTTYNQKFQGRVTITVDKSTSTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSDIVMTQSPDSLAVSLGERATLSCRASQDVGTAVDWYQQKPDQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQYNSYPLTFGAGTKVEIKFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVLDKDDSKAGMEEDHTYEGLDIDQTATYEDIVTLRTGEVKWSVGEHPGQE

pWF-391:

(SEQ ID NO: 54)

GAGGTTCAACTTGTTCAATCTGGGGCAGAAGTGAAGAAGCCCGGGGCATCTGTGAAAGTATCATGCAAAACATCCGGCTATACGTTTACCGAATACACCATTCACTGGGTCAGACAGGCTCCCGGTCAAAGCCTCGAATGGATGGGAAATATTAACCCTAACAATGGCGGAACCACATATAATCAGAAATTCCAAGGCCGAGTGACGATAACTGTCGATAAGAGTACGTCCACAGCTTACATGGAACTCAGCTCTTTGAGATCCGAAGACACTGCAGTTTATTATTGTGCAGCTGGATGGAACTTCGACTATTGGGGACAAGGGACTCTTGTTACGGTGTCCAGTGGCAAACCAGGTAGTGGTAAACCCGGAAGCGGCAAGCCCGGGAGCGGTAAACCTGGTAGCGACATCGTCATGACTCAAAGCCCTGACTCACTCGCCGTGAGCCTGGGAGAGCGTGCAACGCTATCTTGTCGGGCCTCTCAGGATGTCGGAACTGCTGTAGACTGGTATCAACAGAAACCTGACCAATCACCAAAACTCCTGATTTATTGGGCCTCAACACGTCACACAGGAGTGCCAGATAGGTTCACAGGTAGTGGCAGTGGAACTGATTTTACTTTGACAATTAGCAGCCTGCAAGCCGAAGATGTAGCCGTTTACTTCTGTCAACAATATAACTCATACCCACTAACGTTCGGTGCCGGGACGAAGGTAGAGATTAAAGGCGCTGGTAGTGGCGGTAACTGGAGCCACCCTCAATTTGAGAAGGGCGGGTCAGGCGGATCAGGTGGTAGTGGTGGGTCCAACTGGAGCCATCCGCAATTTGAAAAGGGCGGAAGCGGCGGTTCCGGCGGTTCAGGCGGTAGCAACTGGTCACATCCGCAATTTGAGAAAGGCGGGTCAGGCGGCGGGTTTTGGGCTCTCGTGGTGGTGGCTGGAGTGCTTTTCTGCTATGGCCTGCTGGTAACCGTGGCCCTTTGTGTAATCTGGACCGATA AAGACGATGGAAAAGCCGGGATGGAAGAAGACCATACCTACGAGGGGCTCAATATTGATCAAACCGCCACGTATGAAGACATTGTAACACTGCGCACAGGTGAGGTCAATGGTCCGTCGGTGAACACCCAGGACAAGAATAA

pWF-391:

(SEQ ID NO: 55)

EVQLVQSGAEVKKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWMGNINPNNGGTTYNQKFQGRVTITVDKSTSTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSDIVMTQSPDSLAVSLGERATLSCRASQDVGTAVDWYQQKPDQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQYNSYPLTFGAGTKVEIKGAGSGGNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGGFWALVVVAGVLFCYGLLVTVALCVIWTDKDDGKAGMEEDHTYEGLNIDQTATYEDIVTLRTGEVKWSVGEHPGQE

pWF-394:

(SEQ ID NO: 56)

GAAGTCCAATTGGTTGAAAGCGGTGGTGGACTCGTCAAACCTGGCGGTAGCCTTAAACTTTCATGTGCCGCAAGCGGCTTCACGTTTAGTAACTATGCTATGAGTTGGGTCCGCCAAAGTCCAGAAAAGCGCCTCGAATGGGTGGCGGAGATCTCTGGAGGAGGAACATATACATATTATCCAGACACCATGACCGGTAGGTTTACAATCTCAAGAGACAACGCTAAGAACACCCTGTACCTGGAAATGTCAAGCCTGAGATCAGAAGATACGGCCATGTATTATTGTACGCGCCTACTCGACTATTGGGGTCAAGGAACTTCCGTGACGGTGTCAAGCGGAGGAGGTGGGAGCGGAGGAGGCGGAAGTGGCGGTGGTGGCTCTGGTGGCGGTGGAAGTGATATAGTGATGACGCAAGCTGCCTTTTCAAACCCTGTTACTTTGGGGACTAGCGCATCAATCTCCTGTAGGTCCAGCAAATCTTTGCTGCACAGTAATGGAATCACCTATCTTTTCTGGTATTTGCAAAAGCCTGGGCAGAGCCCGCAACTGCTGATCTATCAAATGTCAAATCTTGCTTCCGGAGTTCCAGACCGCTTCTCAAGTTCCGGGTCCGGCACTGATTTTACCTTGAGAATTTCTAGGGTCGAAGCTGAAGACGTCGGTGTCTATTATTGCGCGCAAAACCTTGAGCTTCCATACACCTTCGGGGGGGGCACAAAACTTGAGATCAAGGGCGCTGGGAGCGGCGGGAATTGGAGTCATCCACAATTCGAAAAGGGTGGGTCCGGCGGCAGTGGTGGAAGCGGCGGGAGTAACTGGTCACATCCCCAGTTTGAGAAAGGCGGTAGTGGTGGCAGCGGCGGTAGTGGTGGCAGTAATTGGAGCCATCCCCAATTCGAAAAGGGCGGTTCCGGCGGCGGATTTTGGGCTCTTGTTGTGGTGGCCGGAGTATTGTTTTGCTATGGCCTGCTCGTTACAGTGGCATTGTGCGTAATTT GGACTGATAAAGACGACGGCAAAGCCGGGATGGAAGAAGATCACACCTATGAGGGGCTTAATATAGATCAAACAGCCACATATGAAGATATTGTGACTCTAAGGACTGGAGAGGTTAAATGGAGTGTGGGTGAGCATCCAGGACAAGAATAA

pWF-394:

(SEQ ID NO: 57)

EVQLVESGGGLVKPGGSLKLSCAASGFTFSNYAMSWVRQSPEKRLEWVAEISGGGTYTYYPDTMTGRFTISRDNAKNTLYLEMSSLRSEDTAMYYCTRLLDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLFWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLELPYTFGGGTKLEIKGAGSGGNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGGFWALVVVAGVLFCYGLLVTVALCVIWTDKDDGKAGMEEDHTYEGLNIDQTATYEDIVTLRTGEVKWSVGEHPGQE

pWF-396:

(SEQ ID NO: 58)

CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCGCTGCATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTT GGGTGAGGAAACGATGGCAGAACGAGAAGCTCGGGTTGGATGCCGGGGATGAATATGAAGATGAAAACCTTTATGAAGGCCTGAACCTGGACGACTGCTCCATGTATGAGGACATCTCCCGGGGCCTCCAGGGCACCTACCAGGATGTGGGCAGCCTCAACATAGGAGATGTCCAGCTGGAGAAGCCGTGA

pWF-396:

(SEQ ID NO: 59)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVRKRWQNEKLGLDAGDEYEDENLYEGLNLDDCSMYEDISRGLQGTYQDVGSLNIGDVQLEKP

pWF-397:

(SEQ ID NO: 60)

CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCGCTGCATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAGTGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTT GGGTGCTGGACAAGGATGACAGCAAGGCTGGCATGGAGGAAGATCACACCTACGAGGGCCTGGACATTGACCAGACAGCCACCTATGAGGACATAGTGACGCTGCGGACAGGGGAAGTGAAGTGGTCTGTAGGTGAGCACCCAGGCCAGGAGTGA

pWF-397:

(SEQ ID NO: 61)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVLDKDDSKAGMEEDHTYEGLDIDQTATYEDIVTLRTGEVKWSVGEHPGQE

pWF-460:

(SEQ ID NO: 62)

CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCT ACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGAGCTGCAACTGGAGGAGAGCTGTGCGGAGGCGCAGGACGGGGAGCTGGACGGGCTGTGGACGACCATCACCATCTTCATCACACTCTTCCTGTTAAGCGTGTGCTACAGTGCCACCGTCACCTTCTTCAAGGTGAAGTGGATCTTCTCCTCGGTGGTGGACCTGAAGCAGACCATCATCCCCGACTACAGGAACATGATCGGACAGGGGGCCTGA

pWF-460:

(SEQ ID NO: 63)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFKVKWIFSSVVDLKQTIIPDYRNMIGQGA

pWF-428:

(SEQ ID NO: 64)

CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA

pWF-428:

(SEQ ID NO: 65)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHREKSYSTVCQVTHEGSTVCTV

pWF-429:

(SEQ ID NO: 66)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCG AAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGAGCTGCAACTGGAGGAGAGCTGTGCGGAGGCGCAGGACGGGGAGCTGGACGGGCTGTGGACGACCATCACCATCTTCATCACACTCTTCCTGTTAAGCGTGTGCTACAGTGCCACCGTCACCTTCTTCAAGGTGAAGTGGATCTTCTCCTCGGTGGTGGACCTGAAGCAGACCATCATCCCCGACTACAGGAACATGATCGGACAGGGGGCCTGA

pWF-429:

(SEQ ID NO: 67)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFKVKWIFSSVVDLKQTIIPDYRNMIGQGA-

mu-CXCL13

(SEQ ID NO: 68)

ATGAGACTTTCAACAGCAACACTCCTCCTGTTGCTGGCTTCATGTCTGAGCCCTGGTCATGGTATTTTGGAGGCCCACTATACAAATCTCAAATGTCGGTGTTCAGGCGTAATATCCACCGTAGTCGGCCTGAACATTATCGATAGGATTCAGGTTACACCCCCCGGGAACGGATGTCCTAAGACCGAGGTGGTGATTTGGACCAAGATGAAGAAGGTCATTTGTGTGAACCCACGGGCTAAATGGCTGCAGCGTCTTTTGCGACACGTGCAGTCCAAGAGCTTGTCCAGCACACCTCAGGCCCCAGTTAGCAAGCGACGTGCAGCC

mu-CXCL13

(SEQ ID NO: 69)

MRLSTATLLLLLASCLSPGHGILEAHYTNLKCRCSGVISTVVGLNIIDRIQVTPPGNGCPKTEVVIWTKMKKVICVNPRAKWLQRLLRHVQSKSLSSTPQ APVSKRRAA

mu-FLT3LG

(SEQ ID NO: 70)

ATGACAGTGCTGGCCCCCGCGTGGTCTCCCAATAGCTCACTCCTCCTCTTGCTGCTACTGCTCAGCCCATGCCTCAGGGGCACCCCCGATTGTTACTTCAGCCACAGCCCAATCTCCTCCAACTTCAAAGTGAAATTTAGGGAACTGACCGACCACCTGCTGAAAGATTATCCTGTGACTGTGGCAGTGAACCTGCAAGACGAAAAGCATTGTAAGGCGCTATGGAGCCTCTTTCTTGCCCAACGATGGATTGAGCAACTCAAAACTGTAGCCGGAAGCAAAATGCAGACGCTACTGGAGGACGTGAATACTGAGATTCACTTCGTTACCAGTTGTACTTTCCAGCCACTGCCAGAGTGTCTCAGGTTTGTGCAGACTAATATCAGCCACCTGCTGAAGGATACTTGCACCCAGCTCCTGGCTCTCAAGCCTTGTATAGGCAAGGCTTGTCAAAATTTTAGCAGGTGTCTCGAAGTCCAGTGCCAGCCAGATTCATCCACACTGCTGCCGCCCCGAAGCCCTATCGCACTCGAAGCGACAGAGTTGCCAGAGCCTCGTCCCAGACAGCTTCTGCTGCTGCTACTTCTGCTGCTGCCGCTAACTCTGGTGCTACTTGCTGCCGCCTGGGGCCTCAGATGGCAACGCGCCAGACGCCGAGGCGAACTCCACCCTGGGGTGCCACTGCCATCCCACCCA

mu-FLT3LG

(SEQ ID NO: 71)

MTVLAPAWSPNSSLLLLLLLLSPCLRGTPDCYFSHSPISSNFKVKFRELTDHLLKDYPVTVAVNLQDEKHCKALWSLFLAQRWIEQLKTVAGSKMQTLLEDVNTEIHFVTSCTFQPLPECLRFVQTNISHLLKDTCTQLLALKPCIGKACQNFSRCLEVQCQPDSSTLLPPRSPIALEATELPEPRPRQLLLLLLLLLLLPLTLVLLAAHPLRWQRARRRGEL

mu XCL1

(SEQ ID NO: 72)

ATGCGACTCTTGTTGTTGACTTTTCTCGGAGTGTGCTGCCTGACACCCTGGGTCGTAGAGGGAGTTGGCACTGAAGTACTAGAAGAGTCCTCCTGCGTTAACCTGCAGACACAGCGGCTCCCAGTCCAGAAAATTAAGACCTACATTATATGGGAAGGAGCAATGCGAGCGGTGATTTTTGTGACCAAGAGGGGTCTCAAGATTTGCGCGGACCCTGAGGCCAAGTGGGTCAAAGCAGCTATTAAGACAGTAGACGGAAGAGCCTCCACCAGGAAGAATATGGCAGAAACTGTACCGACCGGTGCGCAGCGGTCAACATCTACCGCAATCACACTCACCGGC

mu XCL1

(SEQ ID NO: 73)

MRLLLLTFLGVCCLTPWVVEGVGTEVLEESSCVNLQTQRLPVQKIKTYIIWEGAMRAVIFVTKRGLKICADPEAKWVKAAIKTVDGRASTRKNMAETVPTGAQRSTSTAI TLTG

mu Tim4(ECD)-muIgG2a Fc

(SEQ ID NO: 74)

ATGAGCAAGGGCCTTCTCCTGCTGTGGCTAGTAACTGAATTGTGGTGGTTGTACCTGACACCTGCCGCTAGTGAGGACACCATCATTGGTTTCCTTGGGCAGCCCGTCACCCTCCCTTGCCATTACCTAAGCTGGAGCCAGTCACGGAACTCTATGTGCTGGGGAAAGGGGTCATGCCCTAATTCCAAGTGCAACGCCGAGCTGTTGCGCACGGACGGCACCAGAATAATCTCAAGAAAGTCCACCAAGTATACGCTGCTCGGCAAGGTGCAATTCGGTGAAGTGAGCTTGACCATAAGTAACACCAACCGCGGTGACTCCGGAGTTTATTGTTGCAGGATCGAAGTGCCAGGCTGGTTTAACGACGTGAAGAAAAACGTGCGGCTGGAACTGAGGAGGGCAACTACGACCAAGAAACCAACAACCACGACGAGACCTACCACCACTCCTTACGTGACAACCACGACACCGGAGCTGTTGCCAACTACCGTCATGACAACATCTGTGTTGCCAACTACCACCCCCCCCCAAACGCTCGCGACAACTGCCTTTTCCACAGCCGTTACCACATGTCCTTCCACCACCCCAGGCTCTTTTTCTCAAGAAACTACCAAGGGATCAGCTTTTACCACCGAGTCTGAAACTCTCCCAGCAAGTAATCACTCACAGCGGTCAATGATGACCATCAGCACAGACATCGCTGTCTTGAGACCTACTGGCAGCAATCCAGGCATTCTGCCCTCCACTTCACAGCTGACTACCCAAAAGACTACACTAACCACCAGCGAAAGTCTGCAGAAAACTACAAAGAGCCATCAAATAAACTCCCGGCAGACTCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAGCGAGGATG ACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAA

mu Tim4(ECD)-muIgG2a Fc

(SEQ ID NO: 75)

MSKGLLLLWLVTELWWLYLTPAASEDTIIGFLGQPVTLPCHYLSWSQSRNSMCWGKGSCPNSKCNAELLRTDGTRIISRKSTKYTLLGKVQFGEVSLTISNTNRGDSGVYCCRIEVPGWFNDVKKNVRLELRRATTTKKPTTTTRPTTTPYVTTTTPELLPTTVMTTSVLPTTTPPQTLATTAFSTAVTTCPSTTPGSFSQETTKGSAFTTESETLPASNHSQRSMMTISTDIAVLRPTGSNPGILPSTSQLTTQKTTLTTSESLQKTTKSHQINSRQTPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK

mu 4-1BB-L

(SEQ ID NO: 76)

ATGGATCAGCATACACTGGACGTGGAAGATACAGCCGATGCCAGACACCCTGCTGGAACGTCCTGTCCCAGCGACGCTGCCCTGCTCAGAGACACCGGGCTGCTCGCAGATGCTGCTCTGCTGAGTGATACCGTTCGGCCAACTAACGCGGCCCTACCCACAGATGCCGCATATCCCGCGGTAAATGTCAGGGACCGGGAAGCTGCCTGGCCACCGGCCCTCAATTTCTGCTCTAGACATCCGAAACTGTACGGTCTGGTCGCACTGGTACTGCTGCTACTTATAGCAGCTTGTGTTCCCATATTTACCCGCACTGAACCCAGACCCGCTCTCACTATTACAACTTCACCAAACTTGGGCACACGTGAAAACAATGCAGATCAGGTTACCCCTGTAAGTCATATTGGATGCCCCAACACCACACAACAGGGAAGTCCGGTGTTTGCAAAACTCCTTGCTAAGAATCAGGCTTCACTGTGTAACACTACTCTTAATTGGCACTCACAAGACGGGGCCGGGAGTAGCTATCTCAGCCAAGGTCTCCGCTATGAAGAAGATAAGAAAGAGTTGGTGGTGGACAGCCCAGGACTCTACTACGTCTTCCTGGAGCTAAAACTAAGCCCCACTTTTACTAACACTGGACATAAGGTCCAAGGTTGGGTGTCCCTCGTACTTCAAGCTAAACCCCAGGTGGACGACTTCGATAACCTGGCGTTGACAGTTGAGCTCTTTCCTTGCTCTATGGAAAATAAGCTCGTGGATCGGAGCTGGTCTCAACTGTTGCTGCTTAAAGCCGGTCATCGTCTGTCTGTTGGACTACGCGCATACTTGCATGGAGCCCAGGACGCATATCGTGATTGGGAACTGAGCTACCCGAATACCACTAGCTTTGGACTATTTCTTGTTAAACCAGATAATCCTTGGGAG

mu 4-1BB-L

(SEQ ID NO: 77)

MDQHTLDVEDTADARHPAGTSCPSDAALLRDTGLLADAALLSDTVRPTNAALPTDAAYPAVNVRDREAAWPPALNFCSRHPKLYGLVALVLLLLIAACVPIFTRTEPRPALTITTSPNLGTRENNADQVTPVSHIGCPNTTQQGSPVFAKLLAKNQASLCNTTLNWHSQDGAGSSYLSQGLRYEEDKKELVVDSPGLYYVFLELKLSPTFTNTGHKVQGWVSLVLQAKPQVDDFDNLALTVELFPCSMENKLVDRSWSQLLLLKAGHRLSVGLRAYLHGAQDAYRDWELSYPNTTSFGLFLVKPDNPWE

mu LIGHT (mitotic deficiency mutation)

(SEQ ID NO: 78)

ATGGAGAGCGTAGTGCAACCCAGCGTATTTGTGGTGGATGGACAGACCGACATCCCATTCAGACGCTTGGAACAGAACCACCGAAGAAGGCGGTGCGGCACCGTCCAGGTGTCCCTCGCTCTCGTGCTGCTGCTTGGTGCTGGCCTCGCAACACAAGGGTGGTTTCTTTTGAGACTCCATCAACGCTTGGGAGACATAGTGGCCCACCTGCCTGATGGTGGGAAGGGCTCTTGGCAGGACCAGCGATCACACCAGGCTAACCCCGCCGCTCACCTGACAGGGGCGAATGCCAGCTTGATCGGAATAGGTGGGCCGCTGCTGTGGGAAACTAGGCTTGGACTTGCCTTTCTGAGAGGGCTTACATACCATGACGGAGCCCTCGTAACAATGGAGCCTGGTTATTACTACGTGTACAGTAAGGTGCAGCTTTCTGGAGTCGGGTGTCCCCAGGGGCTGGCTAACGGACTGCCCATCACTCATGGACTATACAAACGCACATCCAGATATCCTAAAGAGCTGGAACTGTTGGTGTCCCGTAGGAGCCCGTGTGGCAGGGCCAACTCTTCCCGTGTGTGGTGGGACTCCTCTTTTCTGGGCGGCGTGGTCCATCTGGAAGCTGGTGAGGAAGTCGTCGTAAGAGTACCTGGAAACCGTCTGGTTCGCCCCCGCGATGGCACCAGGTCCTACTTCGGAGCTTTCATGGTA

mu LIGHT (mitotic deficiency mutation)

(SEQ ID NO: 79)

MESVVQPSVFVVDGQTDIPFRRLEQNHRRRRCGTVQVSLALVLLLGAGLATQGWFLLRLHQRLGDIVAHLPDGGKGSWQDQRSHQANPAAHLTGANASLIGIGGPLLWETRLGLAFLRGLTYHDGALVTMEPGYYYVYSKVQLSGVGCPQGLANGLPITHGLYKRTSRYPKELELLVSRRSPCGRANSSRVWWDSSFLGGVVHMPVAGERS

mu IL12 (transmembrane)

(SEQ ID NO: 80)

ATGTGCCCACAGAAACTCACAATTTCTTGGTTCGCAATCGTCCTGCTGGTGTCACCCCTGATGGCAATGTGGGAGTTGGAAAAGGATGTATACGTCGTCGAGGTCGACTGGACACCTGACGCTCCGGGTGAAACTGTCAACCTCACTTGCGATACTCCTGAAGAGGACGACATCACGTGGACGAGCGACCAGCGACATGGAGTGATAGGGTCTGGCAAGACGCTTACTATCACGGTTAAGGAATTTCTCGACGCAGGGCAGTACACATGTCACAAGGGCGGCGAGACTCTGAGCCACTCCCATTTGCTGCTGCACAAGAAGGAGAATGGTATCTGGTCTACCGAAATCCTGAAGAATTTTAAGAACAAGACTTTTCTGAAATGCGAGGCCCCAAATTATTCCGGACGTTTCACTTGCAGTTGGCTCGTTCAAAGAAATATGGACTTGAAATTTAACATTAAATCCAGCTCTTCATCTCCTGACAGCAGGGCCGTAACTTGTGGAATGGCTTCATTGTCAGCTGAGAAAGTTACGCTTGACCAAAGGGATTATGAGAAATACAGCGTGAGTTGCCAGGAAGATGTGACATGTCCAACGGCAGAGGAAACGTTGCCAATTGAGCTCGCTTTGGAAGCTCGTCAACAAAACAAGTATGAAAACTATAGTACTAGCTTCTTCATACGGGACATCATCAAACCAGATCCACCTAAGAATTTGCAGATGAAGCCTCTGAAGAATTCACAAGTCGAGGTATCCTGGGAATACCCAGATTCATGGTCCACTCCTCATAGTTACTTTAGCCTGAAATTCTTTGTACGCATACAGCGGAAGAAGGAGAAAATGAAGGAGACGGAAGAAGGCTGCAATCAGAAAGGCGCTTTTCTTGTTGAAAAGACGAGCACTGAGGTTCAATGCAAAGGCGGGAATGTATGTGTTCAAGCCCAAGATAGGTATTATAATAGCTCCTGCTCTAAGTGGGCTTGCGTACCATGCAGAGTTA GAAGTGGCTCAACCTCAGGCTCCGGAAAACCTGGTTCCGGTGAAGGTTCCACAAAAGGGCGTGTGATTCCTGTGTCCGGCCCAGCTAGGTGTCTCTCCCAGTCACGGAATCTCCTGAAAACCACGGATGACATGGTAAAGACAGCTAGGGAGAAACTCAAGCACTACTCCTGCACAGCTGAGGATATCGATCATGAGGACATCACCAGGGACCAGACATCCACTCTGAAAACTTGCCTGCCTTTGGAACTCCACAAGAACGAATCTTGTCTGGCAACGCGTGAAACGAGTTCTACTACAAGAGGGTCCTGTCTTCCCCCTCAAAAGACAAGCCTTATGATGACCTTGTGTCTCGGTAGCATTTATGAGGACCTAAAGATGTATCAAACCGAGTTTCAGGCTATCAATGCAGCGCTCCAGAATCATAACCATCAGCAGATCATTCTTGACAAAGGAATGCTCGTGGCCATTGATGAACTAATGCAGAGCCTAAACCACAATGGCGAGACTCTTCGACAGAAACCGCCTGTGGGCGAGGCCGATCCATATAGAGTCAAAATGAAACTGTGTATTCTCCTGCATGCATTTAGTACTCGTGTAGTGACTATTAACAGAGTGATGGGTTACCTTTCCTCAGCTAATACACTTGTCCTCTTTGGCGCTGGGTTCGGCGCCGTCATAACGGTTGTTGTCATCGTGGTAATAATCAAGTGCTTTTGCAAGCACAGGTCTTGTTTTCGCAGGAATGAAGCCTCTAGAGAAACAAATAATTCACTGACCTTTGGCCCCGAAGAAGCTCTTGCAGAGCAAACGGTGTTTCTC

mu IL12 (transmembrane)

(SEQ ID NO: 81)

MCPQKLTISWFAIVLLVSPLMAMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGSTSGSGKPGSGEGSTKGRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSANTLVLFGAGFGAVITVVVIVVIIKCFCKHRSCFRRNEASRETNNSLTFGPEEALAEQTVFL

mu IL12 (secreted)

(SEQ ID NO: 82)

ATGTGTCAGTCACGCTATCTTCTCTTCCTTGCTACTCTGGCCTTGCTCAATCACTTGTCCCTTGCTCGTGTGATTCCTGTGTCCGGCCCAGCTAGGTGTCTCTCCCAGTCACGGAATCTCCTGAAAACCACGGATGACATGGTAAAGACAGCTAGGGAGAAACTCAAGCACTACTCCTGCACAGCTGAGGATATCGATCATGAGGACATCACCAGGGACCAGACATCCACTCTGAAAACTTGCCTGCCTTTGGAACTCCACAAGAACGAATCTTGTCTGGCAACGCGTGAAACGAGTTCTACTACAAGAGGGTCCTGTCTTCCCCCTCAAAAGACAAGCCTTATGATGACCTTGTGTCTCGGTAGCATTTATGAGGACCTAAAGATGTATCAAACCGAGTTTCAGGCTATCAATGCAGCGCTCCAGAATCATAACCATCAGCAGATCATTCTTGACAAAGGAATGCTCGTGGCCATTGATGAACTAATGCAGAGCCTAAACCACAATGGCGAGACTCTTCGACAGAAACCGCCTGTGGGCGAGGCCGATCCATATAGAGTCAAAATGAAACTGTGTATTCTCCTGCATGCATTTAGTACTCGTGTAGTGACTATTAACAGAGTGATGGGTTACCTTTCCTCAGCTGGAAGCGGCGCCACCAACTTCTCCCTGCTGAAGCAGGCCGGCGACGTGGAGGAGAACCCCGGCCCCATGTGCCCACAGAAACTCACAATTTCTTGGTTCGCAATCGTCCTGCTGGTGTCACCCCTGATGGCAATGTGGGAGTTGGAAAAGGATGTATACGTCGTCGAGGTCGACTGGACACCTGACGCTCCGGGTGAAACTGTCAACCTCACTTGCGATACTCCTGAAGAGGACGACATCACGTGGACGAGCGACCAGCGACATGGAGTGATAGGGTCTGGCAAGACGCTTACTATCACGGTTAAGGAATTTCTCGACGCAGGGCAGTACACATGTCACAAGGGCGGCGAGACTC TGAGCCACTCCCATTTGCTGCTGCACAAGAAGGAGAATGGTATCTGGTCTACCGAAATCCTGAAGAATTTTAAGAACAAGACTTTTCTGAAATGCGAGGCCCCAAATTATTCCGGACGTTTCACTTGCAGTTGGCTCGTTCAAAGAAATATGGACTTGAAATTTAACATTAAATCCAGCTCTTCATCTCCTGACAGCAGGGCCGTAACTTGTGGAATGGCTTCATTGTCAGCTGAGAAAGTTACGCTTGACCAAAGGGATTATGAGAAATACAGCGTGAGTTGCCAGGAAGATGTGACATGTCCAACGGCAGAGGAAACGTTGCCAATTGAGCTCGCTTTGGAAGCTCGTCAACAAAACAAGTATGAAAACTATAGTACTAGCTTCTTCATACGGGACATCATCAAACCAGATCCACCTAAGAATTTGCAGATGAAGCCTCTGAAGAATTCACAAGTCGAGGTATCCTGGGAATACCCAGATTCATGGTCCACTCCTCATAGTTACTTTAGCCTGAAATTCTTTGTACGCATACAGCGGAAGAAGGAGAAAATGAAGGAGACGGAAGAAGGCTGCAATCAGAAAGGCGCTTTTCTTGTTGAAAAGACGAGCACTGAGGTTCAATGCAAAGGCGGGAATGTATGTGTTCAAGCCCAAGATAGGTATTATAATAGCTCCTGCTCTAAGTGGGCTTGCGTACCATGCAGAGTTAGAAGT

mu IL12 (secreted)

(SEQ ID NO: 83)

MCQSRYLLFLATLALLNHLSLARVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGSGATNFSLLKQAGDVEENPGPMCPQKLTISWFAIVLLVSPLMAMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQ AQDRYYNSSCSKWACVPCRV RS

mu IFN Alpha A2

(SEQ ID NO: 84)

ATGGCCAGGCTTTGCGCTTTTCTCGTCATGCTGATCGTCATGAGTTACTGGTCCATTTGCAGCCTCGGATGTGATCTGCCCCACACCTACAACCTGCGCAACAAACGAGCTCTCAAAGTGTTGGCCCAAATGAGGCGGTTGCCCTTCCTTTCCTGTCTCAAAGACAGGCAAGATTTTGGATTTCCACTAGAGAAAGTAGACAATCAACAGATACAGAAAGCTCAAGCTATCCCCGTGTTGAGGGACTTGACTCAACAGACGTTGAATCTATTTACTAGCAAGGCCAGCTCTGCTGCTTGGAATGCCACCCTTCTTGACTCATTTTGCAATGACCTACATCAACAACTGAATGATCTCCAAACATGTTTGATGCAGCAGGTAGGTGTCCAAGAACCCCCGCTTACTCAGGAAGACGCCCTTCTGGCTGTCCGCAAGTACTTTCACAGAATCACAGTGTACCTGCGCGAAAAGAAACACTCCCCCTGCGCTTGGGAAGTGGTCAGGGCCGAGGTTTGGCGAGCCCTGAGTAGCTCCGTCAATCTCCTTCCTCGGTTGTCCGAGGAGAAAGAG

mu IFN Alpha A2

(SEQ ID NO: 85)

MARLCAFLVMLIVMSYWSICSLGCDLPHTYNLRNKRALKVLAQMRRLPFLSCLKDRQDFGFPLEKVDNQQIQKAQAIPVLRDLTQQTLNLFTSKASSAAWNATLLDSFCNDLHQQLNDLQTCLMQQVGVQEPPLTQEDALLAVRKYFHRITVYLREKKHSPCAWEVVRAEVWRALSSSVNLLPRLSEEKE

mu CD80

(SEQ ID NO: 86)

ATGGCTTGCAACTGTCAGCTCATGCAAGATACTCCCCTGCTTAAGTTTCCCTGCCCTAGACTCATTCTCCTCTTCGTCCTTCTCATTCGCCTAAGCCAGGTGAGTTCCGATGTGGATGAACAACTGAGTAAATCTGTCAAGGATAAAGTTCTGCTCCCATGCCGCTACAATAGCCCCCATGAGGACGAGTCCGAAGATAGGATTTACTGGCAGAAACATGATAAGGTGGTGCTATCCGTCATTGCCGGTAAATTGAAGGTGTGGCCCGAATATAAGAATAGAACCCTGTATGACAACACAACTTATAGCCTAATCATCCTCGGTCTCGTACTGAGCGACCGAGGTACTTACTCATGCGTTGTGCAGAAGAAGGAGCGCGGAACATACGAAGTCAAGCACCTTGCATTGGTGAAATTGTCAATAAAAGCTGACTTTTCAACTCCTAATATTACTGAATCAGGTAACCCTTCCGCAGACACTAAAAGAATTACATGCTTCGCCTCTGGCGGGTTTCCCAAACCACGGTTCTCTTGGCTAGAGAATGGGAGAGAACTTCCAGGTATCAATACAACCATCTCTCAAGACCCAGAATCAGAACTGTACACCATCTCCAGCCAACTCGATTTCAATACCACAAGAAATCATACAATAAAATGTCTGATAAAGTACGGAGATGCACATGTCTCTGAAGATTTCACATGGGAGAAACCACCAGAGGACCCGCCAGACAGCAAGAATACACTTGTCCTCTTTGGCGCTGGGTTCGGCGCCGTCATAACGGTTGTTGTCATCGTGGTAATAATCAAGTGCTTTTGCAAGCACAGGTCTTGTTTTCGCAGGAATGAAGCCTCTAGAGAAACAAATAATTCACTGACCTTTGGCCCCGAAGAAGCTCTTGCAGAGCAAACGGTGTTTCTC

mu CD80

(SEQ ID NO: 87)

MACNCQLMQDTPLLKFPCPRLILLFVLLIRLSQVSSDVDEQLSKSVKDKVLLPCRYNSPHEDESEDRIYWQKHDKVVLSVIAGKLKVWPEYKNRTLYDNTTYSLIILGLVLSDRGTYSCVVQKKERGTYEVKHLALVKLSIKADFSTPNITESGNPSADTKRITCFASGGFPKPRFSWLENGRELPGINTTISQDPESELYTISSQLDFNTTRNHTIKCLIKYGDAHVSEDFTWEKPPEDPPDSKNTLVLFGAGFGAVITVVVIVVIIKCFCKHRSCFRR NEASRETNNS LTFGPEEALAEQTVFL

mu CD40-L

(SEQ ID NO: 88)

ATGATCGAAACTTATTCCCAACCCTCACCGCGCTCAGTAGCAACTGGCCTACCAGCCAGCATGAAGATATTCATGTACCTCTTGACTGTATTCTTGATCACGCAAATGATTGGTAGTGTTTTGTTCGCCGTTTATCTCCACAGGCGCCTGGATAAAGTTGAAGAAGAGGTTAATCTCCATGAAGACTTCGTGTTCATTAAGAAACTCAAAAGATGTAACAAAGGTGAGGGATCTCTGTCTCTTCTGAACTGTGAGGAGATGCGACGGCAATTCGAGGACCTCGTAAAAGACATAACTCTCAACAAAGAAGAGAAGAAAGAAAACTCTTTCGAGATGCAACGGGGCGACGAGGACCCTCAAATTGCCGCACATGTCGTTTCTGAAGCGAATTCCAATGCCGCGTCCGTGCTCCAGTGGGCGAAGAAGGGATACTACACGATGAAGAGCAACCTTGTGATGCTTGAAAATGGCAAGCAGCTCACAGTTAAACGCGAGGGACTCTACTATGTATACACCCAAGTGACCTTTTGTTCCAACCGGGAGCCAAGTAGCCAACGCCCGTTCATCGTTGGGCTGTGGCTCAAGCCTTCTTCAGGGAGTGAACGAATCCTTCTCAAGGCAGCCAACACGCATTCCAGCAGCCAACTGTGTGAGCAACAATCCGTGCATCTTGGCGGGGTCTTTGAGCTGCAAGCGGGCGCCTCTGTGTTCGTGAATGTTACCGAAGCCAGCCAGGTTATCCACCGCGTGGGTTTCAGTAGTTTTGGCCTGCTCAAGCTG

mu CD40-L

(SEQ ID NO: 89)

MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVMLENGKQLTVKREGLYYVYTQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHSSSQLCEQQSVHLGGVFELQAGASVFVNVTEASQVIHRVGFSSFGLLKL

mu-IL21

(SEQ ID NO: 90)

ATGGAGCGTACTCTGGTCTGCCTTGTTGTGATATTCTTGGGGACAGTTGCACACAAATCATCACCCCAAGGACCGGATAGACTCCTCATACGCCTGCGCCATCTGATTGACATTGTCGAGCAGTTGAAGATTTATGAGAACGACCTGGACCCTGAACTATTGAGCGCGCCTCAAGACGTCAAAGGGCATTGCGAGCATGCTGCATTTGCATGTTTTCAGAAAGCTAAGCTCAAACCAAGTAATCCCGGTAACAATAAAACATTCATCATCGACCTGGTGGCCCAACTAAGACGCCGGTTGCCGGCGCGCCGGGGTGGTAAGAAACAGAAACATATTGCTAAATGCCCCTCTTGCGACTCTTACGAGAAAAGGACACCTAAGGAATTCCTCGAACGATTGAAATGGTTGTTGCAGAAGATGATCCATCAACATCTGAGC

mu-IL21

(SEQ ID NO: 91)

MERTLVCLVVIFLGTVAHKSSPQGPDRLLIRLRHLIDIVEQLKIYENDLDPELLSAPQDVKGHCEHAAFACFQKAKLKPSNPGNNKTFIIDLVAQLRRRLPARRGGKKQK HIAKCPSCDSYEKRTPKEFLERLKWLLQKM IHQHLS

mu CCL21

(SEQ ID NO: 92)

ATGGCACAAATGATGACACTGTCCCTACTTAGTCTAGTTCTAGCTTTGTGTATTCCCTGGACTCAAGGCAGTGACGGAGGAGGACAAGACTGCTGCCTCAAATATTCTCAAAAGAAAATCCCTTATTCTATAGTCCGAGGTTACCGTAAGCAAGAACCGAGTCTAGGTTGTCCTATCCCCGCAATCCTCTTTCTACCACGGAAACATAGCAAACCAGAATTGTGCGCCAACCCAGAAGAGGGTTGGGTCCAAAATTTGATGAGGCGCCTTGACCAACCACCGGCCCCGGGTAAACAATCACCGGGGTGTCGGAAGAATAGGGGTACATCCAAATCCGGGAAGAAAGGGAAGGGGAGTAAGGGCTGTAAGAGAACGGAACAAACTCAACCTAGCAGAGGT

mu CCL21

(SEQ ID NO: 93)

MAQMMTLSLLSLVLALCIPWTQGSDGGGQDCCLKYSQKKIPYSIVRGYRKQEPSLGCPIPAILFLPRKHSKPELCANPEEGWVQNLMRRLDQPPAPGKQSPGCRKNRGTSKSGKKGKGSKGCKRTEQTQPSRG

anti-mu CD3 scFv-transmembrane

(SEQ ID NO: 94)

ATGGAAACCGACACATTGCTCCTCTGGGTTCTCCTTCTATGGGTCCCCGGTTCCACCGGAGATATCCAAATGACACAATCACCCAGCAGCCTGCCTGCCTCTCTGGGCGACCGCGTTACCATCAATTGTCAAGCTTCCCAAGATATAAGTAATTATCTCAACTGGTACCAGCAAAAGCCCGGTAAAGCGCCTAAATTGCTGATTTATTATACTAATAAACTCGCAGATGGAGTTCCTAGTAGATTTTCTGGTTCAGGGAGTGGACGGGACTCCAGTTTTACCATATCAAGTCTGGAATCCGAGGATATCGGCAGCTACTATTGCCAGCAATATTATAATTACCCTTGGACTTTTGGACCCGGGACTAAACTTGAGATCAAAAGAGGCGGAGGAGGCAGTGGTGGTGGTGGATCAGGCGGCGGTGGTAGTGAGGTACAACTCGTGGAATCAGGCGGCGGACTGGTCCAACCCGGCAAGAGCCTTAAACTCTCTTGTGAGGCCAGTGGATTTACATTCAGCGGTTATGGAATGCACTGGGTGAGACAAGCTCCCGGCAGGGGCCTAGAATCAGTGGCGTACATCACCAGCTCATCAATAAACATTAAATACGCTGATGCAGTCAAGGGCCGGTTTACTGTATCCCGCGACAACGCTAAGAATCTTCTCTTTCTGCAAATGAACATACTTAAGAGCGAGGATACTGCCATGTATTATTGTGCCCGCTTCGATTGGGATAAGAATTATTGGGGACAAGGCACCATGGTTACCGTTAGTAGTCCAAACATCACATCAAATAATAGCAACCCCGTGGAAGGGGACGACTCTGTTTCACTCACCTGTGATTCCTATACCGATCCTGATAATATCAACTATCTATGGTCTCGTAACGGTGAAAGTCTCAGCGAAGGCGACCGGTTGAAACTCTCCGAAGGTAACAGAACCCTTACGCTTCTGAACGTCACCCGGAACGATACCGGGCCCTATGTTTGCGAAACTAGGA ACCCTGTTAGCGTGAATCGTAGCGACCCTTTCTCCCTAAATAATACTCTAGTGCTATTCGGAGCGGGATTCGGTGCCGTCATCACAGTAGTCGTTATTGTAGTCATTATTAAATGCTTTTGTAAACATAGGTCTTGCTTCAGAAGAAATGAGGCCAGCCGTGAAACTAATAATTCCCTGACCTTTGGGCCCGAAGAAGCTTTGGCTGAACAGACTGTGTTTCTC

anti-mu CD3 scFv-transmembrane

(SEQ ID NO: 95)

METDTLLLWVLLLWVPGSTGDIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSSPNITSNNSNPVEGDDSVSLTCDSYTDPDNINYLWSRNGESLSEGDRLKLSEGNRTLTLLNVTRNDTGPYVCETRNPVSVNRSDPFSLNNTLVLFGAGFGAVITVVVIVVIIKCFCKHRSCFRRNEASRETNNSLTFGPEEALAEQTVFL

mu TSLP

(SEQ ID NO: 96)

ATGGTTCTTCTCAGGAGCCTCTTCATCCTGCAAGTACTAGTACGGATGGGGCTAACTTACAACTTTTCTAACTGCAACTTCACGTCAATTACGAAAATATATTGTAACATAATTTTTCATGACCTGACTGGAGATTTGAAAGGGGCTAAGTTCGAGCAAATCGAGGACTGTGAGAGCAAGCCAGCTTGTCTCCTGAAAATCGAGTACTATACTCTCAATCCTATCCCTGGCTGCCCTTCACTCCCCGACAAAACATTTGCCCGGAGAACAAGAGAAGCCCTCAATGACCACTGCCCAGGCTACCCTGAAACTGAGAGAAATGACGGTACTCAGGAAATGGCACAAGAAGTCCAAAACATCTGCCTGAATCAAACCTCACAAATTCTAAGATTGTGGTATTCCTTCATGCAATCTCCAGAA

mu TSLP

(SEQ ID NO: 97)

MVLLRSLFILQVLVRMGLTYNFSNCNFTSITKIYCNIIFHDLTGDLKGAKFEQIEDCESKPACLLKIEYYTLNPIPGCPSLPDKTFARRTREALNDHCPGYPETERNDGTQEMAQEVQNICLNQTSQILRLWYSFMQSPE

mu GM-CSF

(SEQ ID NO: 98)

ATGTGGCTGCAGAATTTACTTTTCCTGGGCATTGTGGTCTACAGCCTCTCAGCACCCACCCGCTCACCCATCACTGTCACCCGGCCTTGGAAGCATGTAGAGGCCATCAAAGAAGCCCTGAACCTCCTGGATGACATGCCTGTCACGTTGAATGAAGAGGTAGAAGTCGTCTCTAACGAGTTCTCCTTCAAGAAGCTAACATGTGTGCAGACCCGCCTGAAGATATTCGAGCAGGGTCTACGGGGCAATTTCACCAAACTCAAGGGCGCCTTGAACATGACAGCCAGCTACTACCAGACATACTGCCCCCCAACTCCGGAAACGGACTGTGAAACACAAGTTACCACCTATGCGGATTTCATAGACAGCCTTAAAACCTTTCTGACTGATATCCCCTTTGAATGCAAAAAACCAGGCCAAAAA

mu GM-CSF

(SEQ ID NO: 99)

MWLQNLLFLGIVVYSLSAPTRSPITVTRPWKHVEAIKEALNLLDDMPVTLNEEVEVVSNEFSFKKLTCVQTRLKIFEQGLRGNFTKLKGALNMTASYYQTYCPPTPETDCETQVTTYADFIDSLKTFLTDIPFECKKPGQK

mu IFN gamma

(SEQ ID NO: 100)

ATGAACGCTACACACTGCATCTTGGCTTTGCAGCTCTTCCTCATGGCTGTTTCTGGCTGTTACTGCCACGGCACAGTCATTGAAAGCCTAGAAAGTCTGAATAACTATTTTAACTCAAGTGGCATAGATGTGGAAGAAAAGAGTCTCTTCTTGGATATCTGGAGGAACTGGCAAAAGGATGGTGACATGAAAATCCTGCAGAGCCAGATTATCTCTTTCTACCTCAGACTCTTTGAAGTCTTGAAAGACAATCAGGCCATCAGCAACAACATAAGCGTCATTGAATCACACCTGATTACTACCTTCTTCAGCAACAGCAAGGCGAAAAAGGATGCATTCATGAGTATTGCCAAGTTTGAGGTCAACAACCCACAGGTCCAGCGCCAAGCATTCAATGAGCTCATCCGAGTGGTCCACCAGCTGTTGCCGGAATCCAGCCTCAGGAAGCGGAAAAGGAGTCGCTGC

mu IFN gamma

(SEQ ID NO: 101)

MNATHCILALQLFLMAVSGCYCHGTVIESLESLNNYFNSSGIDVEEKSLFLDIWRNWQKDGDMKILQSQIISFYLRLFEVLKDNQAISNNISVIESHLITTFFSNSKAKKDAFMSIAKFEVNNPQVQRQAFNELIRVVHQLLPESSLRKRKRSRC

mu IL7

(SEQ ID NO: 102)

ATGTTCCATGTTTCTTTTAGATATATCTTTGGAATTCCTCCACTGATCCTTGTTCTGCTGCCTGTCACATCATCTGAGTGCCACATTAAAGACAAAGAAGGTAAAGCATATGAGAGTGTACTGATGATCAGCATCGATGAATTGGACAAAATGACAGGAACTGATAGTAATTGCCCGAATAATGAACCAAACTTTTTTAGAAAACATGTATGTGATGATACAAAGGAAGCTGCTTTTCTAAATCGTGCTGCTCGCAAGTTGAAGCAATTTCTTAAAATGAATATCAGTGAAGAATTCAATGTCCACTTACTAACAGTATCACAAGGCACACAAACACTGGTGAACTGCACAAGTAAGGAAGAAAAAAACGTAAAGGAACAGAAAAAGAATGATGCATGTTTCCTAAAGAGACTACTGAGAGAAATAAAAACTTGTTGGAATAAAATTTTGAAGGGCAGTATA

mu IL7

(SEQ ID NO: 103)

MFHVSFRYIFGIPPLILVLLPVTSSECHIKDKEGKAYESVLMISIDELDKMTGTDSNCPNNEPNFFRKHVCDDTKEAAFLNRAARKLKQFLKMNISEEFNVHLLTVSQGTQTLVNCTSKEEKNVKEQKKNDACFLKRLLREIKTCWNKILKGSI

mu ICOS-L

(SEQ ID NO: 104)

ATGCAGCTAAAGTGTCCCTGTTTTGTGTCCTTGGGAACCAGGCAGCCTGTTTGGAAGAAGCTCCATGTTTCTAGCGGGTTCTTTTCTGGTCTTGGTCTGTTCTTGCTGCTGTTGAGCAGCCTCTGTGCTGCCTCTGCAGAGACTGAAGTCGGTGCAATGGTGGGCAGCAATGTGGTGCTCAGCTGCATTGACCCCCACAGACGCCATTTCAACTTGAGTGGTCTGTATGTCTATTGGCAAATCGAAAACCCAGAAGTTTCGGTGACTTACTACCTGCCTTACAAGTCTCCAGGGATCAATGTGGACAGTTCCTACAAGAACAGGGGCCATCTGTCCCTGGACTCCATGAAGCAGGGTAACTTCTCTCTGTACCTGAAGAATGTCACCCCTCAGGATACCCAGGAGTTCACATGCCGGGTATTTATGAATACAGCCACAGAGTTAGTCAAGATCTTGGAAGAGGTGGTCAGGCTGCGTGTGGCAGCAAACTTCAGTACACCTGTCATCAGCACCTCTGATAGCTCCAACCCGGGCCAGGAACGTACCTACACCTGCATGTCCAAGAATGGCTACCCAGAGCCCAACCTGTATTGGATCAACACAACGGACAATAGCCTAATAGACACGGCTCTGCAGAATAACACTGTCTACTTGAACAAGTTGGGCCTGTATGATGTAATCAGCACATTAAGGCTCCCTTGGACATCTCGTGGGGATGTTCTGTGCTGCGTAGAGAATGTGGCTCTCCACCAGAACATCACTAGCATTAGCCAGGCAGAAAGTTTCACTGGAAATAACACAAAGAACCCACAGGAAACCCACAATAATGAGTTAAAAGTCCTTGTCCCCGTCCTTGCTGTACTGGCGGCAGCGGCATTCGTTTCCTTCATCATATACAGACGCACGCGTCCCCACCGAAGCTATACAGGACCCAAGACTGTACAGCTTGAACTTACAGACCACGCC

mu ICOS-L

(SEQ ID NO: 105)

MQLKCPCFVSLGTRQPVWKKLHVSSGFFSGLGLFLLLLSSLCAASAETEVGAMVGSNVVLSCIDPHRRHFNLSGLYVYWQIENPEVSVTYYLPYKSPGINVDSSYKNRGHLSLDSMKQGNFSLYLKNVTPQDTQEFTCRVFMNTATELVKILEEVVRLRVAANFSTPVISTSDSSNPGQERTYTCMSKNGYPEPNLYWINTTDNSLIDTALQNNTVYLNKLGLYDVISTLRLPWTSRGDVLCCVENVALHQNITSISQAESFTGNNTKNPQETHNNELKVLVPVLAVLAAAAFVSFIIYRRTRPHRSYTGPKTVQLELTD HA

mu CD47

(SEQ ID NO: 106)

ATGTGGCCCTTGGCGGCGGCGCTGTTGCTGGGCTCCTGCTGCTGCGGTTCAGCTCAACTACTGTTTAGTAACGTCAACTCCATAGAGTTCACTTCATGCAATGAAACTGTGGTCATCCCTTGCATCGTCCGTAATGTGGAGGCGCAAAGCACCGAAGAAATGTTTGTGAAGTGGAAGTTGAACAAATCGTATATTTTCATCTATGATGGAAATAAAAATAGCACTACTACAGATCAAAACTTTACCAGTGCAAAAATCTCAGTCTCAGACTTAATCAATGGCATTGCCTCTTTGAAAATGGATAAGCGCGATGCCATGGTGGGAAACTACACTTGCGAAGTGACAGAGTTATCCAGAGAAGGCAAAACAGTTATAGAGCTGAAAAACCGCACGGTTTCGTGGTTTTCTCCAAATGAAAAGATCCTCATTGTTATTTTCCCAATTTTGGCTATACTCCTGTTCTGGGGAAAGTTTGGTATTTTAACACTCAAATATAAATCCAGCCATACGAATAAGAGAATCATTCTGCTGCTCGTTGCCGGGCTGGTGCTCACAGTCATCGTGGTTGTTGGAGCCATCCTTCTCATCCCAGGAGAAAAGCCCGTGAAGAATGCTTCTGGACTTGGCCTCATTGTAATCTCTACGGGGATATTAATACTACTTCAGTACAATGTGTTTATGACAGCTTTTGGAATGACCTCTTTCACCATTGCCATATTGATCACTCAAGTGCTGGGCTACGTCCTTGCTTTGGTCGGGCTGTGTCTCTGCATCATGGCATGTGAGCCAGTGCACGGCCCCCTTTTGATTTCAGGTTTGGGGATCATAGCTCTAGCAGAACTACTTGGATTAGTTTATATGAAGTTTGTCGCTTCCAACCAGAGGACTATCCAACCTCCTAGGAATAGG

mu CD47

(SEQ ID NO: 107)

MWPLAAALLLGSCCCGSAQLLFSNVNSIEFTSCNETVVIPCIVRNVEAQSTEEMFVKWKLNKSYIFIYDGNKNSTTTDQNFTSAKISVSDLINGIASLKMDKRDAMVGNYTCEVTELSREGKTVIELKNRTVSWFSPNEKILIVIFPILAILLFWGKFGILTLKYKSSHTNKRIILLLVAGLVLTVIVVVGAILLIPGEKPVKNASGLGLIVISTGILILLQYNVFMTAFGMTSFTIAILITQVLGYVLALVGLCLCIMACEPVHGPLLISGLGIIALAELLGLVYMKFVASNQRTIQPPRNR

Mu sarcoglycan alpha:

(SEQ ID NO: 108)

ATGGCAGCAGCAGTAACTTGGATACCTCTCCTGGCAGGTCTCCTGGCAGGACTGAGGGACACCAAGGCCCAGCAGACAACTTTACACCTACTTGTGGGTCGTGTGTTTGTGCATCCTTTGGAACATGCCACCTTCCTGCGCCTTCCAGAACACGTTGCGGTGCCACCCACTGTCCGACTCACCTACCACGCTCACCTCCAGGGACATCCAGACCTGCCCAGGTGGCTGCACTACACACAGCGCAGTCCCTATAACCCTGGCTTCCTCTACGGCTCCCCCACTCCAGAAGATCGTGGGTACCAAGTCATCGAGGTCACAGCCTACAATCGAGACAGTTTTGACACCACTAGACAGAGGCTGCTGCTGCTGATTGGGGACCCCGAAGGTCCCCGGTTGCCATACCAAGCTGAGTTCCTGGTGCGCAGCCATGATGTGGAGGAGGTGCTGCCCACCACACCTGCCAACCGCTTCCTCACCGCCTTGGGGGGACTGTGGGAGCCAGGAGAGCTTCAGCTGCTCAACATCACTTCCGCCTTGGACCGGGGAGGCCGAGTCCCTCTTCCTATTGAGGGACGGAAGGAAGGGGTATACATTAAGGTAGGCTCTGCCACACCCTTCTCCACCTGCCTGAAGATGGTGGCGTCGCCCGACAGCTATGCCCGTTGTGCCCAGGGACAGCCTCCACTACTGTCCTGCTACGACACTTTGGCACCCCACTTCCGCGTTGACTGGTGCAATGTGTCTCTGGTAGACAAGTCAGTACCCGAGCCCCTGGATGAGGTACCTACTCCAGGCGATGGGATCTTGGAGCACGACCCGTTCTTCTGCCCACCCACTGAAGCCACAGACCGAGACTTCCTGACAGATGCCTTGGTGACCCTCTTGGTGCCTTTGTTGGTGGCTCTGCTGCTTACTCTGTTGCTGGCTTACATCATGTGCTTTCGGCGTGAAGGACGGCTGAAGAGAGACATGGCCACCTCTGACATCCAGATGTTTCACC ACTGTTCCATCCATGGGAATACAGAAGAGCTTCGGCAGATGGCAGCCAGCCGAGAGGTGCCCCGGCCTCTTTCCACCTTGCCCATGTTTAATGTTCGTACAGGAGAGCGGTTACCTCCCCGAGTAGACAGCGCACAGATGCCTCTTATCCTGGACCAGCAC

Mu sarcoglycan alpha

(SEQ ID NO: 109)

MAAAVTWIPLLAGLLAGLRDTKAQQTTLHLLVGRVFVHPLEHATFLRLPEHVAVPPTVRLTYHAHLQGHPDLPRWLHYTQRSPYNPGFLYGSPTPEDRGYQVIEVTAYNRDSFDTTRQRLLLLIGDPEGPRLPYQAEFLVRSHDVEEVLPTTPANRFLTALGGLWEPGELQLLNITSALDRGGRVPLPIEGRKEGVYIKVGSATPFSTCLKMVASPDSYARCAQGQPPLLSCYDTLAPHFRVDWCNVSLVDKSVPEPLDEVPTPGDGILEHDPFFCPPTEATDRDFLTDALVTLLVPLLVALLLTLLLAYIMCFRREGRLKRDMATSDIQMFHHCSIHGNTEELRQMAASREVPRPLSTLPMFNVRTGERLPPRVDSAQM PLILDQH

Mu-FGF10

(SEQ ID NO: 110)

ATGTGGAAATGGATACTGACACATTGTGCCTCAGCCTTTCCCCACCTGCCGGGCTGCTGTTGCTGCTTCTTGTTGCTCTTTTTGGTGTCTTCGTTCCCTGTCACCTGCCAAGCTCTTGGTCAGGACATGGTGTCACAGGAGGCCACCAACTGCTCTTCTTCCTCCTCGTCCTTCTCCTCTCCTTCCAGTGCGGGAAGGCATGTGCGGAGCTACAATCACCTCCAAGGAGATGTCCGCTGGAGAAGGCTGTTCTCCTTCACCAAGTACTTTCTCACGATTGAGAAGAACGGCAAGGTCAGCGGGACCAAGAATGAAGACTGTCCGTACAGTGTCCTGGAGATAACATCAGTGGAAATCGGAGTTGTTGCCGTCAAAGCCATCAACAGCAACTATTACTTAGCCATGAACAAGAAGGGGAAACTCTATGGCTCAAAAGAGTTTAACAACGACTGTAAGCTGAAAGAGAGAATAGAGGAAAATGGATACAACACCTATGCATCTTTTAACTGGCAGCACAATGGCAGGCAAATGTATGTGGCATTGAATGGAAAAGGAGCTCCCAGGAGAGGACAAAAAACAAGAAGGAAAAACACCTCTGCTCACTTCCTCCCCATGACGATCCAAACA

Mu-FGF10

(SEQ ID NO: 111)

MMWKWILTHCASAFPHLPGCCCCFLLLFLVSSFPVTCQALGQDMVSQEATNCSSSSSSFSSPSSAGRHVRSYNHLQGDVRWRRLFSFTKYFLTIEKNGKVSGTKNEDCPYSVLEITSVEIGVVAVKAINSNYYLAMNKKGKLYGSKEFNNDCKLKERIEENGYNTYASFNWQHNGRQMYVALNGKGAPRRGQKTRRKNTSAHFLPMTIQT

Mu Agrin

(SEQ ID NO: 112)

ATGCCTCCTCTGCCACTGGAACACAGACCCAGGCAGCAGCCTGGTGCCTCCGTGCTGGTTCGGTACTTCATGATCCCCTGCAACATCTGCTTGATCCTCTTGGCTACTTCTACGTTGGGCTTTGCGGTGCTGCTTTTCCTCAGCAACTACAAACCTGGGATCCACTTCACAGCAGCGCCTTCTATGCCTCCTGATGTGTGCAGGGGAATGTTATGTGGCTTTGGTGCTGTGTGTGAACCTAGTGTTGAGGATCCAGGCCGGGCCTCCTGTGTGTGCAAGAAGAATGTCTGCCCTGCTATGGTAGCTCCTGTGTGTGGCTCAGATGCTTCCACCTATAGCAACGAGTGTGAGCTACAGCGTGCACAGTGCAACCAGCAACGGCGCATCCGCCTACTCCGCCAAGGGCCATGTGGGTCCCGGGACCCCTGTGCCAATGTGACCTGCAGTTTCGGTAGTACCTGTGTACCTTCAGCCGATGGACAGACCGCCTCGTGTCTGTGTCCTACAACCTGCTTTGGGGCCCCTGATGGCACAGTGTGTGGCAGTGATGGTGTTGACTACCCTAGTGAGTGCCAGCTGCTCCGTCATGCCTGTGCCAACCAGGAGCACATCTTTAAGAAGTTCGATGGTCCTTGTGACCCCTGCCAGGGCAGCATGTCAGACCTGAATCATATTTGCCGGGTGAACCCACGTACACGGCACCCAGAAATGCTTCTGCGGCCTGAGAACTGCCCCGCCCAACACACACCTATCTGTGGAGATGATGGGGTCACCTATGAAAACGACTGTGTCATGAGCCGTATAGGTGCAGCCCGTGGCCTGCTTCTCCAGAAAGTGCGCTCTGGTCAATGCCAGACTCGAGACCAGTGCCCGGAGACCTGCCAGTTTAACTCTGTATGCCTGTCCCGCCGCGGCCGTCCCCACTGTTCCTGCGATCGCGTCACCTGTGATGGGGCTTACAGGCCAGTGTGTGCCCAGGATGGGCACACGTATGACAATG ACTGTTGGCGCCAACAGGCCGAGTGTCGACAACAGCAGACCATTCCCCCCAAGCACCAGGGCCCGTGTGACCAGACCCCATCCCCGTGCCGTGGAGCGCAGTGTGCATTTGGGGCAACATGCACAGTGAAGAATGGGAAAGCTGTGTGCGAGTGCCAGCGGGTGTGCTCGGGCGGCTACGATCCTGTGTGCGGCAGTGATGGTGTCACTTACGGCAGTGTGTGCGAGCTGGAATCCATGGCCTGTACCCTTGGGCGGGAAATCCGAGTGGCCCGCAGAGGACCGTGTGACCGATGTGGGCAGTGCCGGTTTGGATCCTTGTGCGAGGTGGAGACTGGACGCTGTGTGTGCCCCTCTGAGTGTGTGGAGTCAGCCCAGCCCGTATGTGGCTCTGACGGACACACATATGCTAGTGAATGTGAGCTGCATGTCCACGCCTGTACACACCAGATCAGCCTATACGTGGCCTCAGCCGGACACTGCCAGACCTGTGGAGAAACAGTTTGTACCTTTGGGGCTGTGTGCTCAGCTGGACAGTGTGTATGTCCCCGTTGTGAGCACCCCCCACCTGGCCCTGTGTGCGGCAGTGATGGCGTCACCTACCTCAGTGCCTGTGAGCTCCGAGAGGCTGCCTGTCAGCAGCAGGTACAAATTGAGGAGGCCCGTGCAGGGCCGTGTGAGCCGGCTGAGTGTGGCTCAGGGGGCTCTGGGTCTGGGGAAGACAATGCGTGTGAGCAGGAGCTGTGTCGGCAGCATGGTGGTGTCTGGGATGAGGACTCAGAAGACGGGCCGTGTGTCTGTGACTTTAGTTGCCAGAGTGTCCTTAAAAGCCCAGTGTGTGGCTCAGATGGAGTCACCTATAGCACGGAGTGCCATCTGAAGAAGGCCAGATGTGAAGCGCGGCAAGAGCTGTACGTCGCTGCTCAGGGAGCCTGCCGGGGCCCTACCTTGGCTCCACTGCTACCTATGGCCTCCCCACACTGTGCCCAAACCCCCTATGG CTGCTGCCAGGACAATGTCACTGCTGCCCAGGGTGTGGGCTTGGCTGGCTGTCCCAGCACCTGCCATTGCAACCCACACGGCTCCTATAGCGGCACTTGTGACCCAGTCACAGGGCAGTGCTCCTGCCGACCAGGTGTAGGAGGCCTCAGGTGTGATCGCTGTGAGCCTGGCTTCTGGAACTTCCGTGGCATTGTCACCGATGGACATAGTGGTTGCACTCCCTGCAGCTGTGACCCTCGGGGTGCTGTAAGAGATGACTGTGAGCAGATGACTGGATTGTGTTCCTGTAGACCTGGTGTGGCTGGTCCCAAGTGTGGGCAGTGTCCAGATGGTCAAGCCCTGGGCCATCTTGGCTGTGAAGCAGATCCCACAACACCAGTGACTTGTGTGGAAATGCACTGTGAGTTTGGCGCCTCCTGCGTAGAGGAGGCTGGTTTTGCCCAGTGTGTCTGCCCAACTCTCACATGTCCAGAGGCTAACTCTACCAAGGTCTGTGGATCAGATGGTGTCACATACGGCAATGAATGCCAGCTGAAGACCATTGCCTGCCGCCAGCGTCTGGACATCTCCATTCAGAGTCTTGGTCCATGCCGGGAGAGTGTTGCTCCTGGGGTTTCCCCTACATCTGCATCTATGACCACCCCAAGGCATATCCTGAGCAGGACACTGGCGTCTCCCCACAGCAGCCTTCCTCTGTCTCCCAGCACTACTGCCCATGATTGGCCCACCCCATTACCCACATCACCTCAGACCGTAGTCGGCACCCCCAGGAGCACTGCAGCCACACCCTCTGATGTGGCCAGTCTTGCTACAGCGATCTTCAGGGAATCTGGCAGCACCAACGGCAGTGGCGATGAGGAGCTCAGTGGCGATGAGGAGGCCAGTGGGGGCGGGTCTGGGGGACTTGAGCCCCCGGTGGGCAGCGTTGTGGTGACCCACGGGCCACCCATCGAGAGGGCTTCCTGTTACAACTCACCTTTGGGCTGCTGCTCAGATGGC AAGACACCCTCACTGGACTCAGAAGGCTCCAACTGTCCAGCTACCAAGGCATTCCAGGGCGTGCTGGAGCTTGAGGGGGTCGAGGGACAGGAACTGTTCTACACACCAGAGATGGCTGACCCCAAGTCAGAGTTGTTTGGGGAGACTGCAAGGAGCATTGAGAGCACGCTGGACGACCTGTTCCGGAATTCGGATGTTAAGAAGGACTTCTGGAGCATCCGCCTACGGGAACTGGGGCCTGGCAAATTAGTCCGTGCCATTGTGGATGTTCACTTTGACCCCACCACAGCCTTCCAGGCACCAGATGTGGGTCAGGCCTTGCTCCAACAGATCCAGGTATCCAGGCCGTGGGCCCTGGCAGTGAGGAGGCCTCTGCGGGAGCATGTGCGATTCTTGGACTTTGACTGGTTTCCCACTTTTTTTACGGGAGCTGCAACAGGAACCACAGCTGCTGTGGCCACAGCCAGAGCCACCACTGTGAGCCGACTGTCTGCCTCTTCTGTCACCCCACGAGTCTACCCCAGTTACACCAGCCGGCCTGTTGGCAGAACTACGGCACCGCTAACCACTCGCCGGCCACCAACCACTACCGCCAGTATTGACCGACCTCGGACTCCAGGCCCGCAACGGCCCCCAAAGTCCTGTGATTCCCAGCCTTGCCTCCACGGAGGTACCTGCCAGGACCTGGATTCTGGCAAGGGTTTCAGCTGCAGCTGTACTGCAGGCAGGGCTGGCACTGTCTGTGAGAAAGTGCAGCTCCCCTCTGTGCCAGCTTTTAAGGGCCACTCCTTCTTGGCCTTCCCCACCCTCCGAGCCTACCACACGCTGCGTCTGGCACTAGAATTCCGGGCGCTGGAGACAGAGGGACTGCTGCTCTACAATGGCAATGCACGTGGCAAAGATTTCCTGGCTCTGGCTCTGTTGGATGGTCATGTACAGTTCAGGTTCGACACGGGCTCAGGGCCGGCGGTGCTAACAAGCTTAGTGCCAGTGGAACCGG GACGGTGGCACCGCCTCGAGTTGTCACGGCATTGGCGGCAGGGCACACTTTCTGTGGATGGCGAGGCTCCTGTTGTAGGTGAAAGTCCGAGTGGCACTGATGGCCTCAACTTGGACACGAAGCTCTATGTGGGTGGTCTCCCAGAAGAACAAGTTGCCACGGTGCTTGATCGGACCTCTGTGGGCATCGGCCTGAAAGGATGCATTCGTATGTTGGACATCAACAACCAGCAGCTGGAGCTGAGCGATTGGCAGAGGGCTGTGGTTCAAAGCTCTGGTGTGGGGGAATGCGGAGACCATCCCTGCTCACCTAACCCCTGCCATGGCGGGGCCCTCTGCCAGGCCCTGGAGGCTGGCGTGTTCCTCTGTCAGTGCCCACCTGGCCGCTTTGGCCCAACTTGTGCAGATGAAAAGAACCCCTGCCAACCGAACCCCTGCCACGGGTCAGCCCCCTGCCATGTGCTTTCCAGGGGTGGGGCCAAGTGTGCGTGCCCCCTGGGACGCAGTGGTTCCTTCTGTGAGACAGTCCTGGAGAATGCTGGCTCCCGGCCCTTCCTGGCTGACTTTAATGGCTTCTCCTACCTGGAACTGAAAGGCTTGCACACCTTCGAGAGAGACCTAGGGGAGAAGATGGCGCTGGAGATGGTGTTCTTGGCTCGTGGGCCCAGTGGCTTACTCCTCTACAATGGGCAGAAGACGGATGGCAAGGGGGACTTTGTATCCCTGGCCCTGCATAACCGGCACCTAGAGTTCCGCTATGACCTTGGCAAGGGGGCTGCAATCATCAGGAGCAAAGAGCCCATAGCCCTGGGCACCTGGGTTAGGGTATTCCTGGAACGAAATGGCCGCAAGGGTGCCCTTCAAGTGGGTGATGGGCCCCGTGTGCTAGGGGAATCTCCGAAATCCCGCAAGGTCCCGCACACCATGCTCAACCTCAAGGAGCCCCTCTATGTGGGGGGAGCTCCTGACTTCAGCAAGCTGGCTCGGGGCGCTGCAGTGGC CTCCGGCTTTGATGGTGCCATCCAGCTGGTGTCTCTAAGAGGCCATCAGCTGCTGACTCAGGAGCATGTGTTGCGGGCAGTAGATGTAGCGCCTTTTGCAGGCCACCCTTGTACCCAGGCCGTGGACAACCCCTGCCTTAATGGGGGCTCCTGTATCCCGAGGGAAGCCACTTATGAGTGCCTGTGTCCTGGGGGCTTCTCTGGGCTGCACTGCGAGAAGGGGATAGTTGAGAAGTCAGTGGGGGACCTAGAAACACTGGCCTTTGATGGGCGGACCTACATCGAGTACCTCAATGCTGTGACTGAGAGCGAGCTGACCAATGAGATCCCAGCCCCCGAAACTCTGGATTCCCGGGCCCTTTTCAGTGAGAAAGCGCTGCAGAGCAACCACTTTGAGCTGAGCTTACGCACTGAGGCCACGCAGGGGCTGGTGCTGTGGATTGGAAAGGTTGGAGAACGTGCAGACTACATGGCTCTGGCCATTGTGGATGGGCACCTACAACTGAGCTATGACCTAGGCTCCCAGCCAGTTGTGCTGCGCTCCACTGTGAAGGTCAACACCAACCGCTGGCTTCGAGTCAGGGCTCACAGGGAGCACAGGGAAGGTTCCCTTCAGGTGGGCAATGAAGCCCCTGTGACTGGCTCTTCCCCGCTGGGTGCCACACAATTGGACACAGATGGAGCCCTGTGGCTTGGAGGCCTACAGAAGCTTCCTGTGGGGCAGGCTCTCCCCAAGGCCTATGGCACGGGTTTTGTGGGCTGTCTGCGGGACGTGGTAGTGGGCCATCGCCAGCTGCATCTGCTGGAGGACGCTGTCACCAAACCAGAGCTAAGACCCTGCCCCACTCTCTGA

Mu Agrin

(SEQ ID NO: 113)

MPPLPLEHRPRQQPGASVLVRYFMIPCNICLILLATSTLGFAVLLFLSNYKPGIHFTAAPSMPPDVCRGMLCGFGAVCEPSVEDPGRASCVCKKNVCPAMVAPVCGSDASTYSNECELQRAQCNQQRRIRLLRQGPCGSRDPCANVTCSFGSTCVPSADGQTASCLCPTTCFGAPDGTVCGSDGVDYPSECQLLRHACANQEHIFKKFDGPCDPCQGSMSDLNHICRVNPRTRHPEMLLRPENCPAQHTPICGDDGVTYENDCVMSRIGAARGLLLQKVRSGQCQTRDQCPETCQFNSVCLSRRGRPHCSCDRVTCDGAYRPVCAQDGHTYDNDCWRQQAECRQQQTIPPKHQGPCDQTPSPCRGAQCAFGATCTVKNGKAVCECQRVCSGGYDPVCGSDGVTYGSVCELESMACTLGREIRVARRGPCDRCGQCRFGSLCEVETGRCVCPSECVESAQPVCGSDGHTYASECELHVHACTHQISLYVASAGHCQTCGETVCTFGAVCSAGQCVCPRCEHPPPGPVCGSDGVTYLSACELREAACQQQVQIEEARAGPCEPAECGSGGSGSGEDNACEQELCRQHGGVWDEDSEDGPCVCDFSCQSVLKSPVCGSDGVTYSTECHLKKARCEARQELYVAAQGACRGPTLAPLLPMASPHCAQTPYGCCQDNVTAAQGVGLAGCPSTCHCNPHGSYSGTCDPVTGQCSCRPGVGGLRCDRCEPGFWNFRGIVTDGHSGCTPCSCDPRGAVRDDCEQMTGLCSCRPGVAGPKCGQCPDGQALGHLGCEADPTTPVTCVEMHCEFGASCVEEAGFAQCVCPTLTCPEANSTKVCGSDGVTYGNECQLKTIACRQRLDISIQSLGPCRESVAPGVSPTSASMTTPRHILSRTLASPHSSLPLSPSTTAHDWPTPLPTSPQTVVGTPRSTAATPSDVASLATAIFRESGSTNGSGDEELSGDEEASGGGSGGLEPPVGSVVVTHGPPIERASCYNSPLGCCSDG KTPSLDSEGSNCPATKAFQGVLELEGVEGQELFYTPEMADPKSELFGETARSIESTLDDLFRNSDVKKDFWSIRLRELGPGKLVRAIVDVHFDPTTAFQAPDVGQALLQQIQVSRPWALAVRRPLREHVRFLDFDWFPTFFTGAATGTTAAVATARATTVSRLSASSVTPRVYPSYTSRPVGRTTAPLTTRRPPTTTASIDRPRTPGPQRPPKSCDSQPCLHGGTCQDLDSGKGFSCSCTAGRAGTVCEKVQLPSVPAFKGHSFLAFPTLRAYHTLRLALEFRALETEGLLLYNGNARGKDFLALALLDGHVQFRFDTGSGPAVLTSLVPVEPGRWHRLELSRHWRQGTLSVDGEAPVVGESPSGTDGLNLDTKLYVGGLPEEQVATVLDRTSVGIGLKGCIRMLDINNQQLELSDWQRAVVQSSGVGECGDHPCSPNPCHGGALCQALEAGVFLCQCPPGRFGPTCADEKNPCQPNPCHGSAPCHVLSRGGAKCACPLGRSGSFCETVLENAGSRPFADFNGFSYLELKGLHTFERDLGEKMALEMVFLARGPSGLLLYNGQKTDGKGDFVSLALHNRHLEFRYDLGKGAAIIRSKEPIALGTWVRVFLERNGRKGALQVGDGPRVLGESPKSRKVPHTMLNLKEPLYVGGAPDFSKLARGAAVASGFDGAIQLVSLRGHQLLTQEHVLRAVDVAPFAGHPCTQAVDNPCLNGGSCIPREATYECLCPGGFSGLHCEKGIVEKSVGDLETLAFDGRTYIEYLNAVTESELTNEIPAPETLDSRALFSEKALQSNHFELSLRTEATQGLVLWIGKVGERADYMALAIVDGHLQLSYDLGSQPVVLRSTVKVNTNRWLRVRAHREHREGSLQVGNEAPVTGSSPLGATQLDTDGALWLGGLQKLPVGQALPKAYGTGFVGCLRDVVVGHRQLHLLEDAVTKPELRPCPTL

MuIL10

(SEQ ID NO: 114)

ATGCCTGGCTCAGCACTGCTATGCTGCCTGCTCTTACTGACTGGCATGAGGATCAGCAGGGGCCAGTACAGCCGGGAAGACAATAACTGCACCCACTTCCCAGTCGGCCAGAGCCACATGCTCCTAGAGCTGCGGACTGCCTTCAGCCAGGTGAAGACTTTCTTTCAAACAAAGGACCAGCTGGACAACATACTGCTAACCGACTCCTTAATGCAGGACTTTAAGGGTTACTTGGGTTGCCAAGCCTTATCGGAAATGATCCAGTTTTACCTGGTAGAAGTGATGCCCCAGGCAGAGAAGCATGGCCCAGAAATCAAGGAGCATTTGAATTCCCTGGGTGAGAAGCTGAAGACCCTCAGGATGCGGCTGAGGCGCTGTCATCGATTTCTCCCCTGTGAAAATAAGAGCAAGGCAGTGGAGCAGGTGAAGAGTGATTTTAATAAGCTCCAAGACCAAGGTGTCTACAAGGCCATGAATGAATTTGACATCTTCATCAACTGCATAGAAGCATACATGATGATCAAAATGAAAAGCTAA

MuIL10

(SEQ ID NO: 115)

MPGSALLCCLLLLTGMRISRGQYSREDNNCTHFPVGQSHMLLELRTAFSQVKTFFQTKDQLDNILLTDSLMQDFKGYLGCQALSEMIQFYLVEVMPQAEKHGPEIKEHLNSLGEKLKTLRMRLRRCHRFLPCENKSKAVEQVKSDFNKLQDQGVYKAMNEFDIFINCIEAYMMIKMKS

MuMYDGF (C19orf10)

(SEQ ID NO: 116)

ATGGCAGCCCCCAGCGGAGGCTTCTGGACTGCGGTGGTCCTGGCGGCCGCAGCGCTGAAATTGGCCGCCGCTGTGTCCGAGCCCACCACCGTGCCATTTGACGTGAGGCCCGGAGGGGTCGTGCATTCGTTCTCCCAGGACGTAGGACCCGGGAACAAGTTTACATGTACATTCACCTACGCTTCCCAAGGAGGGACCAACGAGCAATGGCAGATGAGCCTGGGGACAAGTGAAGACAGCCAGCACTTTACCTGTACCATCTGGAGGCCCCAGGGGAAATCCTACCTCTACTTCACACAGTTCAAGGCTGAGTTGCGAGGTGCTGAGATCGAGTATGCCATGGCCTACTCCAAAGCCGCATTTGAGAGAGAGAGTGATGTCCCCCTGAAAAGTGAGGAGTTTGAAGTGACCAAGACAGCAGTGTCTCACAGGCCTGGGGCCTTCAAAGCTGAGCTCTCCAAGCTGGTGATCGTAGCCAAGGCGGCACGCTCGGAGCTGTGA

MuMYDGF (C19orf10)

(SEQ ID NO: 117)

MAAPSGGFWTAVVLAAAALKLAAAVSEPTTVPFDVRPGGVVHSFSQDVGPGNKFTCTFTYASQGGTNEQWQMSLGTSEDSQHFTCTIWRPQGKSYLYFTQFKAELRGAEEIEYAMAYSKAAFERESDVPLKSEEFEVTKTAVSHRPGAFKAELSKLVIVAKAARSEL

pWF-521

(SEQ ID NO: 118)

CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCAGGCGCCGGATCTGGTGGAAACTGGAGTCATCCCCAATTCGAGAAGGGCGGAAGCGGTGGGAGTGGCGGGTCCGGTGGAAGCAACTGGTCACACCCACAATTCGAGAAAGGCGGTTCTGGCGGATCTGGTGGATCTGGCGGAAGTAACTGGTCTCATCCTCAATTCGAAAAGGGCGGAAGCGGTGGCGGCAGGCTAGGTGGAGGCTCAGTGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGA GTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGAGCTGCAACTGGAGGAGAGCTGTGCGGAGGCGCAGGACGGGGAGCTGGACGGGCTGTGGACGACCATCACCATCTTCATCACACTCTTCCTGTTAAGCGTGTGCTACAGTGCCACCGTCACCTTCTTCAAGGTGAAGTGGATCTTCTCCTCGGTGGTGGACCTGAAGCAGACCATCATCCCCGACTACAGGAACATGATCGGACAGGGGGCCTGA

pWF-521

(SEQ ID NO: 119)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGAGSGGNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGSGGSGGSNWSHPQFEKGGSGGGRLGGGSVQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFKVKWIFSSVVDLKQTIIPDYRNMIGQGA

pWF-533

(SEQ ID NO: 120)

CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAtcttcaGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGC

pWF-533

(SEQ ID NO: 121)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVNHSCKRVNTKPSKDDSGLYSLSSVVTVPSSSLGTQPSKKNV

pWF-534

(SEQ ID NO: 122)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCTCCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGC CAGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGAGCTGCAACTGGAGGAGAGCTGTGCGGAGGCGCAGGACGGGGAGCTGGACGGGCTGTGGACGACCATCACCATCTTCATCACACTCTTCCTGTTAAGCGTGTGCTACAGTGCCACCGTCACCTTCTTCAAGGTGAAGTGGATCTTCTCCTCGGTGGTGGACCTGAAGCAGACCATCATCCCCGACTACAGGAACATGATCGGACAGGGGGCCTGA

pWF-534

(SEQ ID NO: 123)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFKVKWIFSSVVDLKQTIIPDYRNMIGQGA

mu-IL15

(SEQ ID NO: 124)

ATGAAAATTTTGAAACCATATATGAGGAATACATCCATCTCGTGCTACTTGTGTTTCCTTCTAAACAGTCACTTTTTAACTGAGGCTGGCATTCATGTCTTCATTTTGGGCTGTGTCAGTGTAGGTCTCCCTAAAACAGAGGCCAACTGGATAGATGTAAGATATGACCTGGAGAAAATTGAAAGCCTTATTCAATCTATTCATATTGACACCACTTTATACACTGACAGTGACTTTCATCCCAGTTGCAAAGTTACTGCAATGAACTGCTTTCTCCTGGAATTGCAGGTTATTTTACATGAGTACAGTAACATGACTCTTAATGAAACAGTAAGAAACGTGCTCTACCTTGCAAACAGCACTCTGTCTTCTAACAAGAATGTAGCAGAATCTGGCTGCAAGGAATGTGAGGAGCTGGAGGAGAAAACCTTCACAGAGTTTTTGCAAAGCTTTATACGCATTGTCCAAATGTTCATCAACACGTCC

mu-IL15

(SEQ ID NO: 125)

MKILKPYMRNTSISCYLCFLLNSHFLTEAGIHVFILGCVSVGLPKTEANWIDVRYDLEKIESLIQSIHIDTTLYTDSDFHPSCKVTAMNCFLLELQVILHEYSNMTLNETVRNVLYLANSTLSSNKNVAESGCKECEELEEKTFTEFLQSFIRIVQMFINTS

anti-human GPC3 CAR (79a)

(SEQ ID NO: 126)

GTGGTCCCCGTGCTGCAGAAAGTTAATAGCACCACCACTAAACCTGTCCTGAGGACTCCTAGTCCAGTGCACCCAACAGGGACCAGTCAGCCACAGAGACCGGAAGACTGCAGACCAAGAGGTTCAGTGAAGGGAACCGGCCTGGATTTCGCCTGCGAT TTTTGGGCCCTGGTCGTCGTCGCAGGAGTTTTGTTTTGCTATGGACTGCTCGTCACAGTTGCTTTGTGTGTTATCTGGACA AGGAAACGGTGGCAAAATGAGAAGTTTGGGGTGGACATGCCAGATGACTATGAAGATGAAAATCTCTATGAGGGCCTGAACCTTGATGACTGTTCTATGTATGAGGACATCTCCAGGGGACTCCAGGGCACCTACCAGGATGTGGGCAACCTCCACATTGGAGATGCCCAGCTGGAAAAGCCATGA

anti-human GPC3 CAR (79a)

(SEQ ID NO: 127)

QSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSAAA VVPVLQKVNSTTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACD FWALVVVAGVLFCYGLLVTVALCVIWT RKRWQNEKFGVDMPDDYEDENLYEGLNLDDCSMYEDISRGLQGTYQDVGNLHIGDAQLEKP

anti-human PSMA (XENP14484) CAR 79a

(SEQ ID NO: 128)

GTGGTCCCCGTGCTGCAGAAAGTTAATAGCACCACCACTAAACCTGTCCTGAGGACTCCTAGTCCAGTGCACCCAACAGGGACCAGTCAGCCACAGAGACCGGAAGACTGCAGACCAAGAGGTTCAGTGAAGGGAACCGGCCTGGATTTCGCCTGCGAT TTTTGGGCCCTGGTCGTCGTCGCAGGAGTTTTGTTTTGCTATGGACTGCTCGTCACAGTTGCTTTGTGTGTTATCTGGACA AGGAAACGGTGGCAAAATGAGAAGTTTGGGGTGGACATGCCAGATGACTATGAAGATGAAAATCTCTATGAGGGCCTGAACCTTGATGACTGTTCTATGTATGAGGACATCTCCAGGGGACTCCAGGGCACCTACCAGGATGTGGGCAACCTCCACATTGGAGATGCCCAGCTGGAAAAGCCATGA

anti-human PSMA (XENP14484) CAR 79a

(SEQ ID NO: 129)

EVQLVQSGAEVKKPGASVKVSCKTSGYTFTEYTIHWVRQAPGQSLEWMGNINPNNGGTTYNQKFQGRVTITVDKSTSTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLVTVSSGKPGSGKPGSGKPGSGKPGSDIVMTQSPDSLAVSLGERATLSCRASQDVGTAVDWYQQKPDQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQYNSYPLTFGAGTKVEIK VVPVLQKVNSTTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACD FWALVVVAGVLFCYGLLVTVALCVIWT RKRWQNEKFGVDMPDDYEDENLYEGLNLDDCSMYEDISRGLQGTYQDVGNLHIGDAQLEKP

Mouse IL 12a - Mouse IgG2a Fc

(SEQ ID NO: 130)

ATGTGTCAGTCACGCTATCTTCTCTTCCTTGCTACTCTGGCCTTGCTCAATCACTTGTCCCTTGCTCGTGTGATTCCTGTGTCCGGCCCAGCTAGGTGTCTCTCCCAGTCACGGAATCTCCTGAAAACCACGGATGACATGGTAAAGACAGCTAGGGAGAAACTCAAGCACTACTCCTGCACAGCTGAGGATATCGATCATGAGGACATCACCAGGGACCAGACATCCACTCTGAAAACTTGCCTGCCTTTGGAACTCCACAAGAACGAATCTTGTCTGGCAACGCGTGAAACGAGTTCTACTACAAGAGGGTCCTGTCTTCCCCCTCAAAAGACAAGCCTTATGATGACCTTGTGTCTCGGTAGCATTTATGAGGACCTAAAGATGTATCAAACCGAGTTTCAGGCTATCAATGCAGCGCTCCAGAATCATAACCATCAGCAGATCATTCTTGACAAAGGAATGCTCGTGGCCATTGATGAACTAATGCAGAGCCTAAACCACAATGGCGAGACTCTTCGACAGAAACCGCCTGTGGGCGAGGCCGATCCATATAGAGTCAAAATGAAACTGTGTATTCTCCTGCATGCATTTAGTACTCGTGTAGTGACTATTAACAGAGTGATGGGTTACCTTTCCTCAGCTCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGA GAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAATAG

Mouse IL 12a - Mouse IgG2a Fc

(SEQ ID NO: 131)

MCQSRYLLFLATLALLNHLSLARVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK*

Mouse IL 12b-Mouse IgG2a Fc

(SEQ ID NO: 132)

ATGTGCCCACAGAAACTCACAATTTCTTGGTTCGCAATCGTCCTGCTGGTGTCACCCCTGATGGCAATGTGGGAGTTGGAAAAGGATGTATACGTCGTCGAGGTCGACTGGACACCTGACGCTCCGGGTGAAACTGTCAACCTCACTTGCGATACTCCTGAAGAGGACGACATCACGTGGACGAGCGACCAGCGACATGGAGTGATAGGGTCTGGCAAGACGCTTACTATCACGGTTAAGGAATTTCTCGACGCAGGGCAGTACACATGTCACAAGGGCGGCGAGACTCTGAGCCACTCCCATTTGCTGCTGCACAAGAAGGAGAATGGTATCTGGTCTACCGAAATCCTGAAGAATTTTAAGAACAAGACTTTTCTGAAATGCGAGGCCCCAAATTATTCCGGACGTTTCACTTGCAGTTGGCTCGTTCAAAGAAATATGGACTTGAAATTTAACATTAAATCCAGCTCTTCATCTCCTGACAGCAGGGCCGTAACTTGTGGAATGGCTTCATTGTCAGCTGAGAAAGTTACGCTTGACCAAAGGGATTATGAGAAATACAGCGTGAGTTGCCAGGAAGATGTGACATGTCCAACGGCAGAGGAAACGTTGCCAATTGAGCTCGCTTTGGAAGCTCGTCAACAAAACAAGTATGAAAACTATAGTACTAGCTTCTTCATACGGGACATCATCAAACCAGATCCACCTAAGAATTTGCAGATGAAGCCTCTGAAGAATTCACAAGTCGAGGTATCCTGGGAATACCCAGATTCATGGTCCACTCCTCATAGTTACTTTAGCCTGAAATTCTTTGTACGCATACAGCGGAAGAAGGAGAAAATGAAGGAGACGGAAGAAGGCTGCAATCAGAAAGGCGCTTTTCTTGTTGAAAAGACGAGCACTGAGGTTCAATGCAAAGGCGGGAATGTATGTGTTCAAGCCCAAGATAGGTATTATAATAGCTCCTGCTCTAAGTGGGCTTGCGTACCATGCAGAGTTA GAAGTCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAATAG

Mouse IL 12b-Mouse IgG2a Fc

(SEQ ID NO: 133)

MCPQKLTISWFAIVLLVSPLMAMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK

Mouse IL 12a - Mouse IgG2a Fc (Silent)

(SEQ ID NO: 134)

ATGTGTCAGTCACGCTATCTTCTCTTCCTTGCTACTCTGGCCTTGCTCAATCACTTGTCCCTTGCTCGTGTGATTCCTGTGTCCGGCCCAGCTAGGTGTCTCTCCCAGTCACGGAATCTCCTGAAAACCACGGATGACATGGTAAAGACAGCTAGGGAGAAACTCAAGCACTACTCCTGCACAGCTGAGGATATCGATCATGAGGACATCACCAGGGACCAGACATCCACTCTGAAAACTTGCCTGCCTTTGGAACTCCACAAGAACGAATCTTGTCTGGCAACGCGTGAAACGAGTTCTACTACAAGAGGGTCCTGTCTTCCCCCTCAAAAGACAAGCCTTATGATGACCTTGTGTCTCGGTAGCATTTATGAGGACCTAAAGATGTATCAAACCGAGTTTCAGGCTATCAATGCAGCGCTCCAGAATCATAACCATCAGCAGATCATTCTTGACAAAGGAATGCTCGTGGCCATTGATGAACTAATGCAGAGCCTAAACCACAATGGCGAGACTCTTCGACAGAAACCGCCTGTGGGCGAGGCCGATCCATATAGAGTCAAAATGAAACTGTGTATTCTCCTGCATGCATTTAGTACTCGTGTAGTGACTATTAACAGAGTGATGGGTTACCTTTCCTCAGCTCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCAGCACCTAACGCTGCCGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCGGAGCGCCCATCGAGA GAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAATGA

Mouse IL 12a - Mouse IgG2a Fc (Silent)

(SEQ ID NO: 135)

MCQSRYLLFLATLALLNHLSLARVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAPRGPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLGAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK*

Mouse IL 12b-Mouse IgG2a Fc (Silent)

(SEQ ID NO: 136)

ATGTGCCCACAGAAACTCACAATTTCTTGGTTCGCAATCGTCCTGCTGGTGTCACCCCTGATGGCAATGTGGGAGTTGGAAAAGGATGTATACGTCGTCGAGGTCGACTGGACACCTGACGCTCCGGGTGAAACTGTCAACCTCACTTGCGATACTCCTGAAGAGGACGACATCACGTGGACGAGCGACCAGCGACATGGAGTGATAGGGTCTGGCAAGACGCTTACTATCACGGTTAAGGAATTTCTCGACGCAGGGCAGTACACATGTCACAAGGGCGGCGAGACTCTGAGCCACTCCCATTTGCTGCTGCACAAGAAGGAGAATGGTATCTGGTCTACCGAAATCCTGAAGAATTTTAAGAACAAGACTTTTCTGAAATGCGAGGCCCCAAATTATTCCGGACGTTTCACTTGCAGTTGGCTCGTTCAAAGAAATATGGACTTGAAATTTAACATTAAATCCAGCTCTTCATCTCCTGACAGCAGGGCCGTAACTTGTGGAATGGCTTCATTGTCAGCTGAGAAAGTTACGCTTGACCAAAGGGATTATGAGAAATACAGCGTGAGTTGCCAGGAAGATGTGACATGTCCAACGGCAGAGGAAACGTTGCCAATTGAGCTCGCTTTGGAAGCTCGTCAACAAAACAAGTATGAAAACTATAGTACTAGCTTCTTCATACGGGACATCATCAAACCAGATCCACCTAAGAATTTGCAGATGAAGCCTCTGAAGAATTCACAAGTCGAGGTATCCTGGGAATACCCAGATTCATGGTCCACTCCTCATAGTTACTTTAGCCTGAAATTCTTTGTACGCATACAGCGGAAGAAGGAGAAAATGAAGGAGACGGAAGAAGGCTGCAATCAGAAAGGCGCTTTTCTTGTTGAAAAGACGAGCACTGAGGTTCAATGCAAAGGCGGGAATGTATGTGTTCAAGCCCAAGATAGGTATTATAATAGCTCCTGCTCTAAGTGGGCTTGCGTACCATGCAGAGTTA GAAGTCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCAGCACCTAACGCTGCCGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCGGAGCGCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAATGA

Mouse IL 12b-Mouse IgG2a Fc (Silent)

(SEQ ID NO: 137)

MCPQKLTISWFAIVLLVSPLMAMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSPRGPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLGAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK

CD3 zeta cytoplasmic domain - human

(SEQ ID NO: 138)

RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

CD3 zeta cytoplasmic domain - human

(SEQ ID NO: 139)

AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAA

pWF-506

(SEQ ID NO: 140)

METDTLLLWVLLLWVPGSTGQSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFKVKWIFSSVVDLKQTIIPDYRNMIGQGA

pWF-506

(SEQ ID NO: 141)

ATGGAAACCGATACACTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCAGGATCTACCGGTCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGG ACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGAGCTGCAACTGGAGGAGAGCTGTGCGGAGGCGCAGGACGGGGAGCTGGACGGGCTGTGGACGACCATCACCATCTTCATCACACTCTTCCTGTTAAGCGTGTGCTACAGTGCCACCGTCACCTTCTTCAAGGTGAAGTGGATCTTCTCCTCGGTGGTGGACCTGAAGCAGACCATCATCCCCGACTACAGGAACATGATCGGACAGGGGGCCTGA

pWF-507:

(SEQ ID NO: 142)

METDTLLLWVLLLWVPGSTGQSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSYSTVKQPEWAA

pWF-507:

(SEQ ID NO: 143)

ATGGAAACCGATACACTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCAGGATCTACCGGTCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAG

pWF-508:

(SEQ ID NO: 144)

MVFTPQILGLMLFWISASRGQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFKVKWIFSSVVDLKQTIIPDYRNMIGQGA

pWF-508:

(SEQ ID NO: 145)

ATGGTGTTTACACCGCAAATATTGGGGCTCATGCTTTTCTGGATCAGTGCAAGCAGGGGACAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACT GGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGAGCTGCAACTGGAGGAGAGCTGTGCGGAGGCGCAGGACGGGGAGCTGGACGGGCTGTGGACGACCATCACCATCTTCATCACACTCTTCCTGTTAAGCGTGTGCTACAGTGCCACCGTCACCTTCTTCAAGGTGAAGTGGATCTTCTCCTCGGTGGTGGACCTGAAGCAGACCATCATCCCCGACTACAGGAACATGATCGGACAGGGGGCCTGA

pWF-509:

(SEQ ID NO: 146)

METDTLLLWVLLLWVPGSTGQSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVLDKDDSKAGMEEDHTYEGLDIDQTATYEDIVTLRTGEVKWSVGEHPGQE

pWF-509:

(SEQ ID NO: 147)

ATGGAAACCGATACACTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCAGGATCTACCGGTCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCGCTGCATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAG TGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGCTGGACAAGGATGACAGCAAGGCTGGCATGGAGGAAGATCACACCTACGAGGGCCTGGACATTGACCAGACAGCCACCTATGAGGACATAGTGACGCTGCGGACAGGGGAAGTGAAGTGGTCTGTAGGTGAGCACCCAGGCCAGGAGTGA

pWF-510:

(SEQ ID NO: 148)

METDTLLLWVLLLWVPGSTGQSVLTQPPSVSAAPGQRVTISCSGTRSNIGSDYVSWYQHLPGTAPKLLVYGDNLRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDYTLNGVVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTSYLNHGDYWGQGTLVTVSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVRKRWQNEKLGLDAGDEYEDENLYEGLNLDDCSMYEDISRGLQGTYQDVGSLNIGDVQLEKP

pWF-510:

(SEQ ID NO: 149)

ATGGAAACCGATACACTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCAGGATCTACCGGTCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAGGGTCACCATCTCCTGCTCTGGAACCAGGTCCAACATTGGGAGTGATTATGTTTCCTGGTACCAACACCTCCCAGGAACAGCCCCCAAACTCCTCGTTTATGGCGATAATCTGCGACCCTCAGGGATTCCTGACCGATTCTCTGCCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGCACATGGGATTACACCCTGAATGGTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGTAGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGATAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCACTTCTTACCTGAACCATGGTGATTACTGGGGTCAAGGTACTCTGGTGACCGTGTCTAGCGCCGCTGCATTCGTGCCTGTGTTCCTCCCAGCTAAGCCCACTACCACCCCCGCTCCAAGGCCGCCCACGCCCGCTCCTACTATTGCTAGTCAGCCTTTAAGTTTACGACCCGAAGCTTGCAGGCCCGCCGCCGGCGGCGCTGTGCACACCAGGGGGCTTGATTTTGCCTGCGACTTTTGGGTATTGGTAG TGGTGGGCGGAGTTTTAGCCTGCTACAGCCTCCTGGTAACAGTGGCTTTTATCATCTTTTGGGTGAGGAAACGATGGCAGAACGAGAAGCTCGGGTTGGATGCCGGGGATGAATATGAAGATGAAAACCTTTATGAAGGCCTGAACCTGGACGACTGCTCCATGTATGAGGACATCTCCCGGGGCCTCCAGGGCACCTACCAGGATGTGGGCAGCCTCAACATAGGAGATGTCCAGCTGGAGAAGCCGA

Integration by reference

All publications, patents and patent applications mentioned herein are incorporated herein by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. However, citation of any reference herein is not to be construed as an admission that such reference is prior art to the present invention. To the extent that definitions or terms provided in references incorporated by reference differ from the terms and discussion provided herein, the terms and definitions govern.

equivalent

The foregoing specification is considered sufficient to enable any person skilled in the art to practice the present invention. The foregoing description and embodiments detail certain preferred embodiments of the present invention and illustrate the best mode contemplated by the present inventors. However, no matter how detailed the foregoing may appear in text, it is to be understood that the invention may be practiced in many different ways and that the invention should be construed in accordance with the appended claims and any equivalents thereof.

The following experimental examples, including experiments performed and results achieved, are provided for illustrative purposes only and should not be construed as limiting the present invention.

Experimental example

Experimental Example 1 - Chimeric Antigen Receptor to B Cell (CAR-B) Constructs Bind to PSMA.

DNA constructs. An exemplary CAR-B construct was designed to recognize prostate specific membrane antigen ("PSMA"). PSMA is an antigen that is more highly expressed on prostate cancer cells than on other non-cancerous cells. A variety of constructs were prepared that included an extracellular domain containing scFv specific for PSMA, an extracellular hinge region from CD8, a CD28 transmembrane domain, and various intracellular signaling domains. A list of configurations is given in Table 6:

construct Described pWF-82 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-hCD19E (SEQ ID NOs: 39 and 40) pWF-83 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-hCD40E (SEQ ID NOs: 41 and 42) pWF-84 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-h(CD40+CD79b)E (SEQ ID NOs: 43 and 44) pWF-85 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-h(CD40+CD137)E (SEQ ID NOs: 45 and 46) pWF-86 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-h(CD40+Fcγr2a)E (SEQ ID NO: 47) pWF-87 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-h(hMyd88+CD40)E (SEQ ID NOs: 48 and 49) pWF-88 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-hCD79aE (SEQ ID NOs: 50 and 51) pWF-89 pTLPW-SFFV-XENP14484 scFv-hCD8H-hCD28M-hCD79bE (SEQ ID NOs: 52 and 53)

Expression of anti-PSMA CAR-B in HEK-293 cells. Constructs encoding pWF82 to pWF89 were used to prepare lentiviruses in Lentix cells using the Takara Lentivirus Production Kit. Expression of the various CAR-B constructs was measured using flow cytometry using an antibody specific for PSMA (Biotin-PSMA, Sinobiological and shown in FIG. 5 ).

Expression of anti-PSMA CAR-B in human B cells. Two additional constructs were made to measure the expression and binding of anti-PSMA CAR-B in B cells:

construct Described pWF-391 pMMLV(LTR)-hEF1a promoter-anti hPSMA(XENP14484)-CBCR (SEQ ID NOs: 54 and 55) pWF-394 pMMLV(LTR)-hEF1a promoter-anti-sarcoglycan CBCR1 (SEQ ID NOs: 56 and 57)

MMLV-based vectors were used for the production of retroviruses. Retrovirus was used to infect mouse B cells isolated from the spleen. After transduction, B cells were further expanded on feeder cells expressing CD40L and soluble IL-4. Expression of anti-PSMA CAR-B was detected using recombinant biotin-PSMA. PSMA binding was detected in HEK-293 cells using PE-labeled streptavidin.

result. The results of this experiment are shown in FIG. 6 and demonstrate that it is possible to generate mouse B cells expressing CAR-B capable of binding specifically to an antigen. For example, B cells expressing pWF396 or pWF397 bound PSMA, whereas B cells expressing pWF394 did not bind PSMA. pWF398 was designed to bind sarcoglycan, but not PSMA.

Experimental Example 2 - A Chimeric Antigen Receptor (CAR-B) on B cells is constructed to bind to GPC3.

DNA constructs. An exemplary CAR construct was designed to recognize glypican-3 (GPC-3). Glypican-3 is expressed in hepatocellular carcinoma cells, among other tumor types, but not in most non-cancer cells. GPC3 can be used to target anti-GPC3 CARs in hepatocellular carcinoma as well as other cancers in which GPC3 is expressed (e.g., ovarian clear cell carcinoma, pediatric cancer, lung cancer (i.e., lung adenocarcinoma and lung squamous cell carcinoma), urothelial carcinoma, thyroid cancer, gastric cancer, etc. ) can be used to target A variety of constructs were prepared that included an extracellular domain containing an scFv specific for GPC-3, an extracellular hinge region from CD8, a CD28 transmembrane domain, and various intracellular signaling domains. An additional anti-PSMA CAR-B was constructed as a control for these experiments. A list of constructs is provided in Table 8.

construct Described pWF-396 pMMLV(LTR)-hEF1 promoter-anti-GPC3 scFv-hCD8H-hCD28M-hCD79aE (SEQ ID NOs: 58 and 59) pWF-397 pMMLV(LTR)-hEF1 promoter-anti-GPC3 scFv-hCD8H-hCD28M-hCD79bE (SEQ ID NOs: 60 and 61) pWF-398 pMMLV(LTR)-hEF1promoter-anti-hPSMA(XENP14484) scFv-hCD8H-hCD28M-hCD79aE (SEQ ID NOs: 62 and 63)

Expression of anti-GPC-3 in HEK-293 cells. Lentiviral transduction was used to express the GPC3 CAR-B protein on the HEK293 cell surface. Expression was determined by flow cytometry using an anti-idiotypic antibody specific for GPC-3 (Eureka Therapeutics).

Expression of anti-GPC-3 CAR-B in human B cells. MMLV retroviruses were prepared using the pWF 396, 397 and 398 encoding CAR constructs. Mouse B cells isolated by negative selection (Stem Cell Technologies) were transduced using this retrovirus and co-cultured with HeLa cells expressing CD40L and activated for 24 hours by addition of soluble IL-4. 48 hours after transduction, expression was confirmed using flow cytometry. Expression of CAR-B was detected using an anti-idiotypic antibody to human GPC3. Anti-idiotypic antibodies were obtained from Eureka Therapeutics.

result. Mouse B cells expressing anti-GPC-3 CAR-B, pWF-396 and 397 were expressed and specifically bound by anti-GPC3 idiotypic antibodies.

Experimental Example 3 - Adenovirus variant F35 expressing GFP

Adenovirus variant F35 expressing GFP has been demonstrated to efficiently infect human B cells. Human B cells were isolated from peripheral blood. B cells were infected with adenovirus encoding GFP in volumes of 0, 1, 3, and 10 μL. The titer of the adenovirus preparation was approximately 1 xe ¹² particles/ml.

Experimental Example 4 - Payload Delivery to Tumor Cells

A large-scale screening study was conducted to investigate the effect of the payload on NIH3T3 fibroblasts in the CT26 model. Payloads included various immunomodulatory agents including cytokines and chemokines. First, CT26 tumors were injected into the left and right flanks of BALB/c mice. See FIG. 8 . After 12 and 16 days, mice were injected into right flank tumors with various combinations of 4-5 payloads. Tumor volume was measured for up to 35 days.

Generation of the BALB/C CT26 tumor model. A total of 139 mice were injected with CT26 tumors in the left and right flanks.

Choice of payload. The 12 peptides (i) recruit and activate dendritic cells; (ii) initiation of homing and guidance of dendritic cells and T cells to the tumor site; and (iii) potential for activating effector T cells. Selected payloads are listed in Table 9.

payload sequence number FLT3L 70, 71 XCL1 72, 73 TIM4-Fc 74, 75 CXCL13 68, 69 mCCL21 92, 93 mCD80 - membrane bound 86, 87 mCD40L - membrane bound 88, 89 mlFNa A2 84, 85 mlL-12 80, 81 mlL-21 90, 91 mLIGHT mutation 78, 79 M4-1BBL-membrane bound 76, 77 mIL-15 124, 125

Each served a combination of 4-5 payloads, all 12 payloads, or 3T3 cells (no payload) or saline as a control. There were a total of 27 groups (n = 5 mice/group). Experimental groups are identified in Table 10.

army # kill One FLT3L, XCL1, CXCL13, TIM4-Fc, TLR 2 FLT3L, XCL1, CXCL13, CD80-MB 3 FLT3L, XCL1, CXCL13, CD40L-MB, TLR 4 FLT3L, XCL1, CXCL13, IL-12 and TM 5 FLT3L, XCL1, CXCL13, 4-1BBL-MB 6 FLT3L, XCL1, CXCL13, IFNa A2 7 FLT3L, XCL1, LIGHT, TIM4-Fc 8 FLT3L, XCL1, LIGHT, CD80-MB 9 FLT3L, XCL1, LIGHT, CD40L-MB, TLR 10 FLT3L, XCL1, LIGHT, IL-12 and TM 11 FLT3L, XCL1, LIGHT, 4-1BBL-MB 12 FLT3L, XCL1, LIGHT, IFNa A2 13 FLT3L, XCL1, IL-21, TIM4-Fc 14 FLT3L, XCL1, IL-21, CD80-MB 15 FLT3L, XCL1, IL-21, CD40L-MB 16 FLT3L, XCL1, IL-21, IL-12 and TM 17 FLT3L, XCL1, IL-21, 4-1BBL-MB 18 FLT3L, XCL1, IL-21, IFNa A2 19 FLT3L, XCL1, CCL21, TIM4-Fc 20 FLT3L, XCL1, CCL21, CD80-MB 21 FLT3L, XCL1, CCL21, CD40L-MB 22 FLT3L, XCL1, CCL21, IL-12 and TM 23 FLT3L, XCL1, CCL21, 4-1BBL-MB 24 FLT3L, XCL1, CCL21, IFNa A2 25 any payload 26 saline solution 27 3t3 cells (no payload)

administration. Tumor volume was between 100 mm ³ and 150 mm ³ at the time of the first injection. For the group receiving 4 payloads, each payload was delivered at 2.5 x 10 ⁵ cells per injection for a total of 10 ⁶ cells. For the group receiving 5 payloads, each payload was delivered at [x] cells per injection for a total of 3 x 10 ⁶ cells. A fifth payload was administered with poly(I:C), a ds-RNA analogue. Payloads were administered by intratumoral injection. The dose was 50 μL in all groups except for the poly(I:C) group and the large 12-way group (150 μL).

Payload management procedures. Cells were harvested with versene (not in the presence of trypsin). Once collected, cells were counted, spun down, cells counted again and then resuspended in an adjustable volume of 20 x 10 ⁶ /ml. The lyophilized powder is resuspended in water to provide the TLR agonist (Invivogen Cat# ODN:1826). The TLR agonist was resuspended at 10 mg/ml, heated to 70° C. and left at room temperature for 1 hour prior to use. The dose of TLR agonist is 50 μg in 50 μl.

result. Results are shown in Figures 9-11. Several combinations of ipsilaterally injected payloads demonstrated anti-tumor activity in contralateral tumors manifested by delayed tumor growth in this model. Groups 3, 8 and 21 showed the most significant impairment of tumor growth over 30 days.

Experimental Example 5 - Modified B cells expressing and secreting payload

Experimental Design. The BALB/c mouse CT26 tumor model was used to evaluate the efficacy of modified B cells expressing various payloads on tumor volume and survival. Mice were injected with tumor cells in a volume of 100 μL. On day 6, when tumors reached a volume of 175 mm ³ , mice were injected with modified B cells expressing the various payloads described below. Tumor volume and survival were measured for 17 days.

Isolation of mouse PBMC. Mouse PBMCs or splenocytes are isolated from blood or spleen, respectively. PBMCs are isolated using Lymph-M (CedarLane, Cat#CL5030). Splenocytes are isolated by manual cell separation through a 70 micron nylon cell strainer. B cells are then isolated from PBMCs or splenocytes by immunomagnetic negative selection using the EasySep® Mouse B Cell Isolation Kit (Stem Cell Technologies, Cat #19854).

Choice of payload. A nucleic acid sequence expressing a payload peptide or protein is transfected or transduced into isolated B cells. The following 12 peptides (i) recruit and activate dendritic cells (ii) initiate homing and guidance of dendritic cells and T cells to the tumor site; and (iii) potential for activating effector T cells. Selected payloads are listed in Table 9.

Each mouse received 4-5 payload combinations, or isolated B cells (no payload) or saline as a control. There were a total of 27 strains (n = 5 animals/group). Experimental groups are identified in Table 11.

army # kill 3 FLT3L, XCL1, CXCL13, CD40L-MB, TLR 8 FLT3L, XCL1, mLIGHT, CD80-MB 21 FLT3L, XCL1, CCL21, CD40L-MB 26 saline solution 27 B cells (no payload)

Generation of payload expressing B cells. For transfection, purified or cultured B cells were washed and suspended in Cytoporation Medium T (BTX, Cat # 47-0002) at 5 x 10 ⁶ to 25 x 10 ⁶ cells/ml and 7.5 μg to 50 μg RNA (RNA structure is designed and prepared in-house or purchased from TriLink using CleanCap® and completely replaced by Pseudo-U). 200 μL cell/RNA suspension electroporated using the BTX Agilpulse® Electroporation System.

administration. Tumor volume was between 100 mm ³ and 150 mm ³ at the time of the first injection. In the case of the group receiving 4 payloads, each payload was delivered at 2.5 x 10 ⁵ cells per injection, for a total of 10 ⁶ cells. For the group that received 5 payloads, each payload was delivered at 2.5 x 10 ⁵ cells per injection, for a total of 1.25 x 10 ⁶ cells. The payload was injected intratumorally. The dose was 50 μL for the group receiving 4 payloads and 100 μL for the group receiving 5 payloads.

Payload management procedures. Cells were harvested with versene (not in the presence of trypsin). Once collected, cells were counted, spun down and resuspended in an adjustable volume of 20 x 10 ⁶ /ml. TLR agonist (InvivoGen Cat# ODN:1826) by resuspending the lyophilized powder in the water provided. The TLR agonist was resuspended at 10 mg/ml, heated to 70° C. and left at room temperature for 1 hour prior to use. The dose of TLR agonist is 50 μg in 50 μl.

Experimental Example 6 - Antitumor activity of B cells injected intratumorally

Mouse splenocytes were obtained and isolated via manual cell separation using a 70 micron nylon cell strainer. Autologous (BALB/c) or allogeneic (C57Bl/6) donor mice were used (data shown utilizing allogeneic B cells). B cells were isolated from the splenocytes of the stomach using immunomagnetic negative selection via the EasySep® Mouse B Cell Isolation Kit (Stem Cell Technologies®, Cat #19854).

B cells were then either (i) fresh or (ii) first grown in growth medium containing 5 μg/ml lipopolysaccharide (RPMI, 10% FBS, 1% Pen/Strep, 5 ng/ml recombinant mouse IL-4, 100 uM beta-mercaptoethanol) for 16-24 hours and injected. Then, 5X10 ⁶ B cells were intratumorally injected into the CT26 mouse model and the antitumor response was measured in the distal (peritoneal) tumor. Tumors were implanted on day 0, and a palpable tumor mass was observed on day 6. Treatment was started on day 6 intratumorally. Results are shown in FIG. 12 .

Experimental Example 7 - Expression of Chimeric Antigen Receptor (CAR) in B Cells Using RNA Electroporation to Create CAR B Cells

Mouse PBMC or splenocytes were isolated from blood or spleen as follows. Mouse PBMCs were isolated using Lymphatic-M (CedarLane, Cat #CL5030) and splenocytes were isolated by manual cell dissociation via passage through a 70 micron nylon cell strainer. B cells were then isolated from PBMCs or splenocytes, respectively, by immunomagnetic negative selection using the EasySep® Mouse B Cell Isolation Kit (Stem Cell Technologies, Cat #19854).

B cells were then cultured in growth medium (RPMI, 10% FBS, 1% Pen/Strep, 5ng/ml recombinant mouse IL-4, and 100uM beta-mercaptoethanol) with 5-15ug/ml lipopolysaccharide for 16-24 days. stimulated for an hour. B cells are then transduced or transfected using known techniques (viral transfection or electroporation) to achieve stable or transient expression of CAR-B. A strep II tag was incorporated for post-translational detection. Representative CAR-Bs depicted are as follows:

1. XENP PSMA CBCR (3X strep II tag)

2. HyHEL10 CBCR (3X strep II tag)

3. D1.3-M3 HEL CBCR (3X strep II tag)

For transfection, purified or cultured B cells were washed and suspended in Cytoporation Medium T (BTX, Cat #47-0002) at 5x10 ⁶ to 25x10 ⁶ cells/ml and 7.5ug to 50ug RNA (RNA constructs designed in-house). and prepared or purchased from TriLink using CleanCap® and completely replaced by Pseudo-U). A 200ul cell/RNA suspension was obtained and electroporated using the BTX AgilePulse® Electroporation System. Cells were then washed with PBS and prepared for IV injection into immunocompetent mice harboring established HepG2 tumor cells expressing each antigen (eg, GPC3, HEL, PSMA). Then, translation and expression of the protein of interest was measured using an anti-Strep II tag antibody. Results are shown in FIG. 13 . In Figure 13, the X axis represents the intensity of the expression signal measured by flow cytometry, and the Y axis represents the percentage of cells expressing the desired protein of interest (PSMA, HEL).

This experiment demonstrates that the desired RNA sequence is successfully transfected or transduced (and therefore), the RNA is successfully translated, and the desired protein of interest is expressed at the cell surface.

Experimental Example 8 - Modified B cells expressing integrins and homing receptors

Nucleic acid constructs expressing integrins, homing receptors, or both are constructed using known techniques. Mouse and human B cells are (hence) transfected or transduced with nucleic acid constructs expressing integrins, homing receptors, or both. These modified cells are administered intravenously to a mouse or human host. Time-lapse imaging measures the accumulation of transformed B cells in a region/target of interest, such as a homing or target tissue, a specific location or site of inflammation in a tissue, or a tumor or tumor microenvironment, whereby integrins and/or homing receptors of defined homing specificity Delivery of a therapeutic payload to B cells confers the ability to homing and accumulate to a desired site/target of interest. A screening study is performed according to the description of Example 5 to investigate the delivery and effect of the payload at the site/target of interest.

Experimental Example 9 - B cell trafficking change

Isolated B cells are cultured with a specific concentration of all-trans-retinoic acid (ATRA) or a derivative thereof that induces expression of α4β7 integrin and the homing receptor CCR9. B cells are then harvested and administered intravenously to mice. There are two experimental groups of recipient mice. The first group of mice is pre-treated with DSS or TNBS to induce intestinal inflammation. Mice in the second group are not treated with DSS or TNBS. Pretreatment with DSS or TNBS induces inflammation similar to that observed in human intestinal disorders. Administered B cells treated with ATRA or a derivative thereof have an inflammatory zone consistent with homing potential due to increased expression of α4β7 integrin and the homing receptor CCR9.

Experimental Example 10 - Modified B cells expressing immunosuppressive molecules

Nucleic acid constructs expressing an immune suppressive molecule selected from IL-10, TGF-β, PD-L1, PD-L2, LAG-3, and TIM-3, or any combination thereof, are constructed using known techniques. do. Mouse and human B cells are (thus) transfected or transduced with a nucleic acid construct that expresses one or more of the immunosuppressive molecules listed above. These modified cells are administered intravenously to a mouse or human host, or near or elsewhere to the site of inflammation. Time-lapse imaging measures the accumulation of transformed B cells at a site/target of interest, such as a homing or target tissue, a specific location or site of inflammation in a tissue, or a tumor or tumor microenvironment, to measure the accumulation of inflammatory and site-localized B cells at that site. It has been established that the immune activity is reduced, thus eliciting a positive therapeutic response.

Experimental Example 11 - Activation of B cells using TLRs

B cells are treated with TLR agonists to express constitutively active TLRs for use in generating potent effector B cells to enhance B cells for an immune response and increase antigen-specific immune responses in a subject and/or Transformed. Isolated mouse or human B cells are treated in vitro with TLR agonists prior to or concurrently with administration of the B cells. In some cases, mouse or human B cells are treated with one or more TLR agonists.

Modified B cells transfected or transduced in the presence or absence of the CAR-B constructs of the above-described examples are engineered to express one or more constitutively active TLRs. Each TLR is introduced into a modified B cell (transduced or transfected using known techniques) as a DNA construct under the control of a constitutively activated transcriptional pathway. Modified B cells that express one or more constitutively active TLRs (with or without the CAR-B construct) also act upon one or more TLRs prior to or concurrently with administration of the modified B cells to a subject or patient in need thereof. treated as zero. Time-lapse imaging and other known techniques measure the accumulation of modified B cells at desired locations and confirm the expression of TLRs of defined specificity and expressed CAR-B.

This experiment shows that a desired DNA sequence encoding a particular TLR of interest is successfully transfected or transduced into a B cell with or without a CAR-B construct and (thus) treated with or without a TLR agonist, and the RNA is successfully Once translated, it will be demonstrated that the desired TLR is expressed on B cells to generate potent effector B cells that enhance B cells for an immune response.

Experimental Example 12 - Antigen Presentation on Both HLA Class I and Class II Molecules Using RNA Electroporated B Cells

mRNA constructs. Exemplary mRNA constructs are designed by fusing a specific antigen, eg, a tumor antigen or an infectious disease antigen, to the targeting signal of the lysosomal protein LAMP1 to target the specific antigen to lysosomes and to efficiently target the antigen to both HLA class I and class II molecules simultaneously and efficiently. present. Tumor antigens and infectious disease antigens may include antigens of interest that are well known in the art and for which an immune response is desired. A variety of mRNA constructs encoding at least one specific antigen of interest fused to the targeting signal of LAMP1, capable of simultaneous and efficient presentation of specific antigens by both HLA class I and class II molecules when transfected into suitable immune cells. this is made

Experimental Design. Isolated mouse or human B cells are electroporated in vitro with the mRNA construct described above (ie, encoding the specific antigen of interest fused to the targeting signal of LAMP1) using known mRNA electroporation techniques. In some examples, mouse or human B cells are also transduced or transfected using known techniques with CAR-B constructs according to any of the foregoing examples. mRNA electroporated B cells transduced with or without the CAR-B construct of interest are introduced intravenously into a mouse or human host. Time-lapse imaging measures the accumulation of modified B cells at desired locations and also confirms CAR-B expression of defined specificity. Translation and expression of a specific tumor antigen or infectious disease antigen of interest is measured using known techniques to establish that the antigen of interest is targeted to lysosomes and is efficiently presented by both HLA class I and class II molecules simultaneously. .

This experiment shows that the desired mRNA sequence encoding a specific antigen of interest fused to a targeting signal is successfully transfected into a B cell (also transduced with a CAR-B construct, if desired), the mRNA is successfully translated, and the electrochemical Perforated and modified B cells will prove to efficiently present specific antigens of interest simultaneously by both HLA class I and class II molecules to increase antigen-specific immune responses in a subject.

Experimental Example 13 - B cells expressing a PSMA-specific CAR reduce tumor growth in CT26-PSMA tumors

mouse tumor model. A BALB/c CT26-PSMA tumor model engineered to express human PSMA was used to evaluate the efficacy of PSMA-specific CAR engineered murine B cells on tumor volume and survival. 8-week-old BALB/c mice were injected into the hind flank with 1.0x10 ⁶ CT26-PSMA tumor cells in a volume of 50 μl. On day 5, when the tumor volume reached about 60 mm ³ , the mice were divided equally into 3 groups of 10 mice. Mice were treated with murine B cells engineered with mRNA encoding the two different PSMA-specific CAR formats on day 6 or unengineered B cells administered intravenously at a dose of 1.5x10 ⁶ cells in 100 μl on day 6. started using On days 5, 9, 11 and 13, tumor volume was measured using calipers. There was a statistically significant tumor reduction of 57% in the PSMA-CAR group (Format 79a) compared to saline at day 13. There was no significant reduction in tumor volume at day 13 in the PSMA-CAR treated group (Format 79b) compared to saline (FIG. 14).

Manipulation of murine B cells. Mouse splenocytes were isolated from BALB/c donor spleens by manual cell separation through a 70 micron nylon cell strainer. B cells were then isolated from splenocytes by immunomagnetic negative selection using the EasySep Mouse B Cell Isolation Kit (Stem Cell Technologies, Cat #19854). B cells were cultured in growth medium (RPMI, 10% FBS, 25 mM HEPES, 1% Pen/Strep, 5 ng/ml recombinant mouse IL-4, 100 μM beta-mercaptoethanol) with anti-CD40 (250 ng/ml) at 24 stimulated for an hour. Cells were then electroporated with 20 μg CAR mRNA construct per 3.6× ^{10 6} B cells using a BTX AgilePulse electroporation system set at 280 V for 1 ms. Cells were washed and resuspended in PBS at a concentration of 15x10 ⁶ B cells/ml. 100 μl of cell suspension was used per dose.

PSMA construct CD79a: pmRNA_d7_13_anti hPSMA (XENP14484) scFv-mCD8H-mCD28M-mCD79aE #ab-1

PSMA construct CD79b: pmRNA_d7_13_anti hPSMA (XENP14484) scFv-mCD8H-mCD28M-mCD79bE #ac-1

Experimental Example 14 - Allogeneic B cells expressing a PSMA-specific CAR reduce tumor growth in CT26-PSMA tumors

mouse tumor model. A BALB/c CT26-PSMA tumor model engineered to express human PSMA was used to evaluate the efficacy of PSMA-specific CAR engineered allogeneic murine B cells on tumor volume and survival. 8-week-old BALB/c mice were injected into the hind flank with 1.0x10 ⁶ CT26-PSMA tumor cells in a volume of 50 μl. Mice were divided equally into 3 groups of 10 mice on day 5 when the tumor volume reached about 70 mm ³ . Treatment of mice was allogeneic engineered with mRNA encoding the PSMA-specific CAR and mRNA encoding CCR7 or mRNA encoding the PSMA-specific CAR administered intravenously at a dose of 100 μl or 1.5× ^{10 6} cells in saline. Started on day 6 using autologous murine B cells engineered into murine B cells. Tumor volume was measured using calipers on days 5, 8 and 10. There was a statistically significant tumor reduction of 51% in allogeneic and autologous engineered B cell groups compared to saline at day 10 (FIG. 15). (p<0.005).

Manipulation of murine B cells. Mouse splenocytes were isolated from autologous BALB/c and allogeneic C57Bl/6 donor spleens by manual cell separation through a 70 micron nylon cell strainer. B cells were then isolated from splenocytes by immunomagnetic negative selection using the EasySep Mouse B Cell Isolation Kit (Stem Cell Technologies, Cat #19854). B cells were grown in growth medium (RPMI, 10% FBS, 25 mM HEPES, 1% Pen/Strep, 5 ng/ml recombinant mouse IL-4, 100 μM beta-mercaptoethanol) containing anti-CD40 (250 ng/ml). stimulated for 24 hours. Cells were then electroporated with 20 ug of CAR mRNA construct per 3.6x10 ⁶ B cells using a BTX AgilePulse electroporation system set at 280 V for 1 ms. Cells were washed and resuspended in PBS at a concentration of 15x10 ⁶ B cells/ml. 100 μl of cell suspension was used per dose.

Experimental Example 15 - Antitumor activity of PSMA-CAR-engineered B cells depends on intact host immune system

mouse tumor model. The effect of antitumor PSMA-CAR B cells was studied in WT and immunocompromised NSG mice.

WT mouse. A BALB/c CT26-PSMA tumor model engineered to express human PSMA was used to evaluate the efficacy of PSMA-specific CAR engineered murine B cells on tumor volume and survival in WT mice. 8-week-old BALB/c mice were injected into the hind flank with 1.0x10 ⁶ CT26-PSMA tumor cells in a volume of 50 μl. On day 5, when the tumor volume reached about 60 mm ³ , the mice were divided equally into 4 groups of 10 mice. Mice were treated with murine B cells engineered with mRNA encoding the two different PSMA-specific CAR formats on day 6 or unengineered B cells administered intravenously at a dose of 1.5x10 ⁶ cells in 100 μl on day 6. started using On days 5, 9, 11 and 13, tumor volume was measured using calipers. There was a statistically significant tumor reduction of 57% in the PSMA-CAR group (Format 79a) compared to saline at day 13. There was no significant decrease in tumor volume at day 13 in PSMA-CAR treated (Format 79b) or unengineered B cells compared to saline (FIG. 14).

NSG mice. A BALB/c CT26-PSMA tumor model engineered to express human PSMA was used to evaluate the efficacy of PSMA-specific CAR engineered murine B cells on tumor volume and survival in immunocompromised mice. 8-week-old NSG mice were injected into one hind flank with 1.0x10 ⁶ CT26-PSMA tumor cells in a volume of 50 μl. Mice were divided equally into two groups of 10 mice on day 5 when the tumor volume reached approximately 60 mm 3 . Treatment of mice was initiated on day 6 using murine B cells engineered with mRNA encoding a PSMA-specific CAR format administered intravenously at a dose of 100 μl of 1.5×10 6 cells or on day 6 using saline. Tumor volume was measured using calipers on days 5, 8, 10 and 13. There was no significant reduction in tumor volume in the PSMA-CAR group (format 79a) compared to saline at day 13 (FIG. 16B).

Manipulation of murine B cells. Mouse splenocytes were isolated from autologous BALB/c and allogeneic C57Bl/6 donor spleens by manual cell separation through a 70 micron nylon cell strainer. B cells were then isolated from splenocytes by immunomagnetic negative selection using the EasySep Mouse B Cell Isolation Kit (Stem Cell Technologies, Cat #19854). B cells were grown in growth medium containing anti-CD40 (250 ng/ml) (RPMI, 10% FBS, 25 mM HEPES, 1% Pen/Strep, 5 ng/ml recombinant mouse IL-4, 100 μM beta-mercaptoethanol) was stimulated for 24 hours. Cells were then electroporated with 20 ug of CAR mRNA construct per 3.6x10 ⁶ B cells using a BTX AgilePulse electroporation system set at 280 V for 1 ms. Cells were washed and resuspended in PBS at a concentration of 15x10 ⁶ B cells/ml. 100 μl of cell suspension was used per dose.

PSMA construct CD79a: pmRNA_d7_13_anti hPSMA (XENP14484) scFv-mCD8H-mCD28M-mCD79aE #ab-1

PSMA construct CD79b: pmRNA_d7_13_anti hPSMA (XENP14484) scFv-mCD8H-mCD28M-mCD79bE #ac-1

Experimental Example 16 - B cells expressing GPC3-specific CAR reduce tumor growth in HEPA 1-6 GPC3 tumors

mouse tumor model. A C57Bl/6 HEPA 1-6 tumor model engineered to express human GPC3 (HEPA 1-6-GPC3) was used to evaluate the efficacy of murine B cells on tumor volume and survival. 8-week-old C57Bl/6 mice were injected with 5.0x10 ⁶ HEPA 1-6-GPC3 tumor cells in a volume of 200 μl in one hind flank. On day 19, when the tumor volume reached about 250 mm ³ , the mice were divided equally into 3 groups of 10 mice. Mice were treated using saline or murine B cells engineered with mRNA encoding the GPC3-specific CAR or PSMA-specific CAR administered intravenously on days 20 and 27 at a dose of 1.5x10 ⁶ cells in 100 μl. Started on day 20. Tumor volume was measured using calipers on days 19, 23, 26 and 30. There was a statistically significant tumor reduction of 68% in the GPC3-CAR group compared to saline at day 30. There was no significant decrease in tumor volume at day 30 in the PSMA-CAR treated group compared to saline. (Note: This study is still ongoing as of Jan. 19, 2021) (FIG. 17).

Manipulation of murine B cells. Mouse splenocytes were isolated from C57Bl/6 donor spleens by manual cell separation through a 70 micron nylon cell strainer. B cells were then isolated from splenocytes by immunomagnetic negative selection using the EasySep Mouse B Cell Isolation Kit (Stem Cell Technologies, Cat #19854). B cells were grown in growth medium (RPMI, 10% FBS, 25 mM HEPES, 1% Pen/Strep, 5 ng/ml recombinant mouse IL-4, 100 μM beta-mercaptoethanol) containing anti-CD40 (250 ng/ml). stimulated for 24 hours. Cells were then electroporated with 20 μg CAR mRNA construct per 3.6× ^{10 6} B cells using a BTX AgilePulse electroporation system set at 280 V for 1 ms. Cells were washed and resuspended in PBS at a concentration of 15x10 ⁶ B cells/ml. 100 μl of cell suspension was used per dose.

GPC3 mRNA construct: pmRNA_d7_13_anti-hGPC3 scFv-mCD8H-mCD28M-mCD79aE #15-1

PSMA construct: pmRNA_d7_13_anti hPSMA (XENP14484) scFv-mCD8H-mCD28M-mCD79aE #ab-1

Experimental Example 17 - Multimerized GPC3 can activate NFκB expression of luciferase in cells expressing GPC3 CAR in a dose response manner

CAR-B construct design. The five CAR-B structures have three basic formats: (i) CAR 2 (scFv, hinge domain, transmembrane domain and signaling domain (see Figure XA)); (ii) CAR 3 (a multimerized receptor complex with two of each scFv, hinge domain, FC domain, transmembrane domain and cytoplasmic tail (see Figure XB)); (iii) CAR 4 (multimerized receptor complexes each having two of the following: (FAB domain, hinge domain, FC domain, transmembrane domain and cytoplasmic tail (see Figure XC)). Five CAR- The B constructs are as follows:

pWF-506
(SEQ ID NOs: 140/141) pmRNA_d7_13_anti-hGPC3 scFv-hIgG1 Fc [TM + cyto] A-1
(CAR 3) pWF-507 (SEQ ID NOs: 142/143) / pWF-508
(SEQ ID NOs: 144/145) pmRNA_d7_13_anti-hGPC3 vl-hc lambda /
pmRNA_d7_13_anti-hGPC3 vH-hlgHg1 [TM+ cyto]
(CAR 4)
pWF-509 (SEQ ID NOs: 146/147) pmRNA_d7_13_anti-hGPC3 scFv-hCD8H-hCD28M-hCD79bE
(CAR 2) pWF-510 (SEQ ID NOs: 148/149) pmRNA_d7_13_anti-hGPC3 scFv-hCD8H-hCD28M-hCD79aE (CAR 2)

NFκB reporter assay: antigen-induced signaling. Ramos NFκB-luciferase reporter cells were transduced with mRNA encoding one of the CAR-B constructs listed above. Ramos NFκB-luciferase reporter cells were transfected with 10 μg of RNA in 200 μL of electroporation buffer at 280 V and 1 msec and then cultured overnight in growth medium. The cells were left at room temperature for 4 hours to arrest the cells and reduce the background. 30,000 transfected cells were transferred to each well of a multi-well plate in a volume of 30 μL per well. Transfected Ramos cells were then incubated for 3 hours in growth medium with streptavidin, streptavidin control or GPC3 protein multimerized with GPC3-Fc protein. 30 μL of Bioglo substrate (Promega) was added to each well and the plate was read using a luminometer within 5 minutes. As shown in FIG. 18 , multimerized GPC3 was able to activate NFκB expression of luciferase in cells expressing 3 of 4 GPC3 CAR-Bs except for pWF-509 (GPC3-CD79b). All four constructs showed good binding to GPC3 in FACS analysis. Thus, CD79b was an example of a CAR with good binding affinity not signaling.

NFκB Reporter Assay: Tonic Signaling . Tonic signaling was assessed using the NFκB reporter assay. A CAR construct was created that induces elevated tonic signaling in the absence of cognate antigen binding. 19 shows that four CAR-B constructs were expressed in a human B cell reporter line and NFκB luciferase activity was measured in the absence of cognate target antigen. Each construct exhibited significant tonic signaling activity. Engineered B cells with tonic signaling CAR B remained in high numbers in vivo and induced high and durable expression of replacement factors or other payloads.

Experimental Example 18 - CD80 payload enhances anti-tumor activity of anti-GPC3CAR-CD79a B cells

Experimental Design. Syngeneic C57Bl/6 mouse HEPA1-6GPC3 tumors are a model of human HCC engineered to express human GPC3. This model was used to evaluate the efficacy of murine B cells electroporated with anti-GPC3CAR-CD79a and CD80 payload mRNAs. Mice were injected in the hind flank with 5.0 X 10 ⁶ HEPA1-6GPC3 tumor cells in a volume of 200 ul in Matrigel. As shown in Figure 20, on days 11, 14, and 17 mice were injected with 1.5x10 ⁶ B cells engineered with anti-GPC3CAR-CD79a, B cells engineered with anti-GPC3CAR-CD79a and CD80, or saline. of 200 ul IV dose was administered. B cells were engineered with mRNA as described below. Tumor volume was monitored on several days as shown in FIG. 20 .

In FIG. 20 , both the anti-GPC3CAR-CD79a and anti-GPC3CAR-CD79a plus CD80 combos showed statistically significant effects versus saline or unengineered B cells at day 44 and at multiple earlier time points. Additionally, anti-GPC3CAR-CD79a and anti-GPC3CAR-CD79a plus CD80 combos resulted in 4 and 7 complete responses, respectively, as shown in FIGS. 21A to 21C , although there were no complete responses in the saline control or B cell control by day 44. . These data demonstrate that inclusion of the CD80 payload as mRNA enhances the antitumor activity of B cells co-electroporated with the antigen-specific GPC3 CAR.

B cell preparation. Mouse splenocytes were isolated from C57Bl/6 donor spleens by mechanical cell separation through a 70 micron nylon cell strainer. B cells were then isolated from splenocytes by immunomagnetic negative selection using the EasySep Mouse B Cell Isolation Kit (Stem Cell Technologies, Cat #19854). B cells were cultured in growth medium (RPMI, 10% FBS, 1% Pen/Strep, 5ng/ml recombinant mouse IL-4, 100uM beta-mercaptoethanol) with 250 ng/ml CD40 antibody (anti-murine CD40 Ab). stimulated for 24 hours. Cells were then electroporated with 20 μg mRNA per 1.0× ^{10 7} B cells using a BTX AgilePulse electroporation system set at 400 V for 5 pulses at 1 ms and 2 ms intervals. When two mRNAs were cotransfected, 20 μg of each mRNA was used. Immediately after electroporation, cells were washed with PBS and prepared for IV administration at a dose of 1.0x10 ⁷ per 200ul. Electroporated cells were administered to mice within 90 minutes after electroporation.

Twelve hours after electroporation, a small aliquot of cells were stained for expression of anti-GPC3CAR-CD79a and CD80 expression. For detection of anti-GPC3CAR-CD79a expression, GPC3-Avitag and Streptavidin-BV421 were used. CD80 expression was measured with an anti-CD80-PE FACS antibody. FACS plots in FIGS. 22A-22C show the expression of GPC3 CAR after electroporation. CD80 is expressed at basal levels in unengineered B cells, accounting for ~10% positivity. This level remained in the CAR samples but increased dramatically in the CAR + CD80 samples. The latter suggested efficient expression of CD80.

SEQUENCE LISTING <110> WALKING FISH THERAPEUTICS, INC. <120> MODIFIED B CELLS AND METHODS OF USE THEREOF <130> 109036-0046 <140> PCT/US2021/025273 <141> 2021-03-31 <150> US 63/003,120 <151> 2020-03-31 <160> 150 <170> PatentIn version 3.5 <210> 1 <211> 81 <212> DNA 213 <213> <400> 1 ttctgggccc ttgtggtggt tgccggagtg ctgttttgct atgggctcct ggttaccgtt 60 gccctttgtg tgatttggac c 81 <210> 2 <211> 27 <212> PRT 213 <213> <400> 2 Phe Trp Ala Leu Val Val Val Ala Gly Val Leu Phe Cys Tyr Gly Leu 1 5 10 15 Leu Val Thr Val Ala Leu Cys Val Ile Trp Thr 20 25 <210> 3 <211> 81 <212> DNA <213> Homo sapiens <400> 3 ttttgggtat tggtagtggt gggcggagtt ttagcctgct acagcctcct ggtaacagtg 60 gcttttatca tcttttgggt g 81 <210> 4 <211> 27 <212> PRT <213> Homo sapiens <400> 4 Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu 1 5 10 15 Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 20 25 <210> 5 <211> 729 <212> DNA <213> Homo sapiens <400> 5 cagcgggctt tagtcttgcg gcgtaaacgt aaaagaatga cagatccaac tcgcaggttc 60 ttcaaagtga cccccccacc tgggtccgga ccgcagaacc aatatgggaa tgtcctgtct 120 ctgcctacgc ctacaagtgg actgggtagg gctcagaggt gggctgccgg tctcggcgga 180 actgcgccat cttacggaaa tccctcctcc gacgttcagg cagacggggc cctggggtct 240 cgatccccgc ctggtgttgg accagaagag gaagagggcg agggctacga agagcccgac 300 tccgaagagg acagtgagtt ttacgagaac gacagcaacc tggggcagga tcagctgtca 360 caggatggct caggatatga aaaccctgag gacgagcctt tggggcctga agatgaggac 420 tccttttcta atgcagagtc atatgagaat gaggacgaag aattgactca acccgtggca 480 agaacaatgg atttcctcag tccacacggg agtgcatggg acccctccag agaggctact 540 agcctcggtt ctcaaagcta tgaggacatg aggggtattc tgtacgcagc gcctcagttg 600 aggtccatcc gcggccagcc aggcccaaac catgaggaag atgccgattc ttacgaaaac 660 atggacaacc ccgatggtcc tgaccccgca tgggggggcg gcgggaggat ggggcacctgg 720 tctactcgc 729 <210> 6 <211> 243 <212> PRT <213> Homo sapiens <400> 6 Gln Arg Ala Leu Val Leu Arg Arg Lys Arg Lys Arg Met Thr Asp Pro 1 5 10 15 Thr Arg Arg Phe Phe Lys Val Thr Pro Pro Pro Gly Ser Gly Pro Gln 20 25 30 Asn Gln Tyr Gly Asn Val Leu Ser Leu Pro Thr Pro Thr Ser Gly Leu 35 40 45 Gly Arg Ala Gln Arg Trp Ala Ala Gly Leu Gly Gly Thr Ala Pro Ser 50 55 60 Tyr Gly Asn Pro Ser Ser Asp Val Gln Ala Asp Gly Ala Leu Gly Ser 65 70 75 80 Arg Ser Pro Pro Gly Val Gly Pro Glu Glu Glu Glu Gly Glu Gly Tyr 85 90 95 Glu Glu Pro Asp Ser Glu Glu Asp Ser Glu Phe Tyr Glu Asn Asp Ser 100 105 110 Asn Leu Gly Gln Asp Gln Leu Ser Gln Asp Gly Ser Gly Tyr Glu Asn 115 120 125 Pro Glu Asp Glu Pro Leu Gly Pro Glu Asp Glu Asp Ser Phe Ser Asn 130 135 140 Ala Glu Ser Tyr Glu Asn Glu Asp Glu Glu Leu Thr Gln Pro Val Ala 145 150 155 160 Arg Thr Met Asp Phe Leu Ser Pro His Gly Ser Ala Trp Asp Pro Ser 165 170 175 Arg Glu Ala Thr Ser Leu Gly Ser Gln Ser Tyr Glu Asp Met Arg Gly 180 185 190 Ile Leu Tyr Ala Ala Pro Gln Leu Arg Ser Ile Arg Gly Gln Pro Gly 195 200 205 Pro Asn His Glu Glu Asp Ala Asp Ser Tyr Glu Asn Met Asp Asn Pro 210 215 220 Asp Gly Pro Asp Pro Ala Trp Gly Gly Gly Gly Arg Met Gly Thr Trp 225 230 235 240 Ser Thr Arg <210> 7 <211> 186 <212> DNA <213> Homo sapiens <400> 7 aagaaggttg caaaaaaacc tactaataag gctcccccatc ctaagcaaga gccccaagaa 60 attaactttc ccgatgatct tccgggttct aacacggcag ccccggtgca ggagaccctg 120 catggttgtc aacccgtcac tcaggaggac gggaaagagt ctcgtatctc cgtccaggag 180 186 <210> 8 <211> 62 <212> PRT <213> Homo sapiens <400> 8 Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala Pro His Pro Lys Gln 1 5 10 15 Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu Pro Gly Ser Asn Thr 20 25 30 Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys Gln Pro Val Thr Gln 35 40 45 Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln Glu Arg Gln 50 55 60 <210> 9 <211> 330 <212> DNA <213> Homo sapiens <400> 9 aagaaggttg caaaaaaacc tactaataag gctcccccatc ctaagcaaga gccccaagaa 60 attaactttc ccgatgatct tccgggttct aacacggcag ccccggtgca ggagaccctg 120 catggttgtc aacccgtcac tcaggaggac gggaaagagt ctcgtatctc cgtccaggag 180 agacaggaca aggacgatag taaagcaggg atggaggagg accatacata cgagggactg 240 gatatcgatc agacagccac gtacgaagac attgtgacac tgagaactgg cgaggtgaag 300 tggtcagtgg gagaacatcc ggggcaggaa 330 <210> 10 <211> 110 <212> PRT <213> Homo sapiens <400> 10 Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala Pro His Pro Lys Gln 1 5 10 15 Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu Pro Gly Ser Asn Thr 20 25 30 Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys Gln Pro Val Thr Gln 35 40 45 Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln Glu Arg Gln Asp Lys 50 55 60 Asp Asp Ser Lys Ala Gly Met Glu Asp His Thr Tyr Glu Gly Leu 65 70 75 80 Asp Ile Asp Gln Thr Ala Thr Tyr Glu Asp Ile Val Thr Leu Arg Thr 85 90 95 Gly Glu Val Lys Trp Ser Val Gly Glu His Pro Gly Gln Glu 100 105 110 <210> 11 <211> 312 <212> DNA <213> Homo sapiens <400> 11 aagaaggttg caaaaaaacc tactaataag gctcccccatc ctaagcaaga gccccaagaa 60 attaactttc ccgatgatct tccgggttct aacacggcag ccccggtgca ggagaccctg 120 catggttgtc aacccgtcac tcaggaggac gggaaagagt ctcgtatctc cgtccaggag 180 agacagaaaa gaggccgaaa aaagctgctg tacatcttca aacaaccctt catgcgacct 240 gttcagacga cacaggagga ggacggctgc agctgtaggt ttcccgaaga agaggaggga 300 ggatgcgaac tt 312 <210> 12 <211> 104 <212> PRT <213> Homo sapiens <400> 12 Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala Pro His Pro Lys Gln 1 5 10 15 Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu Pro Gly Ser Asn Thr 20 25 30 Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys Gln Pro Val Thr Gln 35 40 45 Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln Glu Arg Gln Lys Arg 50 55 60 Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro 65 70 75 80 Val Gln Thr Thr Gln Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu 85 90 95 Glu Glu Glu Gly Gly Cys Glu Leu 100 <210> 13 <211> 126 <212> DNA <213> Homo sapiens <400> 13 aaaagaggcc gaaaaaagct gctgtacatc ttcaaacaac ccttcatgcg acctgttcag 60 acgacacagg aggagggacgg ctgcagctgt aggtttcccg aagaagagga gggaggatgc 120 gaactt 126 <210> 14 <211> 42 <212> PRT <213> Homo sapiens <400> 14 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 1 5 10 15 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 20 25 30 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 35 40 <210> 15 <211> 414 <212> DNA <213> Homo sapiens <400> 15 aagaaggttg caaaaaaacc tactaataag gctcccccatc ctaagcaaga gccccaagaa 60 attaactttc ccgatgatct tccgggttct aacacggcag ccccggtgca ggagaccctg 120 catggttgtc aacccgtcac tcaggaggac gggaaagagt ctcgtatctc cgtccaggag 180 agacagcgca aaaaacgtat aagcgcaaac tctacagatc cagtaaaagc cgcgcaattc 240 gagcctcccg gccgccagat gattgcaata cggaaacgtc aactggagga aactaataat 300 gactatgaga cggccgacgg tggatacatg acccttaatc cccgcgcgcc aaccgacgat 360 gataagaaca tatatctgac gctcccccct aacgatcacg ttaacagtaa taat 414 <210> 16 <211> 138 <212> PRT <213> Homo sapiens <400> 16 Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala Pro His Pro Lys Gln 1 5 10 15 Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu Pro Gly Ser Asn Thr 20 25 30 Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys Gln Pro Val Thr Gln 35 40 45 Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln Glu Arg Gln Arg Lys 50 55 60 Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala Gln Phe 65 70 75 80 Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln Leu Glu 85 90 95 Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met Thr Leu 100 105 110 Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu Thr Leu 115 120 125 Pro Pro Asn Asp His Val Asn Ser Asn Asn 130 135 <210> 17 <211> 228 <212> DNA <213> Homo sapiens <400> 17 cgcaaaaaac gtataagcgc aaactctaca gatccagtaa aagccgcgca attcgagcct 60 cccggccgcc agatgattgc aatacggaaa cgtcaactgg aggaaactaa taatgactat 120 gagacggccg acggtggata catgaccctt aatccccgcg cgccaaccga cgatgataag 180 aacatatatc tgacgctccc ccctaacgat cacgttaaca gtaataat 228 <210> 18 <211> 76 <212> PRT <213> Homo sapiens <400> 18 Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala 1 5 10 15 Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln 20 25 30 Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met 35 40 45 Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu 50 55 60 Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn 65 70 75 <210> 19 <211> 681 <212> DNA <213> Homo sapiens <400> 19 atggcggcgg gcgggcccgg cgccggaagc gccgcgccag tctcatctac gtccagtctg 60 ccactggctg ccctgaacat gagagtgaga cgccgtttat ccctcttcct gaatgtgcgg 120 acccaggtcg ccgctgattg gaccgccctg gccgaagaga tggactttga atacttggaa 180 atcagacagc tggaaacaca ggcagaccca accgggagac tgcttgacgc ctggcaggga 240 cgcccagggg caagtgttgg tcggttactg gagcttttaa ctaagttggg ccgcgatgac 300 gtgctgttgg agttaggacc cagtatcgag gaggattgtc agaaatacat cttgaaacag 360 cagcaggagg aggcggaaaa gcccctgcag gtggcggccg ttgacagcag tgtacccaga 420 acagctgagc tggccggcat cacaaccctg gatgatcccc tggggccacat gcctgagagg 480 ttcgacgctt tcataaagaa ggttgcaaaa aaacctacta ataaggctcc ccatcctaag 540 caagagcccc aagaaattaa ctttcccgat gatcttccgg gttctaacac ggcagccccg 600 gtgcaggaga ccctgcatgg ttgtcaaccc gtcactcagg aggacgggaa agagtctcgt 660 atctccgtcc aggagagaca g 681 <210> 20 <211> 227 <212> PRT <213> Homo sapiens <400> 20 Met Ala Ala Gly Gly Pro Gly Ala Gly Ser Ala Ala Pro Val Ser Ser 1 5 10 15 Thr Ser Ser Leu Pro Leu Ala Ala Leu Asn Met Arg Val Arg Arg Arg 20 25 30 Leu Ser Leu Phe Leu Asn Val Arg Thr Gln Val Ala Ala Asp Trp Thr 35 40 45 Ala Leu Ala Glu Glu Met Asp Phe Glu Tyr Leu Glu Ile Arg Gln Leu 50 55 60 Glu Thr Gln Ala Asp Pro Thr Gly Arg Leu Leu Asp Ala Trp Gln Gly 65 70 75 80 Arg Pro Gly Ala Ser Val Gly Arg Leu Leu Glu Leu Leu Thr Lys Leu 85 90 95 Gly Arg Asp Asp Val Leu Leu Glu Leu Gly Pro Ser Ile Glu Glu Asp 100 105 110 Cys Gln Lys Tyr Ile Leu Lys Gln Gln Gln Glu Glu Ala Glu Lys Pro 115 120 125 Leu Gln Val Ala Ala Val Asp Ser Ser Val Pro Arg Thr Ala Glu Leu 130 135 140 Ala Gly Ile Thr Thr Leu Asp Asp Pro Leu Gly His Met Pro Glu Arg 145 150 155 160 Phe Asp Ala Phe Ile Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala 165 170 175 Pro His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu 180 185 190 Pro Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys 195 200 205 Gln Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln 210 215 220 Glu Arg Gln 225 <210> 21 <211> 495 <212> DNA <213> Homo sapiens <400> 21 atggcggcgg gcgggcccgg cgccggaagc gccgcgccag tctcatctac gtccagtctg 60 ccactggctg ccctgaacat gagagtgaga cgccgtttat ccctcttcct gaatgtgcgg 120 acccaggtcg ccgctgattg gaccgccctg gccgaagaga tggactttga atacttggaa 180 atcagacagc tggaaacaca ggcagaccca accgggagac tgcttgacgc ctggcaggga 240 cgcccagggg caagtgttgg tcggttactg gagcttttaa ctaagttggg ccgcgatgac 300 gtgctgttgg agttaggacc cagtatcgag gaggattgtc agaaatacat cttgaaacag 360 cagcaggagg aggcggaaaa gcccctgcag gtggcggccg ttgacagcag tgtacccaga 420 acagctgagc tggccggcat cacaaccctg gatgatcccc tggggccacat gcctgagagg 480 ttcgacgctt tcata 495 <210> 22 <211> 165 <212> PRT <213> Homo sapiens <400> 22 Met Ala Ala Gly Gly Pro Gly Ala Gly Ser Ala Ala Pro Val Ser Ser 1 5 10 15 Thr Ser Ser Leu Pro Leu Ala Ala Leu Asn Met Arg Val Arg Arg Arg 20 25 30 Leu Ser Leu Phe Leu Asn Val Arg Thr Gln Val Ala Ala Asp Trp Thr 35 40 45 Ala Leu Ala Glu Glu Met Asp Phe Glu Tyr Leu Glu Ile Arg Gln Leu 50 55 60 Glu Thr Gln Ala Asp Pro Thr Gly Arg Leu Leu Asp Ala Trp Gln Gly 65 70 75 80 Arg Pro Gly Ala Ser Val Gly Arg Leu Leu Glu Leu Leu Thr Lys Leu 85 90 95 Gly Arg Asp Asp Val Leu Leu Glu Leu Gly Pro Ser Ile Glu Glu Asp 100 105 110 Cys Gln Lys Tyr Ile Leu Lys Gln Gln Gln Glu Glu Ala Glu Lys Pro 115 120 125 Leu Gln Val Ala Ala Val Asp Ser Ser Val Pro Arg Thr Ala Glu Leu 130 135 140 Ala Gly Ile Thr Thr Leu Asp Asp Pro Leu Gly His Met Pro Glu Arg 145 150 155 160 Phe Asp Ala Phe Ile 165 <210> 23 <211> 183 <212> DNA <213> Homo sapiens <400> 23 aggaaacgat ggcagaacga gaagctcggg ttggatgccg gggatgaata tgaagatgaa 60 aacctttatg aaggcctgaa cctggacgac tgctccatgt atgaggacat ctcccggggc 120 ctccagggca cctaccagga tgtgggcagc ctcaacatag gagatgtcca gctggagaag 180 CCG 183 <210> 24 <211> 61 <212> PRT <213> Homo sapiens <400> 24 Arg Lys Arg Trp Gln Asn Glu Lys Leu Gly Leu Asp Ala Gly Asp Glu 1 5 10 15 Tyr Glu Asp Glu Asn Leu Tyr Glu Gly Leu Asn Leu Asp Asp Cys Ser 20 25 30 Met Tyr Glu Asp Ile Ser Arg Gly Leu Gln Gly Thr Tyr Gln Asp Val 35 40 45 Gly Ser Leu Asn Ile Gly Asp Val Gln Leu Glu Lys Pro 50 55 60 <210> 25 <211> 147 <212> DNA <213> Homo sapiens <400> 25 ctggacaagg atgacagcaa ggctggcatg gaggaagatc acacctacga gggcctggac 60 attgaccaga cagccaccta tgaggacata gtgacgctgc ggacagggga agtgaagtgg 120 tctgtaggtg agcacccagg ccaggag 147 <210> 26 <211> 49 <212> PRT <213> Homo sapiens <400> 26 Leu Asp Lys Asp Asp Ser Lys Ala Gly Met Glu Glu Asp His Thr Tyr 1 5 10 15 Glu Gly Leu Asp Ile Asp Gln Thr Ala Thr Tyr Glu Asp Ile Val Thr 20 25 30 Leu Arg Thr Gly Glu Val Lys Trp Ser Val Gly Glu His Pro Gly Gln 35 40 45 Glu <210> 27 <211> 165 <212> DNA <213> Homo sapiens <400> 27 ttcgtgcctg tgttcctccc agctaagccc actaccaccc ccgctccaag gccgcccacg 60 cccgctccta ctattgctag tcagccttta agtttacgac ccgaagcttg caggcccgcc 120 gccggcggcg ctgtgcacac cagggggctt gattttgcct gcgac 165 <210> 28 <211> 55 <212> PRT <213> Homo sapiens <400> 28 Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro 1 5 10 15 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 20 25 30 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 35 40 45 Gly Leu Asp Phe Ala Cys Asp 50 55 <210> 29 <211> 189 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 29 ggcgctggta gtggcggtaa ctggagccac cctcaatttg agaagggcgg gtcaggcgga 60 tcaggtggta gtggtgggtc caactggagc catccgcaat ttgaaaaggg cggaagcggc 120 ggttccggcg gttcaggcgg tagcaactgg tcacatccgc aatttgagaa aggcgggtca 180 189 <210> 30 <211> 63 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 30 Gly Ala Gly Ser Gly Gly Asn Trp Ser His Pro Gln Phe Glu Lys Gly 1 5 10 15 Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Asn Trp Ser His Pro 20 25 30 Gln Phe Glu Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 35 40 45 Asn Trp Ser His Pro Gln Phe Glu Lys Gly Gly Ser Gly Gly Gly 50 55 60 <210> 31 <211> 903 <212> DNA <213> Homo sapiens <400> 31 cccaagagct gcgacaagac ccacacctgc cccccctgcc cagccccaga gctgctgggc 60 ggaccctccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc 120 cccgaggtga cctgcgtggt ggtggacgtg agccacgagg acccagaggt gaagttcaac 180 240 aacagcacct acagggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 300 aaggaataca agtgcaaggt ctccaacaag gccctgccag cccccatcga aaagaccatc 360 agcaaggcca agggccagcc acgggagccc caggtgtaca ccctgccccc ctcccggggag 420 gagatgacca agaaccaggt gtccctgacc tgtctggtga agggcttcta ccccagcgac 480 atcgccgtgg agtggggagag caacggccag cccgagaaca actacaagac caccccccca 540 gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg 600 tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 660 acccagaaga gcctgagcct gtccccccgag ctgcaactgg aggagagctg tgcggaggcg 720 caggacgggg agctggacgg gctgtggacg accatcacca tcttcatcac actcttcctg 780 ttaagcgtgt gctacagtgc caccgtcacc ttcttcaagg tgaagtggat cttctcctcg 840 gtggtggacc tgaagcagac catcatcccc gactacagga acatgatcgg acagggggcc 900 tga 903 <210> 32 <211> 300 <212> PRT <213> Homo sapiens <400> 32 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 1 5 10 15 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 75 80 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 90 95 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 100 105 110 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 115 120 125 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 165 170 175 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Glu Leu Gln Leu Glu Glu Ser Cys Ala Glu Ala 225 230 235 240 Gln Asp Gly Glu Leu Asp Gly Leu Trp Thr Thr Ile Thr Ile Phe Ile 245 250 255 Thr Leu Phe Leu Leu Ser Val Cys Tyr Ser Ala Thr Val Thr Phe Phe 260 265 270 Lys Val Lys Trp Ile Phe Ser Ser Val Val Asp Leu Lys Gln Thr Ile 275 280 285 Ile Pro Asp Tyr Arg Asn Met Ile Gly Gln Gly Ala 290 295 300 <210> 33 <211> 726 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 33 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaa 726 <210> 34 <211> 242 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 34 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys <210> 35 <211> 735 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 35 gaagtccaat tggttgaaag cggtggtgga ctcgtcaaac ctggcggtag ccttaaactt 60 tcatgtgccg caagcggctt cacgtttagt aactatgcta tgagttgggt ccgccaaagt 120 ccagaaaagc gcctcgaatg ggtggcggag atctctggag gaggaacata tacatattat 180 ccagacacca tgaccggtag gtttacaatc tcaagagaca acgctaagaa caccctgtac 240 ctggaaatgt caagcctgag atcagaagat acggccatgt attattgtac gcgcctactc 300 gactattggg gtcaaggaac ttccgtgacg gtgtcaagcg gaggaggtgg gagcggagga 360 ggcggaagtg gcggtggtgg ctctggtggc ggtggaagtg atatagtgat gacgcaagct 420 gccttttcaa accctgttac tttggggact agcgcatcaa tctcctgtag gtccagcaaa 480 tctttgctgc acagtaatgg aatcacctat cttttctggt atttgcaaaa gcctgggcag 540 agcccgcaac tgctgatcta tcaaatgtca aatcttgctt ccggagttcc agaccgcttc 600 tcaagttccg ggtccggcac tgattttacc ttgagaattt ctagggtcga agctgaagac 660 gtcggtgtct attattgcgc gcaaaacctt gagcttccat acaccttcgg ggggggcaca 720 aaacttgaga tcaag 735 <210> 36 <211> 245 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 36 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Glu Ile Ser Gly Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Thr Met 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Leu Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser 100 105 110 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn 130 135 140 Pro Val Thr Leu Gly Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys 145 150 155 160 Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Phe Trp Tyr Leu Gln 165 170 175 Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu 180 185 190 Ala Ser Gly Val Pro Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr 210 215 220 Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Leu Glu Ile Lys 245 <210> 37 <211> 759 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 37 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 360 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggagtctggg 420 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 540 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 600 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 660 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 720 ggtcaaggta ctctggtgac cgtgtctagc gccgctgca 759 <210> 38 <211> 253 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 38 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser 100 105 110 Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175 Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220 Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala 245 250 <210> 39 <211> 1704 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 39 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgcagcgggc tttagtcttg cggcgtaaac gtaaaagaat gacagatcca 1020 actcgcaggt tcttcaaagt gaccccccca cctgggtccg gaccgcagaa ccaatatggg 1080 aatgtcctgt ctctgcctac gcctacaagt ggactgggta gggctcagag gtgggctgcc 1140 ggtctcggcg gaactgcgcc atcttacgga aatccctcct ccgacgttca ggcagacggg 1200 gccctggggt ctcgatcccc gcctggtgtt ggaccagaag aggaagaggg cgagggctac 1260 gaagagcccg actccgaaga ggacagtgag ttttacgaga acgacagcaa cctggggcag 1320 gatcagctgt cacaggatgg ctcaggatat gaaaaccctg aggacgagcc tttggggcct 1380 gaagatgagg actccttttc taatgcagag tcatatgaga atgaggacga agaattgact 1440 caacccgtgg caagaacaat ggatttcctc agtccacacg ggagtgcatg ggacccctcc 1500 agagaggcta ctagcctcgg ttctcaaagc tatgaggaca tgaggggtat tctgtacgca 1560 gcgcctcagt tgaggtccat ccgcggccag ccaggcccaa accatgagga agatgccgat 1620 tcttacgaaa acatggacaa ccccgatggt cctgaccccg catggggggg cggcgggagg 1680 atgggcacct ggtctactcg ctag 1704 <210> 40 <211> 567 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 40 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Gln Arg Ala Leu Val Leu Arg Arg Lys Arg Lys Arg 325 330 335 Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val Thr Pro Pro Pro Gly 340 345 350 Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu Ser Leu Pro Thr Pro 355 360 365 Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala Ala Gly Leu Gly Gly 370 375 380 Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp Val Gln Ala Asp Gly 385 390 395 400 Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly Pro Glu Glu Glu Glu 405 410 415 Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu Asp Ser Glu Phe Tyr 420 425 430 Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu Ser Gln Asp Gly Ser 435 440 445 Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly Pro Glu Asp Glu Asp 450 455 460 Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu Asp Glu Glu Leu Thr 465 470 475 480 Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser Pro His Gly Ser Ala 485 490 495 Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Gly Ser Gln Ser Tyr Glu 500 505 510 Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro Gln Leu Arg Ser Ile Arg 515 520 525 Gly Gln Pro Gly Pro Asn His Glu Glu Asp Ala Asp Ser Tyr Glu Asn 530 535 540 Met Asp Asn Pro Asp Gly Pro Asp Pro Ala Trp Gly Gly Gly Gly Arg 545 550 555 560 Met Gly Thr Trp Ser Thr Arg 565 <210> 41 <211> 1122 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 41 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgctggacaa ggatgacagc aaggctggca tggaggaaga tcacacctac 1020 gagggcctgg acattgacca gacagccacc tatgaggaca tagtgacgct gcggacaggg 1080 gaagtgaagt ggtctgtagg tgagcaccca ggccaggagt ga 1122 <210> 42 <211> 373 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 42 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Leu Asp Lys Asp Asp Ser Lys Ala Gly Met Glu Glu 325 330 335 Asp His Thr Tyr Glu Gly Leu Asp Ile Asp Gln Thr Ala Thr Tyr Glu 340 345 350 Asp Ile Val Thr Leu Arg Thr Gly Glu Val Lys Trp Ser Val Gly Glu 355 360 365 His Pro Gly Gln Glu 370 <210> 43 <211> 1305 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 43 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgaagaaggt tgcaaaaaaa cctactaata aggctcccca tcctaagcaa 1020 gagccccaag aaattaactt tcccgatgat cttccgggtt ctaacacggc agccccggtg 1080 caggagaccc tgcatggttg tcaacccgtc actcaggagg acgggaaaga gtctcgtatc 1140 tccgtccagg agagacagga caaggacgat agtaaagcag ggatggagga ggaccataca 1200 tacgagggac tggatatcga tcagacagcc acgtacgaag acattgtgac actgagaact 1260 ggcgaggtga agtggtcagt gggagaacat ccggggcagg aataa 1305 <210> 44 <211> 434 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 44 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala Pro 325 330 335 His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu Pro 340 345 350 Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys Gln 355 360 365 Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln Glu 370 375 380 Arg Gln Asp Lys Asp Asp Ser Lys Ala Gly Met Glu Glu Asp His Thr 385 390 395 400 Tyr Glu Gly Leu Asp Ile Asp Gln Thr Ala Thr Tyr Glu Asp Ile Val 405 410 415 Thr Leu Arg Thr Gly Glu Val Lys Trp Ser Val Gly Glu His Pro Gly 420 425 430 Gln Glu <210> 45 <211> 1287 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 45 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgaagaaggt tgcaaaaaaa cctactaata aggctcccca tcctaagcaa 1020 gagccccaag aaattaactt tcccgatgat cttccgggtt ctaacacggc agccccggtg 1080 caggagaccc tgcatggttg tcaacccgtc actcaggagg acgggaaaga gtctcgtatc 1140 tccgtccagg agagacagaa aagaggccga aaaaagctgc tgtacatctt caaacaaccc 1200 ttcatgcgac ctgttcagac gacacaggag gaggacggct gcagctgtag gtttcccgaa 1260 gaagaggagg gaggatgcga actttaa 1287 <210> 46 <211> 428 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 46 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala Pro 325 330 335 His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu Pro 340 345 350 Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys Gln 355 360 365 Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln Glu 370 375 380 Arg Gln Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro 385 390 395 400 Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys 405 410 415 Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 420 425 <210> 47 <211> 462 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 47 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Lys Lys Val Ala Lys Lys Pro Thr Asn Lys Ala Pro 325 330 335 His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe Pro Asp Asp Leu Pro 340 345 350 Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr Leu His Gly Cys Gln 355 360 365 Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg Ile Ser Val Gln Glu 370 375 380 Arg Gln Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys 385 390 395 400 Ala Ala Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys 405 410 415 Arg Gln Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly 420 425 430 Tyr Met Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile 435 440 445 Tyr Leu Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn 450 455 460 <210> 48 <211> 1656 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 48 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgatggcggc gggcgggccc ggcgccggaa gcgccgcgcc agtctcatct 1020 acgtccagtc tgccactggc tgccctgaac atgagagtga gacgccgttt atccctcttc 1080 ctgaatgtgc ggacccaggt cgccgctgat tggaccgccc tggccgaaga gatggacttt 1140 gaatacttgg aaatcagaca gctggaaaca caggcagacc caaccgggag actgcttgac 1200 gcctggcagg gacgcccagg ggcaagtgtt ggtcggttac tggagctttt aactaagttg 1260 ggccgcgatg acgtgctgtt ggaggttagga cccagtatcg aggaggattg tcagaaatac 1320 atcttgaaac agcagcagga ggaggcggaa aagcccctgc aggtggcggc cgttgacagc 1380 agtgtaccca gaacagctga gctggccggc atcacaaccc tggatgatcc cctgggccac 1440 atgcctgaga ggttcgacgc tttcataaag aaggttgcaa aaaaacctac taataaggct 1500 ccccatccta agcaagagcc ccaagaaatt aactttcccg atgatcttcc gggttctaac 1560 acggcagccc cggtgcagga gaccctgcat ggttgtcaac ccgtcactca ggaggacggg 1620 aaagagtctc gtatctccgt ccaggagaga cagtga 1656 <210> 49 <211> 551 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 49 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Met Ala Ala Gly Gly Pro Gly Ala Gly Ser Ala Ala 325 330 335 Pro Val Ser Ser Thr Ser Ser Leu Pro Leu Ala Ala Leu Asn Met Arg 340 345 350 Val Arg Arg Arg Leu Ser Leu Phe Leu Asn Val Arg Thr Gln Val Ala 355 360 365 Ala Asp Trp Thr Ala Leu Ala Glu Glu Met Asp Phe Glu Tyr Leu Glu 370 375 380 Ile Arg Gln Leu Glu Thr Gln Ala Asp Pro Thr Gly Arg Leu Leu Asp 385 390 395 400 Ala Trp Gln Gly Arg Pro Gly Ala Ser Val Gly Arg Leu Leu Glu Leu 405 410 415 Leu Thr Lys Leu Gly Arg Asp Asp Val Leu Leu Glu Leu Gly Pro Ser 420 425 430 Ile Glu Glu Asp Cys Gln Lys Tyr Ile Leu Lys Gln Gln Gln Glu Glu 435 440 445 Ala Glu Lys Pro Leu Gln Val Ala Ala Val Asp Ser Ser Val Pro Arg 450 455 460 Thr Ala Glu Leu Ala Gly Ile Thr Thr Leu Asp Asp Pro Leu Gly His 465 470 475 480 Met Pro Glu Arg Phe Asp Ala Phe Ile Lys Lys Val Ala Lys Lys Pro 485 490 495 Thr Asn Lys Ala Pro His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe 500 505 510 Pro Asp Asp Leu Pro Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr 515 520 525 Leu His Gly Cys Gln Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg 530 535 540 Ile Ser Val Gln Glu Arg Gln 545 550 <210> 50 <211> 1158 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 50 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgaggaaacg atggcagaac gagaagctcg ggttggatgc cggggatgaa 1020 tatgaagatg aaaaccttta tgaaggcctg aacctggacg actgctccat gtatgaggac 1080 atctcccggg gcctccaggg cacctaccag gatgtgggca gcctcaacat aggagatgtc 1140 cagctggaga agccgtga 1158 <210> 51 <211> 385 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 51 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Arg Lys Arg Trp Gln Asn Glu Lys Leu Gly Leu Asp 325 330 335 Ala Gly Asp Glu Tyr Glu Asp Glu Asn Leu Tyr Glu Gly Leu Asn Leu 340 345 350 Asp Asp Cys Ser Met Tyr Glu Asp Ile Ser Arg Gly Leu Gln Gly Thr 355 360 365 Tyr Gln Asp Val Gly Ser Leu Asn Ile Gly Asp Val Gln Leu Glu Lys 370 375 380 Pro 385 <210> 52 <211> 1122 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 52 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgctggacaa ggatgacagc aaggctggca tggaggaaga tcacacctac 1020 gagggcctgg acattgacca gacagccacc tatgaggaca tagtgacgct gcggacaggg 1080 gaagtgaagt ggtctgtagg tgagcaccca ggccaggagt ga 1122 <210> 53 <211> 373 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 53 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro 245 250 255 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 260 265 270 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 275 280 285 Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val 290 295 300 Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile 305 310 315 320 Ile Phe Trp Val Leu Asp Lys Asp Asp Ser Lys Ala Gly Met Glu Glu 325 330 335 Asp His Thr Tyr Glu Gly Leu Asp Ile Asp Gln Thr Ala Thr Tyr Glu 340 345 350 Asp Ile Val Thr Leu Arg Thr Gly Glu Val Lys Trp Ser Val Gly Glu 355 360 365 His Pro Gly Gln Glu 370 <210> 54 <211> 1143 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 54 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaaggcg ctggtagtgg cggtaactgg agccaccctc aatttgagaa gggcgggtca 780 ggcggatcag gtggtagtgg tgggtccaac tggagccatc cgcaatttga aaagggcgga 840 agcggcggtt ccggcggttc aggcggtagc aactggtcac atccgcaatt tgagaaaggc 900 gggtcaggcg gcgggttttg ggctctcgtg gtggtggctg gagtgctttt ctgctatggc 960 ctgctggtaa ccgtggccct ttgtgtaatc tggaccgata aagacgatgg aaaagccggg 1020 atggaagaag accataccta cgaggggctc aatattgatc aaaccgccac gtatgaagac 1080 attgtaacac tgcgcacagg tgaggtcaag tggtccgtcg gtgaacaccc aggacaagaa 1140 taa 1143 <210> 55 <211> 380 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 55 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Gly Ala Gly Ser Gly Gly Asn Trp Ser His Pro Gln Phe Glu 245 250 255 Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Asn Trp Ser 260 265 270 His Pro Gln Phe Glu Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 275 280 285 Gly Ser Asn Trp Ser His Pro Gln Phe Glu Lys Gly Gly Ser Gly Gly 290 295 300 Gly Phe Trp Ala Leu Val Val Val Ala Gly Val Leu Phe Cys Tyr Gly 305 310 315 320 Leu Leu Val Thr Val Ala Leu Cys Val Ile Trp Thr Asp Lys Asp Asp 325 330 335 Gly Lys Ala Gly Met Glu Glu Asp His Thr Tyr Glu Gly Leu Asn Ile 340 345 350 Asp Gln Thr Ala Thr Tyr Glu Asp Ile Val Thr Leu Arg Thr Gly Glu 355 360 365 Val Lys Trp Ser Val Gly Glu His Pro Gly Gln Glu 370 375 380 <210> 56 <211> 1152 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 56 gaagtccaat tggttgaaag cggtggtgga ctcgtcaaac ctggcggtag ccttaaactt 60 tcatgtgccg caagcggctt cacgtttagt aactatgcta tgagttgggt ccgccaaagt 120 ccagaaaagc gcctcgaatg ggtggcggag atctctggag gaggaacata tacatattat 180 ccagacacca tgaccggtag gtttacaatc tcaagagaca acgctaagaa caccctgtac 240 ctggaaatgt caagcctgag atcagaagat acggccatgt attattgtac gcgcctactc 300 gactattggg gtcaaggaac ttccgtgacg gtgtcaagcg gaggaggtgg gagcggagga 360 ggcggaagtg gcggtggtgg ctctggtggc ggtggaagtg atatagtgat gacgcaagct 420 gccttttcaa accctgttac tttggggact agcgcatcaa tctcctgtag gtccagcaaa 480 tctttgctgc acagtaatgg aatcacctat cttttctggt atttgcaaaa gcctgggcag 540 agcccgcaac tgctgatcta tcaaatgtca aatcttgctt ccggagttcc agaccgcttc 600 tcaagttccg ggtccggcac tgattttacc ttgagaattt ctagggtcga agctgaagac 660 gtcggtgtct attattgcgc gcaaaacctt gagcttccat acaccttcgg ggggggcaca 720 aaacttgaga tcaagggcgc tgggagcggc gggaattgga gtcatccaca attcgaaaag 780 ggtgggtccg gcggcagtgg tggaagcggc gggagtaact ggtcacatcc ccagtttgag 840 aaaggcggta gtggtggcag cggcggtagt ggtggcagta attggagcca tccccaattc 900 gaaaagggcg gttccggcgg cggattttgg gctcttgttg tggtggccgg agtattgttt 960 tgctatggcc tgctcgttac agtggcattg tgcgtaattt ggactgataa agacgacggc 1020 aaagccggga tggaagaaga tcacacctat gaggggctta atatagatca aacagccaca 1080 tatgaagata ttgtgactct aaggactgga gaggttaaat ggaggtgtggg tgagcatcca 1140 ggacaagaat aa 1152 <210> 57 <211> 383 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 57 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Glu Ile Ser Gly Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Thr Met 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Leu Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser 100 105 110 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn 130 135 140 Pro Val Thr Leu Gly Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys 145 150 155 160 Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Phe Trp Tyr Leu Gln 165 170 175 Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu 180 185 190 Ala Ser Gly Val Pro Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr 210 215 220 Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Leu Glu Ile Lys Gly Ala Gly Ser Gly Gly Asn Trp Ser His Pro 245 250 255 Gln Phe Glu Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 260 265 270 Asn Trp Ser His Pro Gln Phe Glu Lys Gly Gly Ser Gly Gly Ser Gly 275 280 285 Gly Ser Gly Gly Ser Asn Trp Ser His Pro Gln Phe Glu Lys Gly Gly 290 295 300 Ser Gly Gly Gly Phe Trp Ala Leu Val Val Val Ala Gly Val Leu Phe 305 310 315 320 Cys Tyr Gly Leu Leu Val Thr Val Ala Leu Cys Val Ile Trp Thr Asp 325 330 335 Lys Asp Asp Gly Lys Ala Gly Met Glu Glu Asp His Thr Tyr Glu Gly 340 345 350 Leu Asn Ile Asp Gln Thr Ala Thr Tyr Glu Asp Ile Val Thr Leu Arg 355 360 365 Thr Gly Glu Val Lys Trp Ser Val Gly Glu His Pro Gly Gln Glu 370 375 380 <210> 58 <211> 1191 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 58 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 360 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggagtctggg 420 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 540 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 600 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 660 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 720 ggtcaaggta ctctggtgac cgtgtctagc gccgctgcat tcgtgcctgt gttcctccca 780 gctaagccca ctaccacccc cgctccaagg ccgcccacgc ccgctcctac tattgctagt 840 cagcctttaa gtttacgacc cgaagcttgc aggcccgccg ccggcggcgc tgtgcacacc 900 agggggcttg attttgcctg cgacttttgg gtattggtag tggtgggcgg agttttagcc 960 tgctacagcc tcctggtaac agtggctttt atcatctttt gggtgaggaa acgatggcag 1020 aacgagaagc tcgggttgga tgccggggat gaatatgaag atgaaaacct ttatgaaggc 1080 ctgaacctgg acgactgctc catgtatgag gacatctccc ggggcctcca gggcacctac 1140 caggatgtgg gcagcctcaa cataggagat gtccagctgg agaagccgtg a 1191 <210> 59 <211> 396 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 59 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser 100 105 110 Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175 Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220 Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Phe Val Pro 245 250 255 Val Phe Leu Pro Ala Lys 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 290 295 300 Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala 305 310 315 320 Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg 325 330 335 Lys Arg Trp Gln Asn Glu Lys Leu Gly Leu Asp Ala Gly Asp Glu Tyr 340 345 350 Glu Asp Glu Asn Leu Tyr Glu Gly Leu Asn Leu Asp Asp Cys Ser Met 355 360 365 Tyr Glu Asp Ile Ser Arg Gly Leu Gln Gly Thr Tyr Gln Asp Val Gly 370 375 380 Ser Leu Asn Ile Gly Asp Val Gln Leu Glu Lys Pro 385 390 395 <210> 60 <211> 1155 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 60 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 360 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggagtctggg 420 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 540 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 600 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 660 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 720 ggtcaaggta ctctggtgac cgtgtctagc gccgctgcat tcgtgcctgt gttcctccca 780 gctaagccca ctaccacccc cgctccaagg ccgcccacgc ccgctcctac tattgctagt 840 cagcctttaa gtttacgacc cgaagcttgc aggcccgccg ccggcggcgc tgtgcacacc 900 agggggcttg attttgcctg cgacttttgg gtattggtag tggtgggcgg agttttagcc 960 tgctacagcc tcctggtaac agtggctttt atcatctttt ggggtgctgga caaggatgac 1020 agcaaggctg gcatggagga agatcacacc tacgagggcc tggacattga ccagacagcc 1080 acctatgagg acatagtgac gctgcggaca ggggaagtga agtggtctgt aggtgagcac 1140 ccaggccagg agtga 1155 <210> 61 <211> 384 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 61 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser 100 105 110 Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175 Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220 Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Phe Val Pro 245 250 255 Val Phe Leu Pro Ala Lys 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 290 295 300 Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala 305 310 315 320 Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Leu 325 330 335 Asp Lys Asp Asp Ser Lys Ala Gly Met Glu Glu Asp His Thr Tyr Glu 340 345 350 Gly Leu Asp Ile Asp Gln Thr Ala Thr Tyr Glu Asp Ile Val Thr Leu 355 360 365 Arg Thr Gly Glu Val Lys Trp Ser Val Gly Glu His Pro Gly Gln Glu 370 375 380 <210> 62 <211> 1653 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 62 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 360 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggagtctggg 420 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 540 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 600 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 660 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 720 ggtcaaggta ctctggtgac cgtgtctagc cccaagagct gcgacaagac ccacacctgc 780 cccccctgcc cagccccaga gctgctgggc ggaccctccg tgttcctgtt cccccccaag 840 cccaaggaca ccctgatgat cagcaggacc cccgaggtga cctgcgtggt ggtggacgtg 900 agccacgagg acccagaggt gaagttcaac tggtacgtgg acggcgtgga ggtgcacaac 960 gccaagacca agcccagaga ggagcagtac aacagcacct acagggtggt gtccgtgctg 1020 accgtgctgc accaggactg gctgaacggc aaggaataca agtgcaaggt ctccaacaag 1080 gccctgccag cccccatcga aaagaccatc agcaaggcca agggccagcc acgggagccc 1140 caggtgtaca ccctgcccccc ctcccggggag gagatgacca agaaccaggt gtccctgacc 1200 tgtctggtga agggcttcta ccccagcgac atcgccgtgg agtggggagag caacggccag 1260 cccgagaaca actacaagac caccccccca gtgctggaca gcgacggcag cttcttcctg 1320 tacagcaagc tgaccgtgga caagtccagg tggcagcagg gcaacgtgtt cagctgcagc 1380 gtgatgcacg aggccctgca caaccactac acccagaaga gcctgagcct gtcccccgag 1440 ctgcaactgg aggagagctg tgcggaggcg caggacgggg agctggacgg gctgtggacg 1500 accatcacca tcttcatcac actcttcctg ttaagcgtgt gctacagtgc caccgtcacc 1560 ttcttcaagg tgaagtggat cttctcctcg gtggtggacc tgaagcagac catcatcccc 1620 gactacagga acatgatcgg acagggggcc tga 1653 <210> 63 <211> 550 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 63 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser 100 105 110 Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175 Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220 Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Pro Lys Ser Cys Asp Lys 245 250 255 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 260 265 270 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 275 280 285 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 290 295 300 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 305 310 315 320 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 325 330 335 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 340 345 350 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 355 360 365 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 370 375 380 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 385 390 395 400 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 405 410 415 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 420 425 430 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 435 440 445 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 450 455 460 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Glu 465 470 475 480 Leu Gln Leu Glu Glu Ser Cys Ala Glu Ala Gln Asp Gly Glu Leu Asp 485 490 495 Gly Leu Trp Thr Thr Ile Thr Ile Phe Ile Thr Leu Phe Leu Leu Ser 500 505 510 Val Cys Tyr Ser Ala Thr Val Thr Phe Phe Lys Val Lys Trp Ile Phe 515 520 525 Ser Ser Val Val Asp Leu Lys Gln Thr Ile Ile Pro Asp Tyr Arg Asn 530 535 540 Met Ile Gly Gln Gly Ala 545 550 <210> 64 <211> 648 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 64 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta ggtcagccca aggccaaccc cactgtcact 360 ctgttcccgc cctcctctga ggagctccaa gccaacaagg ccacactagt gtgtctgatc 420 agtgacttct acccgggagc tgtgacagtg gcctggaagg cagatggcag ccccgtcaag 480 gcgggagtgg agaccaccaa accctccaaa cagagcaaca acaagtacgc ggccagcagc 540 tacctgagcc tgacgcccga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600 catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca 648 <210> 65 <211> 216 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 65 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 66 <211> 1554 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 66 caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagtag cacatactat 180 gcagactccg tgaagggccg gttcaccatc tccagagata attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gcgcacttct 300 tacctgaacc atggtgatta ctggggtcaa ggtactctgg tgaccgtgtc tagcgcctcc 360 accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420 gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540 tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600 tgcaacgtga accacaagcc cagcaacacc aaggtggaca agagagtgga gcccaagagc 660 tgcgacaaga cccacacctg ccccccctgc ccagccccag agctgctggg cggaccctcc 720 gtgttcctgt tcccccccaa gcccaaggac accctgatga tcagcaggac ccccgaggtg 780 acctgcgtgg tggtggacgt gagccacgag gacccagagg tgaagttcaa ctggtacgtg 840 gacggcgtgg aggtgcacaa cgccaagacc aagcccagag aggagcagta caacagcacc 900 tacagggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaggaatac 960 aagtgcaagg tctccaacaa ggccctgcca gcccccatcg aaaagaccat cagcaaggcc 1020 aagggccagc cacgggagcc ccaggtgtac accctgcccc cctcccggga ggagatgacc 1080 aagaaccagg tgtccctgac ctgtctggtg aagggcttct accccagcga catcgccgtg 1140 gagtgggaga gcaacggcca gcccgagaac aactacaaga ccaccccccc agtgctggac 1200 agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaagtccag gtggcagcag 1260 ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacccagaag 1320 agcctgagcc tgtccccccga gctgcaactg gaggagagct gtgcggaggc gcaggacggg 1380 gagctggacg ggctgtggac gaccatcacc atcttcatca cactcttcct gttaagcgtg 1440 tgctacagtg ccaccgtcac cttcttcaag gtgaagtgga tcttctcctc ggtggtggac 1500 ctgaagcaga ccatcatccc cgactacagg aacatgatcg gacagggggc ctga 1554 <210> 67 <211> 517 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 67 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Glu Leu 435 440 445 Gln Leu Glu Glu Ser Cys Ala Glu Ala Gln Asp Gly Glu Leu Asp Gly 450 455 460 Leu Trp Thr Thr Ile Thr Ile Phe Ile Thr Leu Phe Leu Leu Ser Val 465 470 475 480 Cys Tyr Ser Ala Thr Val Thr Phe Phe Lys Val Lys Trp Ile Phe Ser 485 490 495 Ser Val Val Asp Leu Lys Gln Thr Ile Ile Pro Asp Tyr Arg Asn Met 500 505 510 Ile Gly Gln Gly Ala 515 <210> 68 <211> 327 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 68 atgagacttt caacagcaac actcctcctg ttgctggctt catgtctgag ccctggtcat 60 ggtattttgg aggcccacta tacaaatctc aaatgtcggt gttcaggcgt aatatccacc 120 gtagtcggcc tgaacattat cgataggatt caggttacac cccccgggaa cggatgtcct 180 aagaccgagg tggtgatttg gaccaagatg aagaaggtca tttgtgtgaa cccacgggct 240 aaatggctgc agcgtctttt gcgacacgtg cagtccaaga gcttgtccag cacacctcag 300 gccccagtta gcaagcgacg tgcagcc 327 <210> 69 <211> 109 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 69 Met Arg Leu Ser Thr Ala Thr Leu Leu Leu Leu Leu Ala Ser Cys Leu 1 5 10 15 Ser Pro Gly His Gly Ile Leu Glu Ala His Tyr Thr Asn Leu Lys Cys 20 25 30 Arg Cys Ser Gly Val Ile Ser Thr Val Val Gly Leu Asn Ile Ile Asp 35 40 45 Arg Ile Gln Val Thr Pro Pro Gly Asn Gly Cys Pro Lys Thr Glu Val 50 55 60 Val Ile Trp Thr Lys Met Lys Lys Val Ile Cys Val Asn Pro Arg Ala 65 70 75 80 Lys Trp Leu Gln Arg Leu Leu Arg His Val Gln Ser Lys Ser Leu Ser 85 90 95 Ser Thr Pro Gln Ala Pro Val Ser Lys Arg Arg Ala Ala 100 105 <210> 70 <211> 696 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 70 atgacagtgc tggccccccgc gtggtctccc aatagctcac tcctcctctt gctgctactg 60 ctcagcccat gcctcagggg cacccccgat tgttacttca gccacagccc aatctcctcc 120 aacttcaaag tgaaatttag ggaactgacc gaccacctgc tgaaagatta tcctgtgact 180 gtggcagtga acctgcaaga cgaaaagcat tgtaaggcgc tatggagcct ctttcttgcc 240 caacgatgga ttgagcaact caaaactgta gccggaagca aaatgcagac gctactggag 300 gacgtgaata ctgagattca cttcgttacc agttgtactt tccagccact gccagagtgt 360 ctcaggtttg tgcagactaa tatcagccac ctgctgaagg atacttgcac ccagctcctg 420 gctctcaagc cttgtatagg caaggcttgt caaaatttta gcaggtgtct cgaagtccag 480 tgccagccag attcatccac actgctgccg ccccgaagcc ctatcgcact cgaagcgaca 540 gagttgccag agcctcgtcc cagacagctt ctgctgctgc tacttctgct gctgccgcta 600 actctggtgc tacttgctgc cgcctggggc ctcagatggc aacgcgccag acgccgaggc 660 gaactccacc ctggggtgcc actgccatcc caccca 696 <210> 71 <211> 232 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 71 Met Thr Val Leu Ala Pro Ala Trp Ser Pro Asn Ser Ser Leu Leu Leu 1 5 10 15 Leu Leu Leu Leu Leu Ser Pro Cys Leu Arg Gly Thr Pro Asp Cys Tyr 20 25 30 Phe Ser His Ser Pro Ile Ser Ser Asn Phe Lys Val Lys Phe Arg Glu 35 40 45 Leu Thr Asp His Leu Leu Lys Asp Tyr Pro Val Thr Val Ala Val Asn 50 55 60 Leu Gln Asp Glu Lys His Cys Lys Ala Leu Trp Ser Leu Phe Leu Ala 65 70 75 80 Gln Arg Trp Ile Glu Gln Leu Lys Thr Val Ala Gly Ser Lys Met Gln 85 90 95 Thr Leu Leu Glu Asp Val Asn Thr Glu Ile His Phe Val Thr Ser Cys 100 105 110 Thr Phe Gln Pro Leu Pro Glu Cys Leu Arg Phe Val Gln Thr Asn Ile 115 120 125 Ser His Leu Leu Lys Asp Thr Cys Thr Gln Leu Leu Ala Leu Lys Pro 130 135 140 Cys Ile Gly Lys Ala Cys Gln Asn Phe Ser Arg Cys Leu Glu Val Gln 145 150 155 160 Cys Gln Pro Asp Ser Ser Thr Leu Leu Pro Pro Arg Ser Pro Ile Ala 165 170 175 Leu Glu Ala Thr Glu Leu Pro Glu Pro Arg Pro Arg Gln Leu Leu Leu 180 185 190 Leu Leu Leu Leu Leu Leu Pro Leu Thr Leu Val Leu Leu Ala Ala Ala 195 200 205 Trp Gly Leu Arg Trp Gln Arg Ala Arg Arg Arg Gly Glu Leu His Pro 210 215 220 Gly Val Pro Leu Pro Ser His Pro 225 230 <210> 72 <211> 342 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 72 atgcgactct tgttgttgac ttttctcgga gtgtgctgcc tgacaccctg ggtcgtagag 60 ggagttggca ctgaagtact agaagagtcc tcctgcgtta acctgcagac acagcggctc 120 ccagtccaga aaattaagac ctacattata tgggaaggag caatgcgagc ggtgattttt 180 gtgaccaaga ggggtctcaa gatttgcgcg gaccctgagg ccaagtgggt caaagcagct 240 attaagacag tagacggaag agcctccacc aggaagaata tggcagaaac tgtaccgacc 300 ggtgcgcagc ggtcaacatc taccgcaatc acactcaccg gc 342 <210> 73 <211> 114 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 73 Met Arg Leu Leu Leu Leu Thr Phe Leu Gly Val Cys Cys Leu Thr Pro 1 5 10 15 Trp Val Val Glu Gly Val Gly Thr Glu Val Leu Glu Glu Ser Ser Cys 20 25 30 Val Asn Leu Gln Thr Gln Arg Leu Pro Val Gln Lys Ile Lys Thr Tyr 35 40 45 Ile Ile Trp Glu Gly Ala Met Arg Ala Val Ile Phe Val Thr Lys Arg 50 55 60 Gly Leu Lys Ile Cys Ala Asp Pro Glu Ala Lys Trp Val Lys Ala Ala 65 70 75 80 Ile Lys Thr Val Asp Gly Arg Ala Ser Thr Arg Lys Asn Met Ala Glu 85 90 95 Thr Val Pro Thr Gly Ala Gln Arg Ser Thr Ser Thr Ala Ile Thr Leu 100 105 110 Thr Gly <210> 74 <211> 1533 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 74 atgagcaagg gccttctcct gctgtggcta gtaactgaat tgtggtggtt gtacctgaca 60 cctgccgcta gtgaggacac catcattggt ttccttgggc agcccgtcac cctcccttgc 120 cattacctaa gctggagcca gtcacggaac tctatgtgct ggggaaaggg gtcatgccct 180 aattccaagt gcaacgccga gctgttgcgc acggacggca ccagaataat ctcaagaaag 240 tccaccaagt atacgctgct cggcaaggtg caattcggtg aagtgagctt gaccataagt 300 aacaccaacc gcggtgactc cggagtttat tgttgcagga tcgaagtgcc aggctggttt 360 aacgacgtga agaaaaacgt gcggctggaa ctgaggaggg caactacgac caagaaacca 420 acaaccacga cgagacctac caccactcct tacgtgacaa ccacgacacc ggagctgttg 480 ccaactaccg tcatgacaac atctgtgttg ccaactacca ccccccccca aacgctcgcg 540 acaactgcct tttccacagc cgttaccaca tgtccttcca ccaccccagg ctctttttct 600 caagaaacta ccaagggatc agcttttacc accgagtctg aaactctccc agcaagtaat 660 cactcacagc ggtcaatgat gaccatcagc acagacatcg ctgtcttgag acctactggc 720 agcaatccag gcattctgcc ctccacttca cagctgacta cccaaaagac tacactaacc 780 accagcgaaa gtctgcagaa aactacaaag agccatcaaa taaactcccg gcagactccc 840 agagggccca caatcaagcc ctgtcctcca tgcaaatgcc cagcacctaa cctcttgggt 900 ggaccatccg tcttcatctt ccctccaaag atcaaggatg tactcatgat ctccctgagc 960 cccatagtca catgtgtggt ggtggatgtg agcgaggatg acccagatgt ccagatcagc 1020 tggtttgtga acaacgtgga agtacacaca gctcagacac aaacccatag agaggattac 1080 aacagtactc tccgggtggt cagtgccctc cccatccagc accaggactg gatgagtggc 1140 aaggagttca aatgcaaggt caacaacaaa gacctcccag cgcccatcga gagaaccatc 1200 tcaaaaccca aagggtcagt aagagctcca caggtatatg tcttgcctcc accagaagaa 1260 gagatgacta agaaacaggt cactctgacc tgcatggtca cagacttcat gcctgaagac 1320 atttacgtgg agtggaccaa caacgggaaa acagagctaa actacaagaa cactgaacca 1380 gtcctggact ctgatggttc ttacttcatg tacagcaagc tgagagtgga aaagaagaac 1440 tgggtgggaaa gaaatagcta ctcctgttca gtggtccacg agggtctgca caatcaccac 1500 acgactaaga gcttctcccg gactccgggt aaa 1533 <210> 75 <211> 511 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 75 Met Ser Lys Gly Leu Leu Leu Leu Trp Leu Val Thr Glu Leu Trp Trp 1 5 10 15 Leu Tyr Leu Thr Pro Ala Ala Ser Glu Asp Thr Ile Ile Gly Phe Leu 20 25 30 Gly Gln Pro Val Thr Leu Pro Cys His Tyr Leu Ser Trp Ser Gln Ser 35 40 45 Arg Asn Ser Met Cys Trp Gly Lys Gly Ser Cys Pro Asn Ser Lys Cys 50 55 60 Asn Ala Glu Leu Leu Arg Thr Asp Gly Thr Arg Ile Ile Ser Arg Lys 65 70 75 80 Ser Thr Lys Tyr Thr Leu Leu Gly Lys Val Gln Phe Gly Glu Val Ser 85 90 95 Leu Thr Ile Ser Asn Thr Asn Arg Gly Asp Ser Gly Val Tyr Cys Cys 100 105 110 Arg Ile Glu Val Pro Gly Trp Phe Asn Asp Val Lys Lys Asn Val Arg 115 120 125 Leu Glu Leu Arg Arg Ala Thr Thr Thr Lys Lys Pro Thr Thr Thr Thr 130 135 140 Arg Pro Thr Thr Thr Pro Tyr Val Thr Thr Thr Thr Thr Pro Glu Leu Leu 145 150 155 160 Pro Thr Thr Val Met Thr Thr Ser Val Leu Pro Thr Thr Thr Pro Pro 165 170 175 Gln Thr Leu Ala Thr Thr Ala Phe Ser Thr Ala Val Thr Thr Cys Pro 180 185 190 Ser Thr Thr Pro Gly Ser Phe Ser Gln Glu Thr Thr Lys Gly Ser Ala 195 200 205 Phe Thr Thr Glu Ser Glu Thr Leu Pro Ala Ser Asn His Ser Gln Arg 210 215 220 Ser Met Met Thr Ile Ser Thr Asp Ile Ala Val Leu Arg Pro Thr Gly 225 230 235 240 Ser Asn Pro Gly Ile Leu Pro Ser Thr Ser Gln Leu Thr Thr Gln Lys 245 250 255 Thr Thr Leu Thr Thr Ser Glu Ser Leu Gln Lys Thr Thr Lys Ser His 260 265 270 Gln Ile Asn Ser Arg Gln Thr Pro Arg Gly Pro Thr Ile Lys Pro Cys 275 280 285 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 290 295 300 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 305 310 315 320 Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 325 330 335 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 340 345 350 Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 355 360 365 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 370 375 380 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 385 390 395 400 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 405 410 415 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 420 425 430 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 435 440 445 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 450 455 460 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 465 470 475 480 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 485 490 495 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 500 505 510 <210> 76 <211> 927 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 76 atggatcagc atacactgga cgtggaagat acagccgatg ccagacaccc tgctggaacg 60 tcctgtccca gcgacgctgc cctgctcaga gacaccgggc tgctcgcaga tgctgctctg 120 ctgagtgata ccgttcggcc aactaacgcg gccctaccca cagatgccgc atatcccgcg 180 gtaaatgtca gggaccggga agctgcctgg ccaccggccc tcaatttctg ctctagacat 240 ccgaaactgt acggtctggt cgcactggta ctgctgctac ttatagcagc ttgtgttccc 300 atatttaccc gcactgaacc cagacccgct ctcactatta caacttcacc aaacttgggc 360 acacgtgaaa acaatgcaga tcaggttacc cctgtaagtc atattggatg ccccaacacc 420 acacaacagg gaagtccggt gtttgcaaaa ctccttgcta agaatcaggc ttcactgtgt 480 aacactactc ttaattggca ctcacaagac ggggccggga gtagctatct cagccaaggt 540 ctccgctatg aagaagataa gaaagagttg gtggtggaca gcccaggact ctactacgtc 600 ttcctggagc taaaactaag ccccactttt actaacactg gacataaggt ccaaggttgg 660 gtgtccctcg tacttcaagc taaaccccag gtggacgact tcgataacct ggcgttgaca 720 gttgagctct ttccttgctc tatggaaaat aagctcgtgg atcggagctg gtctcaactg 780 ttgctgctta aagccggtca tcgtctgtct gttggactac gcgcatactt gcatggagcc 840 caggacgcat atcgtgattg ggaactgagc tacccgaata ccactagctt tggactattt 900 cttgttaaac cagataatcc ttgggag 927 <210> 77 <211> 309 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 77 Met Asp Gln His Thr Leu Asp Val Glu Asp Thr Ala Asp Ala Arg His 1 5 10 15 Pro Ala Gly Thr Ser Cys Pro Ser Asp Ala Ala Leu Leu Arg Asp Thr 20 25 30 Gly Leu Leu Ala Asp Ala Ala Leu Leu Ser Asp Thr Val Arg Pro Thr 35 40 45 Asn Ala Ala Leu Pro Thr Asp Ala Ala Tyr Pro Ala Val Asn Val Arg 50 55 60 Asp Arg Glu Ala Ala Trp Pro Pro Ala Leu Asn Phe Cys Ser Arg His 65 70 75 80 Pro Lys Leu Tyr Gly Leu Val Ala Leu Val Leu Leu Leu Leu Ile Ala 85 90 95 Ala Cys Val Pro Ile Phe Thr Arg Thr Glu Pro Arg Pro Ala Leu Thr 100 105 110 Ile Thr Thr Ser Pro Asn Leu Gly Thr Arg Glu Asn Asn Ala Asp Gln 115 120 125 Val Thr Pro Val Ser His Ile Gly Cys Pro Asn Thr Thr Gln Gln Gly 130 135 140 Ser Pro Val Phe Ala Lys Leu Leu Ala Lys Asn Gln Ala Ser Leu Cys 145 150 155 160 Asn Thr Thr Leu Asn Trp His Ser Gln Asp Gly Ala Gly Ser Ser Tyr 165 170 175 Leu Ser Gln Gly Leu Arg Tyr Glu Glu Asp Lys Lys Glu Leu Val Val 180 185 190 Asp Ser Pro Gly Leu Tyr Tyr Val Phe Leu Glu Leu Lys Leu Ser Pro 195 200 205 Thr Phe Thr Asn Thr Gly His Lys Val Gln Gly Trp Val Ser Leu Val 210 215 220 Leu Gln Ala Lys Pro Gln Val Asp Asp Phe Asp Asn Leu Ala Leu Thr 225 230 235 240 Val Glu Leu Phe Pro Cys Ser Met Glu Asn Lys Leu Val Asp Arg Ser 245 250 255 Trp Ser Gln Leu Leu Leu Leu Lys Ala Gly His Arg Leu Ser Val Gly 260 265 270 Leu Arg Ala Tyr Leu His Gly Ala Gln Asp Ala Tyr Arg Asp Trp Glu 275 280 285 Leu Ser Tyr Pro Asn Thr Thr Ser Phe Gly Leu Phe Leu Val Lys Pro 290 295 300 Asp Asn Pro Trp Glu 305 <210> 78 <211> 705 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 78 atggagagcg tagtgcaacc cagcgtattt gtggtggatg gacagaccga catcccattc 60 agacgcttgg aacagaacca ccgaagaagg cggtgcggca ccgtccaggt gtccctcgct 120 ctcgtgctgc tgcttggtgc tggcctcgca acacaagggt ggtttctttt gagactccat 180 caacgcttgg gagacatagt ggcccacctg cctgatggtg ggaagggctc ttggcaggac 240 cagcgatcac accaggctaa ccccgccgct cacctgacag gggcgaatgc cagcttgatc 300 ggaataggtg ggccgctgct gtgggaaact aggcttggac ttgcctttct gagagggctt 360 acataccatg acggagccct cgtaacaatg gagcctggtt attactacgt gtacagtaag 420 gtgcagcttt ctggagtcgg gtgtccccag gggctggcta acggactgcc catcactcat 480 ggactataca aacgcacatc cagatatcct aaagagctgg aactgttggt gtcccgtagg 540 agcccgtgtg gcagggccaa ctcttcccgt gtgtggtggg actcctcttt tctgggcggc 600 gtggtccatc tggaagctgg tgaggaagtc gtcgtaagag tacctggaaa ccgtctggtt 660 cgcccccgcg atggcaccag gtcctacttc ggagctttca tggta 705 <210> 79 <211> 235 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 79 Met Glu Ser Val Val Gln Pro Ser Val Phe Val Val Asp Gly Gln Thr 1 5 10 15 Asp Ile Pro Phe Arg Arg Leu Glu Gln Asn His Arg Arg Arg Arg Cys 20 25 30 Gly Thr Val Gln Val Ser Leu Ala Leu Val Leu Leu Leu Gly Ala Gly 35 40 45 Leu Ala Thr Gln Gly Trp Phe Leu Leu Arg Leu His Gln Arg Leu Gly 50 55 60 Asp Ile Val Ala His Leu Pro Asp Gly Gly Lys Gly Ser Trp Gln Asp 65 70 75 80 Gln Arg Ser His Gln Ala Asn Pro Ala Ala His Leu Thr Gly Ala Asn 85 90 95 Ala Ser Leu Ile Gly Ile Gly Gly Pro Leu Leu Trp Glu Thr Arg Leu 100 105 110 Gly Leu Ala Phe Leu Arg Gly Leu Thr Tyr His Asp Gly Ala Leu Val 115 120 125 Thr Met Glu Pro Gly Tyr Tyr Tyr Val Tyr Ser Lys Val Gln Leu Ser 130 135 140 Gly Val Gly Cys Pro Gln Gly Leu Ala Asn Gly Leu Pro Ile Thr His 145 150 155 160 Gly Leu Tyr Lys Arg Thr Ser Arg Tyr Pro Lys Glu Leu Glu Leu Leu 165 170 175 Val Ser Arg Arg Ser Pro Cys Gly Arg Ala Asn Ser Ser Arg Val Trp 180 185 190 Trp Asp Ser Ser Phe Leu Gly Gly Val Val His Leu Glu Ala Gly Glu 195 200 205 Glu Val Val Val Arg Val Pro Gly Asn Arg Leu Val Arg Pro Arg Asp 210 215 220 Gly Thr Arg Ser Tyr Phe Gly Ala Phe Met Val 225 230 235 <210> 80 <211> 1821 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 80 atgtgcccac agaaactcac aatttcttgg ttcgcaatcg tcctgctggt gtcacccctg 60 atggcaatgt ggggagttgga aaaggatgta tacgtcgtcg aggtcgactg gacacctgac 120 gctccgggtg aaactgtcaa cctcacttgc gatactcctg aagaggacga catcacgtgg 180 acgagcgacc agcgacatgg agtgataggg tctggcaaga cgcttactat cacggttaag 240 gaatttctcg acgcagggca gtacacatgt cacaagggcg gcgagactct gagccactcc 300 catttgctgc tgcacaagaa ggagaatggt atctggtcta ccgaaatcct gaagaatttt 360 aagaacaaga cttttctgaa atgcgaggcc ccaaattatt ccggacgttt cacttgcagt 420 tggctcgttc aaagaaatat ggacttgaaa tttaacatta aatccagctc ttcatctcct 480 gacagcaggg ccgtaacttg tggaatggct tcattgtcag ctgagaaagt tacgcttgac 540 caaagggatt atgagaaata cagcgtgagt tgccaggaag atgtgacatg tccaacggca 600 gaggaaacgt tgccaattga gctcgctttg gaagctcgtc aacaaaacaa gtatgaaaac 660 tatagtacta gcttcttcat acgggacatc atcaaaccag atccacctaa gaatttgcag 720 atgaagcctc tgaagaattc acaagtcgag gtatcctggg aatacccaga ttcatggtcc 780 actcctcata gttactttag cctgaaattc tttgtacgca tacagcggaa gaaggagaaa 840 atgaaggaga cggaagaagg ctgcaatcag aaaggcgctt ttcttgttga aaagacgagc 900 actgaggttc aatgcaaagg cgggaatgta tgtgttcaag cccaagatag gtattataat 960 agctcctgct ctaagtgggc ttgcgtacca tgcagagtta gaagtggctc aacctcaggc 1020 tccggaaaac ctggttccgg tgaaggttcc acaaaagggc gtgtgattcc tgtgtccggc 1080 ccagctaggt gtctctccca gtcacggaat ctcctgaaaa ccacggatga catggtaaag 1140 acagctaggg agaaactcaa gcactactcc tgcacagctg aggatatcga tcatgaggac 1200 atcaccaggg accagacatc cactctgaaa acttgcctgc ctttggaact ccacaagaac 1260 gaatcttgtc tggcaacgcg tgaaacgagt tctactacaa gagggtcctg tcttccccct 1320 caaaagacaa gccttatgat gaccttgtgt ctcggtagca tttatgagga cctaaagatg 1380 tatcaaaccg agtttcaggc tatcaatgca gcgctccaga atcataacca tcagcagatc 1440 attcttgaca aaggaatgct cgtggccatt gatgaactaa tgcagagcct aaaccacaat 1500 ggcgagactc ttcgacagaa accgcctgtg ggcgaggccg atccatatag agtcaaaatg 1560 aaactgtgta ttctcctgca tgcatttagt actcgtgtag tgactattaa cagagtgatg 1620 ggttaccttt cctcagctaa tacacttgtc ctctttggcg ctgggttcgg cgccgtcata 1680 acggttgttg tcatcgtggt aataatcaag tgcttttgca agcacaggtc ttgttttcgc 1740 aggaatgaag cctctagaga aacaaataat tcactgacct ttggccccga agaagctctt 1800 gcagagcaaa cggtgtttct c 1821 <210> 81 <211> 607 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 81 Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu 1 5 10 15 Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu 35 40 45 Thr Cys Asp Thr Pro Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys 65 70 75 80 Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr 85 90 95 Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp 100 105 110 Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys 115 120 125 Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln 130 135 140 Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro 145 150 155 160 Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys 165 170 175 Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln 180 185 190 Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu 195 200 205 Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser 210 215 220 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 225 230 235 240 Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro 245 250 255 Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val 260 265 270 Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys 275 280 285 Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln 290 295 300 Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn 305 310 315 320 Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser Gly 325 330 335 Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys 340 345 350 Gly Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser 355 360 365 Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu 370 375 380 Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp 385 390 395 400 Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu 405 410 415 Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr 420 425 430 Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr 435 440 445 Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu 450 455 460 Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile 465 470 475 480 Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser 485 490 495 Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu 500 505 510 Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala 515 520 525 Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser 530 535 540 Ser Ala Asn Thr Leu Val Leu Phe Gly Ala Gly Phe Gly Ala Val Ile 545 550 555 560 Thr Val Val Val Ile Val Val Ile Ile Lys Cys Phe Cys Lys His Arg 565 570 575 Ser Cys Phe Arg Arg Asn Glu Ala Ser Arg Glu Thr Asn Asn Ser Leu 580 585 590 Thr Phe Gly Pro Glu Glu Ala Leu Ala Glu Gln Thr Val Phe Leu 595 600 605 <210> 82 <211> 1716 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 82 atgtgtcagt cacgctatct tctcttcctt gctactctgg ccttgctcaa tcacttgtcc 60 cttgctcgtg tgattcctgt gtccggccca gctaggtgtc tctcccagtc acggaatctc 120 ctgaaaacca cggatgacat ggtaaagaca gctagggaga aactcaagca ctactcctgc 180 acagctgagg atatcgatca tgaggacatc accagggacc agacatccac tctgaaaact 240 tgcctgcctt tggaactcca caagaacgaa tcttgtctgg caacgcgtga aacgagttct 300 actacaagag ggtcctgtct tccccctcaa aagacaagcc ttatgatgac cttgtgtctc 360 ggtagcattt atgaggacct aaagatgtat caaaccgagt ttcaggctat caatgcagcg 420 ctccagaatc ataaccatca gcagatcatt cttgacaaag gaatgctcgt ggccattgat 480 gaactaatgc agagcctaaa ccacaatggc gagactcttc gacagaaacc gcctgtggggc 540 gaggccgatc catatagagt caaaatgaaa ctgtgtattc tcctgcatgc atttagtact 600 cgtgtagtga ctattaacag agtgatgggt tacctttcct cagctggaag cggcgccacc 660 aacttctccc tgctgaagca ggccggcgac gtggaggaga accccggccc catgtgccca 720 cagaaactca caatttcttg gttcgcaatc gtcctgctgg tgtcacccct gatggcaatg 780 tgggagttgg aaaaggatgt atacgtcgtc gaggtcgact ggacacctga cgctccgggt 840 gaaactgtca acctcacttg cgatactcct gaagaggacg acatcacgtg gacgagcgac 900 cagcgacatg gagtgatagg gtctggcaag acgcttacta tcacggttaa ggaatttctc 960 gacgcagggc agtacacatg tcacaagggc ggcgagactc tgagccactc ccatttgctg 1020 ctgcacaaga aggagaatgg tatctggtct accgaaatcc tgaagaattt taagaacaag 1080 actttctga aatgcgaggc cccaaattat tccggacgtt tcacttgcag ttggctcgtt 1140 caaagaaata tggacttgaa atttaacatt aaatccagct cttcatctcc tgacagcagg 1200 gccgtaactt gtggaatggc ttcattgtca gctgagaaag ttacgcttga ccaaagggat 1260 tatgagaaat acagcgtgag ttgccaggaa gatgtgacat gtccaacggc agaggaaacg 1320 ttgccaattg agctcgcttt ggaagctcgt caacaaaaca agtatgaaaa ctatagtact 1380 agcttcttca tacgggacat catcaaacca gatccaccta agaatttgca gatgaagcct 1440 ctgaagaatt cacaagtcga ggtatcctgg gaatacccag attcatggtc cactcctcat 1500 agttacttta gcctgaaatt ctttgtacgc atacagcgga agaaggagaa aatgaaggag 1560 acggaagaag gctgcaatca gaaaggcgct tttcttgttg aaaagacgag cactgaggtt 1620 caatgcaaag gcgggaatgt atgtgttcaa gcccaagata ggtattataa tagctcctgc 1680 tctaagtggg cttgcgtacc atgcagagtt agaagt 1716 <210> 83 <211> 572 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 83 Met Cys Gln Ser Arg Tyr Leu Leu Phe Leu Ala Thr Leu Ala Leu Leu 1 5 10 15 Asn His Leu Ser Leu Ala Arg Val Ile Pro Val Ser Gly Pro Ala Arg 20 25 30 Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val 35 40 45 Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp 50 55 60 Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr 65 70 75 80 Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg 85 90 95 Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr 100 105 110 Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys 115 120 125 Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His 130 135 140 Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp 145 150 155 160 Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys 165 170 175 Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys 180 185 190 Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val 195 200 205 Met Gly Tyr Leu Ser Ser Ala Gly Ser Gly Ala Thr Asn Phe Ser Leu 210 215 220 Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Cys Pro 225 230 235 240 Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu Val Ser Pro 245 250 255 Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val 260 265 270 Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp 275 280 285 Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly 290 295 300 Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu 305 310 315 320 Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His 325 330 335 Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu 340 345 350 Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro 355 360 365 Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met 370 375 380 Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg 385 390 395 400 Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu 405 410 415 Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val 420 425 430 Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu 435 440 445 Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile 450 455 460 Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro 465 470 475 480 Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp 485 490 495 Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln 500 505 510 Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys 515 520 525 Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly 530 535 540 Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys 545 550 555 560 Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser 565 570 <210> 84 <211> 570 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 84 atggccaggc tttgcgcttt tctcgtcatg ctgatcgtca tgagttactg gtccatttgc 60 agcctcggat gtgatctgcc ccacacctac aacctgcgca acaaacgagc tctcaaagtg 120 ttggcccaaa tgaggcggtt gcccttcctt tcctgtctca aagacaggca agattttgga 180 tttccactag agaaagtaga caatcaacag atacagaaag ctcaagctat ccccgtgttg 240 agggacttga ctcaacagac gttgaatcta tttactagca aggccagctc tgctgcttgg 300 aatgccaccc ttcttgactc attttgcaat gacctacatc aacaactgaa tgatctccaa 360 acatgtttga tgcagcaggt aggtgtccaa gaacccccgc ttactcagga agacgccctt 420 ctggctgtcc gcaagtactt tcacagaatc acagtgtacc tgcgcgaaaa gaaacactcc 480 ccctgcgctt gggaagtggt cagggccgag gtttggcgag ccctgagtag ctccgtcaat 540 ctccttcctc ggttgtccga ggagaaagag 570 <210> 85 <211> 190 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 85 Met Ala Arg Leu Cys Ala Phe Leu Val Met Leu Ile Val Met Ser Tyr 1 5 10 15 Trp Ser Ile Cys Ser Leu Gly Cys Asp Leu Pro His Thr Tyr Asn Leu 20 25 30 Arg Asn Lys Arg Ala Leu Lys Val Leu Ala Gln Met Arg Arg Leu Pro 35 40 45 Phe Leu Ser Cys Leu Lys Asp Arg Gln Asp Phe Gly Phe Pro Leu Glu 50 55 60 Lys Val Asp Asn Gln Gln Ile Gln Lys Ala Gln Ala Ile Pro Val Leu 65 70 75 80 Arg Asp Leu Thr Gln Gln Thr Leu Asn Leu Phe Thr Ser Lys Ala Ser 85 90 95 Ser Ala Ala Trp Asn Ala Thr Leu Leu Asp Ser Phe Cys Asn Asp Leu 100 105 110 His Gln Gln Leu Asn Asp Leu Gln Thr Cys Leu Met Gln Gln Val Gly 115 120 125 Val Gln Glu Pro Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val Arg 130 135 140 Lys Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His Ser 145 150 155 160 Pro Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu Ser 165 170 175 Ser Ser Val Asn Leu Leu Pro Arg Leu Ser Glu Glu Lys Glu 180 185 190 <210> 86 <211> 918 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 86 atggcttgca actgtcagct catgcaagat actcccctgc ttaagtttcc ctgccctaga 60 ctcattctcc tcttcgtcct tctcattcgc ctaagccagg tgagttccga tgtggatgaa 120 caactgagta aatctgtcaa ggataaagtt ctgctcccat gccgctacaa tagcccccat 180 gaggacgagt ccgaagatag gatttactgg cagaaacatg ataaggtggt gctatccgtc 240 attgccggta aattgaaggt gtggcccgaa tataagaata gaaccctgta tgacaacaca 300 acttatagcc taatcatcct cggtctcgta ctgagcgacc gaggtactta ctcatgcgtt 360 gtgcagaaga aggagcgcgg aacatacgaa gtcaagcacc ttgcattggt gaaattgtca 420 ataaaagctg acttttcaac tcctaatatt actgaatcag gtaacccttc cgcagacact 480 aaaagaatta catgcttcgc ctctggcggg tttcccaaac cacggttctc ttggctagag 540 aatggggagag aacttccagg tatcaataca accatctctc aagacccaga atcagaactg 600 tacaccatct ccagccaact cgatttcaat accacaagaa atcatacaat aaaatgtctg 660 ataaagtacg gagatgcaca tgtctctgaa gatttcacat gggagaaacc accagaggac 720 ccgccagaca gcaagaatac acttgtcctc tttggcgctg ggttcggcgc cgtcataacg 780 gttgttgtca tcgtggtaat aatcaagtgc ttttgcaagc acaggtcttg ttttcgcagg 840 aatgaagcct ctagagaaac aaataattca ctgacctttg gccccgaaga agctcttgca 900 gagcaaacgg tgtttctc 918 <210> 87 <211> 306 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 87 Met Ala Cys Asn Cys Gln Leu Met Gln Asp Thr Pro Leu Leu Lys Phe 1 5 10 15 Pro Cys Pro Arg Leu Ile Leu Leu Phe Val Leu Leu Ile Arg Leu Ser 20 25 30 Gln Val Ser Ser Asp Val Asp Glu Gln Leu Ser Lys Ser Val Lys Asp 35 40 45 Lys Val Leu Leu Pro Cys Arg Tyr Asn Ser Pro His Glu Asp Glu Ser 50 55 60 Glu Asp Arg Ile Tyr Trp Gln Lys His Asp Lys Val Val Leu Ser Val 65 70 75 80 Ile Ala Gly Lys Leu Lys Val Trp Pro Glu Tyr Lys Asn Arg Thr Leu 85 90 95 Tyr Asp Asn Thr Thr Tyr Ser Leu Ile Ile Leu Gly Leu Val Leu Ser 100 105 110 Asp Arg Gly Thr Tyr Ser Cys Val Val Gln Lys Lys Glu Arg Gly Thr 115 120 125 Tyr Glu Val Lys His Leu Ala Leu Val Lys Leu Ser Ile Lys Ala Asp 130 135 140 Phe Ser Thr Pro Asn Ile Thr Glu Ser Gly Asn Pro Ser Ala Asp Thr 145 150 155 160 Lys Arg Ile Thr Cys Phe Ala Ser Gly Gly Phe Pro Lys Pro Arg Phe 165 170 175 Ser Trp Leu Glu Asn Gly Arg Glu Leu Pro Gly Ile Asn Thr Thr Ile 180 185 190 Ser Gln Asp Pro Glu Ser Glu Leu Tyr Thr Ile Ser Ser Gln Leu Asp 195 200 205 Phe Asn Thr Thr Arg Asn His Thr Ile Lys Cys Leu Ile Lys Tyr Gly 210 215 220 Asp Ala His Val Ser Glu Asp Phe Thr Trp Glu Lys Pro Pro Glu Asp 225 230 235 240 Pro Pro Asp Ser Lys Asn Thr Leu Val Leu Phe Gly Ala Gly Phe Gly 245 250 255 Ala Val Ile Thr Val Val Val Ile Val Val Ile Ile Lys Cys Phe Cys 260 265 270 Lys His Arg Ser Cys Phe Arg Arg Asn Glu Ala Ser Arg Glu Thr Asn 275 280 285 Asn Ser Leu Thr Phe Gly Pro Glu Glu Ala Leu Ala Glu Gln Thr Val 290 295 300 Phe Leu 305 <210> 88 <211> 780 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 88 atgatcgaaa cttattccca accctcaccg cgctcagtag caactggcct accagccagc 60 atgaagatat tcatgtacct cttgactgta ttcttgatca cgcaaatgat tggtagtgtt 120 ttgttcgccg tttatctcca caggcgcctg gataaagttg aagaagaggt taatctccat 180 gaagacttcg tgttcattaa gaaactcaaa agatgtaaca aaggtgaggg atctctgtct 240 cttctgaact gtgaggagat gcgacggcaa ttcgaggacc tcgtaaaaga cataactctc 300 aacaaagaag agaagaaaga aaactctttc gagatgcaac ggggcgacga ggaccctcaa 360 attgccgcac atgtcgtttc tgaagcgaat tccaatgccg cgtccgtgct ccagtgggcg 420 aagaagggat actacacgat gaagagcaac cttgtgatgc ttgaaaatgg caagcagctc 480 acagttaaac gcgagggact ctactatgta tacacccaag tgaccttttg ttccaaccgg 540 gagccaagta gccaacgccc gttcatcgtt gggctgtggc tcaagccttc ttcagggagt 600 gaacgaatcc ttctcaaggc agccaacacg cattccagca gccaactgtg tgagcaacaa 660 tccgtgcatc ttggcggggt ctttgagctg caagcgggcg cctctgtgtt cgtgaatgtt 720 accgaagcca gccaggttat ccaccgcgtg ggtttcagta gttttggcct gctcaagctg 780 <210> 89 <211> 260 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 89 Met Ile Glu Thr Tyr Ser Gln Pro Ser Pro Arg Ser Val Ala Thr Gly 1 5 10 15 Leu Pro Ala Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Val Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Val Glu Glu Glu Val Asn Leu His Glu Asp Phe Val 50 55 60 Phe Ile Lys Lys Leu Lys Arg Cys Asn Lys Gly Glu Gly Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Met Arg Arg Gln Phe Glu Asp Leu Val Lys 85 90 95 Asp Ile Thr Leu Asn Lys Glu Glu Lys Lys Glu Asn Ser Phe Glu Met 100 105 110 Gln Arg Gly Asp Glu Asp Pro Gln Ile Ala Ala His Val Val Ser Glu 115 120 125 Ala Asn Ser Asn Ala Ala Ser Val Leu Gln Trp Ala Lys Lys Gly Tyr 130 135 140 Tyr Thr Met Lys Ser Asn Leu Val Met Leu Glu Asn Gly Lys Gln Leu 145 150 155 160 Thr Val Lys Arg Glu Gly Leu Tyr Tyr Val Tyr Thr Gln Val Thr Phe 165 170 175 Cys Ser Asn Arg Glu Pro Ser Ser Gln Arg Pro Phe Ile Val Gly Leu 180 185 190 Trp Leu Lys Pro Ser Ser Gly Ser Glu Arg Ile Leu Leu Lys Ala Ala 195 200 205 Asn Thr His Ser Ser Ser Gln Leu Cys Glu Gln Gln Ser Val His Leu 210 215 220 Gly Gly Val Phe Glu Leu Gln Ala Gly Ala Ser Val Phe Val Asn Val 225 230 235 240 Thr Glu Ala Ser Gln Val Ile His Arg Val Gly Phe Ser Ser Phe Gly 245 250 255 Leu Leu Lys Leu 260 <210> 90 <211> 438 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 90 atggagcgta ctctggtctg ccttgttgg atattcttgg ggacagttgc acacaaatca 60 tcaccccaag gaccggatag actcctcata cgcctgcgcc atctgattga cattgtcgag 120 cagttgaaga tttatgagaa cgacctggac cctgaactat tgagcgcgcc tcaagacgtc 180 aaagggcatt gcgagcatgc tgcatttgca tgttttcaga aagctaagct caaaccaagt 240 aatcccggta acaataaaac attcatcatc gacctggtgg cccaactaag acgccggttg 300 ccggcgcgcc ggggtggtaa gaaacagaaa catattgcta aatgcccctc ttgcgactct 360 tacgagaaaa ggacacctaa ggaattcctc gaacgattga aatggttgtt gcagaagatg 420 atccatcaac atctgagc 438 <210> 91 <211> 146 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 91 Met Glu Arg Thr Leu Val Cys Leu Val Val Ile Phe Leu Gly Thr Val 1 5 10 15 Ala His Lys Ser Ser Pro Gln Gly Pro Asp Arg Leu Leu Ile Arg Leu 20 25 30 Arg His Leu Ile Asp Ile Val Glu Gln Leu Lys Ile Tyr Glu Asn Asp 35 40 45 Leu Asp Pro Glu Leu Leu Ser Ala Pro Gln Asp Val Lys Gly His Cys 50 55 60 Glu His Ala Ala Phe Ala Cys Phe Gln Lys Ala Lys Leu Lys Pro Ser 65 70 75 80 Asn Pro Gly Asn Asn Lys Thr Phe Ile Ile Asp Leu Val Ala Gln Leu 85 90 95 Arg Arg Arg Leu Pro Ala Arg Arg Gly Gly Lys Lys Gln Lys His Ile 100 105 110 Ala Lys Cys Pro Ser Cys Asp Ser Tyr Glu Lys Arg Thr Pro Lys Glu 115 120 125 Phe Leu Glu Arg Leu Lys Trp Leu Leu Gln Lys Met Ile His Gln His 130 135 140 Leu Ser 145 <210> 92 <211> 399 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 92 atggcacaaa tgatgacact gtccctactt agtctagttc tagctttgtg tattccctgg 60 actcaaggca gtgacggagg aggacaagac tgctgcctca aatattctca aaagaaaatc 120 ccctattcta tagtccgagg ttaccgtaag caagaaccga gtctaggttg tcctatcccc 180 gcaatcctct ttctaccacg gaaacatagc aaaccagaat tgtgcgccaa cccagaagag 240 ggttgggtcc aaaatttgat gaggcgcctt gaccaaccac cggccccggg taaacaatca 300 ccggggtgtc ggaagaatag gggtacatcc aaatccggga agaaagggaa ggggagtaag 360 ggctgtaaga gaacggaaca aactcaacct agcagaggt 399 <210> 93 <211> 133 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 93 Met Ala Gln Met Met Thr Leu Ser Leu Leu Ser Leu Val Leu Ala Leu 1 5 10 15 Cys Ile Pro Trp Thr Gln Gly Ser Asp Gly Gly Gly Gln Asp Cys Cys 20 25 30 Leu Lys Tyr Ser Gln Lys Lys Ile Pro Tyr Ser Ile Val Arg Gly Tyr 35 40 45 Arg Lys Gln Glu Pro Ser Leu Gly Cys Pro Ile Pro Ala Ile Leu Phe 50 55 60 Leu Pro Arg Lys His Ser Lys Pro Glu Leu Cys Ala Asn Pro Glu Glu 65 70 75 80 Gly Trp Val Gln Asn Leu Met Arg Arg Leu Asp Gln Pro Pro Ala Pro 85 90 95 Gly Lys Gln Ser Pro Gly Cys Arg Lys Asn Arg Gly Thr Ser Lys Ser 100 105 110 Gly Lys Lys Gly Lys Gly Ser Lys Gly Cys Lys Arg Thr Glu Gln Thr 115 120 125 Gln Pro Ser Arg Gly 130 <210> 94 <211> 1224 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 94 atggaaaccg acacattgct cctctgggtt ctccttctat gggtccccgg ttccaccgga 60 gatatccaaa tgacacaatc acccagcagc ctgcctgcct ctctgggcga ccgcgttacc 120 atcaattgtc aagcttccca agatataagt aattatctca actggtacca gcaaaagccc 180 ggtaaagcgc ctaaattgct gatttattat actaataaac tcgcagatgg agttcctagt 240 agattttctg gttcagggag tggacgggac tccagtttta ccatatcaag tctggaatcc 300 gaggatatcg gcagctacta ttgccagcaa tattataatt acccttggac ttttggaccc 360 gggactaaac ttgagatcaa aagaggcgga ggaggcagtg gtggtggtgg atcaggcggc 420 ggtggtagtg aggtacaact cgtggaatca ggcggcggac tggtccaacc cggcaagagc 480 cttaaactct cttgtgaggc cagtggattt acattcagcg gttatggaat gcactgggtg 540 agacaagctc ccggcagggg cctagaatca gtggcgtaca tcaccagctc atcaataaac 600 attaaatacg ctgatgcagt caagggccgg tttactgtat cccgcgacaa cgctaagaat 660 cttctctttc tgcaaatgaa catacttaag agcgaggata ctgccatgta ttattgtgcc 720 780 aacatcacat caaataatag caaccccgtg gaaggggacg actctgtttc actcacctgt 840 gattcctata ccgatcctga taatatcaac tatctatggt ctcgtaacgg tgaaagtctc 900 agcgaaggcg accggttgaa actctccgaa ggtaacagaa cccttacgct tctgaacgtc 960 acccggaacg ataccgggcc ctatgtttgc gaaactagga accctgttag cgtgaatcgt 1020 agcgaccctt tctccctaaa taatactcta gtgctattcg gagcgggatt cggtgccgtc 1080 atcacagtag tcgttattgt agtcattatt aaatgctttt gtaaacatag gtcttgcttc 1140 agaagaaatg aggccagccg tgaaactaat aattccctga cctttgggcc cgaagaagct 1200 ttggctgaac agactgtgtt tctc 1224 <210> 95 <211> 408 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 95 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Pro 20 25 30 Ala Ser Leu Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asp 35 40 45 Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr Ile Ser 85 90 95 Ser Leu Glu Ser Glu Asp Ile Gly Ser Tyr Tyr Cys Gln Gln Tyr Tyr 100 105 110 Asn Tyr Pro Trp Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Arg 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 130 135 140 Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys Ser 145 150 155 160 Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr Gly 165 170 175 Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Ser Val Ala 180 185 190 Tyr Ile Thr Ser Ser Ser Ile Asn Ile Lys Tyr Ala Asp Ala Val Lys 195 200 205 Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe Leu 210 215 220 Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240 Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gln Gly Thr Met Val Thr 245 250 255 Val Ser Ser Pro Asn Ile Thr Ser Asn Asn Ser Asn Pro Val Glu Gly 260 265 270 Asp Asp Ser Val Ser Leu Thr Cys Asp Ser Tyr Thr Asp Pro Asp Asn 275 280 285 Ile Asn Tyr Leu Trp Ser Arg Asn Gly Glu Ser Leu Ser Glu Gly Asp 290 295 300 Arg Leu Lys Leu Ser Glu Gly Asn Arg Thr Leu Thr Leu Leu Asn Val 305 310 315 320 Thr Arg Asn Asp Thr Gly Pro Tyr Val Cys Glu Thr Arg Asn Pro Val 325 330 335 Ser Val Asn Arg Ser Asp Pro Phe Ser Leu Asn Asn Thr Leu Val Leu 340 345 350 Phe Gly Ala Gly Phe Gly Ala Val Ile Thr Val Val Val Ile Val Val 355 360 365 Ile Ile Lys Cys Phe Cys Lys His Arg Ser Cys Phe Arg Arg Asn Glu 370 375 380 Ala Ser Arg Glu Thr Asn Asn Ser Leu Thr Phe Gly Pro Glu Glu Ala 385 390 395 400 Leu Ala Glu Gln Thr Val Phe Leu 405 <210> 96 <211> 420 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 96 atggttcttc tcaggagcct cttcatcctg caagtactag tacggatggg gctaacttac 60 aacttttcta actgcaactt cacgtcaatt acgaaaatat attgtaacat aatttttcat 120 gacctgactg gagatttgaa aggggctaag ttcgagcaaa tcgaggactg tgagagcaag 180 ccagcttgtc tcctgaaaat cgagtactat actctcaatc ctatccctgg ctgcccttca 240 ctccccgaca aaacatttgc ccggagaaca agagaagccc tcaatgacca ctgcccaggc 300 taccctgaaa ctgagagaaa tgacggtact caggaaatgg cacaagaagt ccaaaacatc 360 tgcctgaatc aaacctcaca aattctaaga ttgtggtatt ccttcatgca atctccagaa 420 <210> 97 <211> 140 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 97 Met Val Leu Leu Arg Ser Leu Phe Ile Leu Gln Val Leu Val Arg Met 1 5 10 15 Gly Leu Thr Tyr Asn Phe Ser Asn Cys Asn Phe Thr Ser Ile Thr Lys 20 25 30 Ile Tyr Cys Asn Ile Ile Phe His Asp Leu Thr Gly Asp Leu Lys Gly 35 40 45 Ala Lys Phe Glu Gln Ile Glu Asp Cys Glu Ser Lys Pro Ala Cys Leu 50 55 60 Leu Lys Ile Glu Tyr Tyr Thr Leu Asn Pro Ile Pro Gly Cys Pro Ser 65 70 75 80 Leu Pro Asp Lys Thr Phe Ala Arg Arg Thr Arg Glu Ala Leu Asn Asp 85 90 95 His Cys Pro Gly Tyr Pro Glu Thr Glu Arg Asn Asp Gly Thr Gln Glu 100 105 110 Met Ala Gln Glu Val Gln Asn Ile Cys Leu Asn Gln Thr Ser Gln Ile 115 120 125 Leu Arg Leu Trp Tyr Ser Phe Met Gln Ser Pro Glu 130 135 140 <210> 98 <211> 423 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 98 atgtggctgc agaatttact tttcctggggc attgtggtct acagcctctc agcacccacc 60 cgctcaccca tcactgtcac ccggccttgg aagcatgtag aggccatcaa agaagccctg 120 aacctcctgg atgacatgcc tgtcacgttg aatgaagagg tagaagtcgt ctctaacgag 180 ttctccttca agaagctaac atgtgtgcag acccgcctga agatattcga gcagggtcta 240 cggggcaatt tcaccaaact caagggcgcc ttgaacatga cagccagcta ctaccagaca 300 tactgccccc caactccgga aacggactgt gaaacacaag ttaccaccta tgcggatttc 360 atagacagcc ttaaaacctt tctgactgat atcccctttg aatgcaaaaa accaggccaa 420 423 <210> 99 <211> 141 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 99 Met Trp Leu Gln Asn Leu Leu Phe Leu Gly Ile Val Val Tyr Ser Leu 1 5 10 15 Ser Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His 20 25 30 Val Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val 35 40 45 Thr Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys 50 55 60 Lys Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu 65 70 75 80 Arg Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser 85 90 95 Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr 100 105 110 Gln Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu 115 120 125 Thr Asp Ile Pro Phe Glu Cys Lys Lys Pro Gly Gln Lys 130 135 140 <210> 100 <211> 465 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 100 atgaacgcta cacactgcat cttggctttg cagctcttcc tcatggctgt ttctggctgt 60 tactgccacg gcacagtcat tgaaagccta gaaagtctga ataactattt taactcaagt 120 ggcatagatg tggaagaaaa gagtctcttc ttggatatct ggaggaactg gcaaaaggat 180 ggtgacatga aaatcctgca gagccagatt atctctttct acctcagact ctttgaagtc 240 ttgaaagaca atcaggccat cagcaacaac ataagcgtca ttgaatcaca cctgattact 300 accttcttca gcaacagcaa ggcgaaaaag gatgcattca tgagtattgc caagtttgag 360 gtcaacaacc cacaggtcca gcgccaagca ttcaatgagc tcatccgagt ggtccaccag 420 ctgttgccgg aatccagcct caggaagcgg aaaaggagtc gctgc 465 <210> 101 <211> 155 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 101 Met Asn Ala Thr His Cys Ile Leu Ala Leu Gln Leu Phe Leu Met Ala 1 5 10 15 Val Ser Gly Cys Tyr Cys His Gly Thr Val Ile Glu Ser Leu Glu Ser 20 25 30 Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser 35 40 45 Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys 50 55 60 Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val 65 70 75 80 Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser 85 90 95 His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala 100 105 110 Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg 115 120 125 Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu 130 135 140 Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys 145 150 155 <210> 102 <211> 462 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 102 atgttccatg tttcttttag atatatcttt ggaattcctc cactgatcct tgttctgctg 60 cctgtcacat catctgagtg ccacattaaa gacaaagaag gtaaagcata tgagagtgta 120 ctgatgatca gcatcgatga attggacaaa atgacaggaa ctgatagtaa ttgcccgaat 180 aatgaaccaa acttttttag aaaacatgta tgtgatgata caaaggaagc tgcttttcta 240 aatcgtgctg ctcgcaagtt gaagcaattt cttaaaatga atatcagtga agaattcaat 300 gtccacttac taacagtatc acaaggcaca caaacactgg tgaactgcac aagtaaggaa 360 gaaaaaaacg taaaggaaca gaaaaagaat gatgcatgtt tcctaaagag actactgaga 420 gaaataaaaa cttgttggaa taaaattttg aagggcagta ta 462 <210> 103 <211> 154 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 103 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Ile Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Thr Ser Ser Glu Cys His Ile Lys Asp Lys 20 25 30 Glu Gly Lys Ala Tyr Glu Ser Val Leu Met Ile Ser Ile Asp Glu Leu 35 40 45 Asp Lys Met Thr Gly Thr Asp Ser Asn Cys Pro Asn Asn Glu Pro Asn 50 55 60 Phe Phe Arg Lys His Val Cys Asp Asp Thr Lys Glu Ala Ala Phe Leu 65 70 75 80 Asn Arg Ala Ala Arg Lys Leu Lys Gln Phe Leu Lys Met Asn Ile Ser 85 90 95 Glu Glu Phe Asn Val His Leu Leu Thr Val Ser Gln Gly Thr Gln Thr 100 105 110 Leu Val Asn Cys Thr Ser Lys Glu Glu Lys Asn Val Lys Glu Gln Lys 115 120 125 Lys Asn Asp Ala Cys Phe Leu Lys Arg Leu Leu Arg Glu Ile Lys Thr 130 135 140 Cys Trp Asn Lys Ile Leu Lys Gly Ser Ile 145 150 <210> 104 <211> 966 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 104 atgcagctaa agtgtccctg ttttgtgtcc ttgggaacca ggcagcctgt ttggaagaag 60 ctccatgttt ctagcgggtt cttttctggt cttggtctgt tcttgctgct gttgagcagc 120 ctctgtgctg cctctgcaga gactgaagtc ggtgcaatgg tgggcagcaa tgtggtgctc 180 agctgcattg acccccacag acgccatttc aacttgagtg gtctgtatgt ctattggcaa 240 atcgaaaacc cagaagtttc ggtgacttac tacctgcctt acaagtctcc agggatcaat 300 gtggacagtt cctacaagaa caggggccat ctgtccctgg actccatgaa gcagggtaac 360 ttctctctgt acctgaagaa tgtcacccct caggataccc aggagttcac atgccgggta 420 tttatgaata cagccacaga gttagtcaag atcttggaag aggtggtcag gctgcgtgtg 480 gcagcaaact tcagtacacc tgtcatcagc acctctgata gctccaaccc gggccaggaa 540 cgtacctaca cctgcatgtc caagaatggc tacccagagc ccaacctgta ttggatcaac 600 acaacggaca atagcctaat agacacggct ctgcagaata acactgtcta cttgaacaag 660 ttgggcctgt atgatgtaat cagcacatta aggctccctt ggacatctcg tggggatgtt 720 ctgtgctgcg tagagaatgt ggctctccac cagaaca ctagcattag ccaggcagaa 780 agtttcactg gaaataacac aaagaaccca caggaaaccc acaataatga gttaaaagtc 840 cttgtccccg tccttgctgt actggcggca gcggcattcg tttccttcat catatacaga 900 cgcacgcgtc cccaccgaag ctatacagga cccaagactg tacagcttga acttacagac 960 cacgcc 966 <210> 105 <211> 322 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 105 Met Gln Leu Lys Cys Pro Cys Phe Val Ser Leu Gly Thr Arg Gln Pro 1 5 10 15 Val Trp Lys Lys Leu His Val Ser Ser Gly Phe Phe Ser Gly Leu Gly 20 25 30 Leu Phe Leu Leu Leu Leu Ser Ser Leu Cys Ala Ala Ser Ala Glu Thr 35 40 45 Glu Val Gly Ala Met Val Gly Ser Asn Val Val Leu Ser Cys Ile Asp 50 55 60 Pro His Arg Arg His Phe Asn Leu Ser Gly Leu Tyr Val Tyr Trp Gln 65 70 75 80 Ile Glu Asn Pro Glu Val Ser Val Thr Tyr Tyr Leu Pro Tyr Lys Ser 85 90 95 Pro Gly Ile Asn Val Asp Ser Ser Tyr Lys Asn Arg Gly His Leu Ser 100 105 110 Leu Asp Ser Met Lys Gln Gly Asn Phe Ser Leu Tyr Leu Lys Asn Val 115 120 125 Thr Pro Gln Asp Thr Gln Glu Phe Thr Cys Arg Val Phe Met Asn Thr 130 135 140 Ala Thr Glu Leu Val Lys Ile Leu Glu Glu Val Val Arg Leu Arg Val 145 150 155 160 Ala Ala Asn Phe Ser Thr Pro Val Ile Ser Thr Ser Asp Ser Ser Asn 165 170 175 Pro Gly Gln Glu Arg Thr Tyr Thr Cys Met Ser Lys Asn Gly Tyr Pro 180 185 190 Glu Pro Asn Leu Tyr Trp Ile Asn Thr Thr Asp Asn Ser Leu Ile Asp 195 200 205 Thr Ala Leu Gln Asn Asn Thr Val Tyr Leu Asn Lys Leu Gly Leu Tyr 210 215 220 Asp Val Ile Ser Thr Leu Arg Leu Pro Trp Thr Ser Arg Gly Asp Val 225 230 235 240 Leu Cys Cys Val Glu Asn Val Ala Leu His Gln Asn Ile Thr Ser Ile 245 250 255 Ser Gln Ala Glu Ser Phe Thr Gly Asn Asn Thr Lys Asn Pro Gln Glu 260 265 270 Thr His Asn Asn Glu Leu Lys Val Leu Val Pro Val Leu Ala Val Leu 275 280 285 Ala Ala Ala Ala Phe Val Ser Phe Ile Ile Tyr Arg Arg Thr Arg Pro 290 295 300 His Arg Ser Tyr Thr Gly Pro Lys Thr Val Gln Leu Glu Leu Thr Asp 305 310 315 320 His Ala <210> 106 <211> 909 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 106 atgtggccct tggcggcggc gctgttgctg ggctcctgct gctgcggttc agctcaacta 60 ctgtttagta acgtcaactc catagagttc acttcatgca atgaaactgt ggtcatccct 120 tgcatcgtcc gtaatgtgga ggcgcaaagc accgaagaaa tgtttgtgaa gtggaagttg 180 aacaaatcgt atattttcat ctatgatgga aataaaaata gcactactac agatcaaaac 240 tttaccagtg caaaaatctc agtctcagac ttaatcaatg gcattgcctc tttgaaaatg 300 gataagcgcg atgccatggt gggaaactac acttgcgaag tgacagagtt atccagagaa 360 ggcaaaacag ttatagagct gaaaaaccgc acggtttcgt ggttttctcc aaatgaaaag 420 atcctcattg ttattttccc aattttggct atactcctgt tctgggggaaa gtttggtatt 480 ttaacactca aatataaatc cagccatacg aataagagaa tcattctgct gctcgttgcc 540 gggctggtgc tcacagtcat cgtggttgtt ggagccatcc ttctcatccc aggagaaaag 600 cccgtgaaga atgcttctgg acttggcctc attgtaatct ctacggggat attaatacta 660 cttcagtaca atgtgtttat gacagctttt ggaatgacct ctttcaccat tgccatattg 720 atcactcaag tgctgggcta cgtccttgct ttggtcgggc tgtgtctctg catcatggca 780 tgtgagccag tgcacggccc ccttttgatt tcaggtttgg ggatcatagc tctagcagaa 840 ctacttggat tagtttatat gaagtttgtc gcttccaacc agaggactat ccaacctcct 900 aggaatagg 909 <210> 107 <211> 303 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 107 Met Trp Pro Leu Ala Ala Ala Leu Leu Leu Gly Ser Cys Cys Cys Gly 1 5 10 15 Ser Ala Gln Leu Leu Phe Ser Asn Val Asn Ser Ile Glu Phe Thr Ser 20 25 30 Cys Asn Glu Thr Val Val Ile Pro Cys Ile Val Arg Asn Val Glu Ala 35 40 45 Gln Ser Thr Glu Glu Met Phe Val Lys Trp Lys Leu Asn Lys Ser Tyr 50 55 60 Ile Phe Ile Tyr Asp Gly Asn Lys Asn Ser Thr Thr Thr Asp Gln Asn 65 70 75 80 Phe Thr Ser Ala Lys Ile Ser Val Ser Asp Leu Ile Asn Gly Ile Ala 85 90 95 Ser Leu Lys Met Asp Lys Arg Asp Ala Met Val Gly Asn Tyr Thr Cys 100 105 110 Glu Val Thr Glu Leu Ser Arg Glu Gly Lys Thr Val Ile Glu Leu Lys 115 120 125 Asn Arg Thr Val Ser Trp Phe Ser Pro Asn Glu Lys Ile Leu Ile Val 130 135 140 Ile Phe Pro Ile Leu Ala Ile Leu Leu Phe Trp Gly Lys Phe Gly Ile 145 150 155 160 Leu Thr Leu Lys Tyr Lys Ser Ser His Thr Asn Lys Arg Ile Ile Leu 165 170 175 Leu Leu Val Ala Gly Leu Val Leu Thr Val Ile Val Val Val Gly Ala 180 185 190 Ile Leu Leu Ile Pro Gly Glu Lys Pro Val Lys Asn Ala Ser Gly Leu 195 200 205 Gly Leu Ile Val Ile Ser Thr Gly Ile Leu Ile Leu Leu Gln Tyr Asn 210 215 220 Val Phe Met Thr Ala Phe Gly Met Thr Ser Phe Thr Ile Ala Ile Leu 225 230 235 240 Ile Thr Gln Val Leu Gly Tyr Val Leu Ala Leu Val Gly Leu Cys Leu 245 250 255 Cys Ile Met Ala Cys Glu Pro Val His Gly Pro Leu Leu Ile Ser Gly 260 265 270 Leu Gly Ile Ile Ala Leu Ala Glu Leu Leu Gly Leu Val Tyr Met Lys 275 280 285 Phe Val Ala Ser Asn Gln Arg Thr Ile Gln Pro Pro Arg Asn Arg 290 295 300 <210> 108 <211> 1161 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 108 atggcagcag cagtaacttg gatacctctc ctggcaggtc tcctggcagg actgagggac 60 accaaggccc agcagacaac tttacaccta cttgtgggtc gtgtgtttgt gcatcctttg 120 gaacatgcca ccttcctgcg ccttccagaa cacgttgcgg tgccacccac tgtccgactc 180 acctaccacg ctcacctcca ggggacatcca gacctgccca ggtggctgca ctacacacag 240 cgcagtccct ataaccctgg cttcctctac ggctccccca ctccagaaga tcgtgggtac 300 caagtcatcg aggtcacagc ctacaatcga gacagttttg acaccactag acagaggctg 360 ctgctgctga ttggggaccc cgaaggtccc cggttgccat accaagctga gttcctggtg 420 cgcagccatg atgtggagga ggtgctgccc accacacctg ccaaccgctt cctcaccgcc 480 ttggggggac tgtgggagcc aggagagctt cagctgctca acatcacttc cgccttggac 540 cggggaggcc gagtccctct tcctattgag ggacggaagg aaggggtata cattaaggta 600 ggctctgcca cacccttctc cacctgcctg aagatggtgg cgtcgcccga cagctatgcc 660 cgttgtgccc agggacagcc tccactactg tcctgctacg acactttggc accccacttc 720 cgcgttgact ggtgcaatgt gtctctggta gacaagtcag tacccgagcc cctggatgag 780 gtacctactc caggcgatgg gatcttggag cacgacccgt tcttctgccc acccactgaa 840 gccacagacc gagacttcct gacagatgcc ttggtgaccc tcttggtgcc tttgttggtg 900 gctctgctgc ttactctgtt gctggcttac atcatgtgct ttcggcgtga aggacggctg 960 aagagagaca tggccacctc tgacatccag atgtttcacc actgttccat ccatgggaat 1020 acagaagagc ttcggcagat ggcagccagc cgagaggtgc cccggcctct ttccaccttg 1080 cccatgttta atgttcgtac aggagagcgg ttacctcccc gagtagacag cgcacagatg 1140 cctcttatcc tggaccagca c 1161 <210> 109 <211> 387 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 109 Met Ala Ala Ala Val Thr Trp Ile Pro Leu Leu Ala Gly Leu Leu Ala 1 5 10 15 Gly Leu Arg Asp Thr Lys Ala Gln Gln Thr Thr Leu His Leu Leu Val 20 25 30 Gly Arg Val Phe Val His Pro Leu Glu His Ala Thr Phe Leu Arg Leu 35 40 45 Pro Glu His Val Ala Val Pro Pro Thr Val Arg Leu Thr Tyr His Ala 50 55 60 His Leu Gln Gly His Pro Asp Leu Pro Arg Trp Leu His Tyr Thr Gln 65 70 75 80 Arg Ser Pro Tyr Asn Pro Gly Phe Leu Tyr Gly Ser Pro Thr Pro Glu 85 90 95 Asp Arg Gly Tyr Gln Val Ile Glu Val Thr Ala Tyr Asn Arg Asp Ser 100 105 110 Phe Asp Thr Thr Arg Gln Arg Leu Leu Leu Leu Ile Gly Asp Pro Glu 115 120 125 Gly Pro Arg Leu Pro Tyr Gln Ala Glu Phe Leu Val Arg Ser His Asp 130 135 140 Val Glu Glu Val Leu Pro Thr Thr Pro Ala Asn Arg Phe Leu Thr Ala 145 150 155 160 Leu Gly Gly Leu Trp Glu Pro Gly Glu Leu Gln Leu Leu Asn Ile Thr 165 170 175 Ser Ala Leu Asp Arg Gly Gly Arg Val Pro Leu Pro Ile Glu Gly Arg 180 185 190 Lys Glu Gly Val Tyr Ile Lys Val Gly Ser Ala Thr Pro Phe Ser Thr 195 200 205 Cys Leu Lys Met Val Ala Ser Pro Asp Ser Tyr Ala Arg Cys Ala Gln 210 215 220 Gly Gln Pro Pro Leu Leu Ser Cys Tyr Asp Thr Leu Ala Pro His Phe 225 230 235 240 Arg Val Asp Trp Cys Asn Val Ser Leu Val Asp Lys Ser Val Pro Glu 245 250 255 Pro Leu Asp Glu Val Pro Thr Pro Gly Asp Gly Ile Leu Glu His Asp 260 265 270 Pro Phe Phe Cys Pro Pro Thr Glu Ala Thr Asp Arg Asp Phe Leu Thr 275 280 285 Asp Ala Leu Val Thr Leu Leu Val Pro Leu Leu Val Ala Leu Leu Leu 290 295 300 Thr Leu Leu Leu Ala Tyr Ile Met Cys Phe Arg Arg Glu Gly Arg Leu 305 310 315 320 Lys Arg Asp Met Ala Thr Ser Asp Ile Gln Met Phe His His Cys Ser 325 330 335 Ile His Gly Asn Thr Glu Glu Leu Arg Gln Met Ala Ala Ser Arg Glu 340 345 350 Val Pro Arg Pro Leu Ser Thr Leu Pro Met Phe Asn Val Arg Thr Gly 355 360 365 Glu Arg Leu Pro Pro Arg Val Asp Ser Ala Gln Met Pro Leu Ile Leu 370 375 380 Asp Gln His 385 <210> 110 <211> 627 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 110 atgtggaaat ggatactgac acattgtgcc tcagcctttc cccacctgcc gggctgctgt 60 tgctgcttct tgttgctctt tttggtgtct tcgttccctg tcacctgcca agctcttggt 120 caggacatgg tgtcacagga ggccaccaac tgctcttctt cctcctcgtc cttctcctct 180 ccttccagtg cgggaaggca tgtgcggagc tacaatcacc tccaaggaga tgtccgctgg 240 agaaggctgt tctccttcac caagtacttt ctcacgattg agaagaacgg caaggtcagc 300 gggaccaaga atgaagactg tccgtacagt gtcctggaga taacatcagt ggaaatcgga 360 gttgttgccg tcaaagccat caacagcaac tattacttag ccatgaacaa gaaggggaaa 420 ctctatggct caaaagagtt taacaacgac tgtaagctga aagagagaat agaggaaaat 480 ggatacaaca cctatgcatc ttttaactgg cagcacaatg gcaggcaaat gtatgtggca 540 ttgaatggaa aaggagctcc caggagagga caaaaaacaa gaaggaaaaa cacctctgct 600 cacttcctcc ccatgacgat ccaaaca 627 <210> 111 <211> 209 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 111 Met Trp Lys Trp Ile Leu Thr His Cys Ala Ser Ala Phe Pro His Leu 1 5 10 15 Pro Gly Cys Cys Cys Cys Phe Leu Leu Leu Phe Leu Val Ser Ser Phe 20 25 30 Pro Val Thr Cys Gln Ala Leu Gly Gln Asp Met Val Ser Gln Glu Ala 35 40 45 Thr Asn Cys Ser Ser Ser Ser Ser Ser Phe Ser Ser Pro Ser Ser Ala 50 55 60 Gly Arg His Val Arg Ser Tyr Asn His Leu Gln Gly Asp Val Arg Trp 65 70 75 80 Arg Arg Leu Phe Ser Phe Thr Lys Tyr Phe Leu Thr Ile Glu Lys Asn 85 90 95 Gly Lys Val Ser Gly Thr Lys Asn Glu Asp Cys Pro Tyr Ser Val Leu 100 105 110 Glu Ile Thr Ser Val Glu Ile Gly Val Val Ala Val Lys Ala Ile Asn 115 120 125 Ser Asn Tyr Tyr Leu Ala Met Asn Lys Lys Gly Lys Leu Tyr Gly Ser 130 135 140 Lys Glu Phe Asn Asn Asp Cys Lys Leu Lys Glu Arg Ile Glu Glu Asn 145 150 155 160 Gly Tyr Asn Thr Tyr Ala Ser Phe Asn Trp Gln His Asn Gly Arg Gln 165 170 175 Met Tyr Val Ala Leu Asn Gly Lys Gly Ala Pro Arg Arg Gly Gln Lys 180 185 190 Thr Arg Arg Lys Asn Thr Ser Ala His Phe Leu Pro Met Thr Ile Gln 195 200 205 Thr <210> 112 <211> 5853 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 112 atgcctcctc tgccactgga acacagaccc aggcagcagc ctggtgcctc cgtgctggtt 60 cggtacttca tgatcccctg caacatctgc ttgatcctct tggctacttc tacgttgggc 120 tttgcggtgc tgcttttcct cagcaactac aaacctggga tccacttcac agcagcgcct 180 tctatgcctc ctgatgtgtg caggggaatg ttatgtggct ttggtgctgt gtgtgaacct 240 agtgttgagg atccaggccg ggcctcctgt gtgtgcaaga agaatgtctg ccctgctatg 300 gtagctcctg tgtgtggctc agatgcttcc acctatagca acgagtgtga gctacagcgt 360 gcacagtgca accagcaacg gcgcatccgc ctactccgcc aagggccatg tgggtcccgg 420 gacccctgg ccaatgtgac ctgcagtttc ggtagtacct gtgtaccttc agccgatgga 480 cagaccgcct cgtgtctgtg tcctacaacc tgctttgggg cccctgatgg cacagtgtgt 540 ggcagtgatg gtgttgacta ccctagtgag tgccagctgc tccgtcatgc ctgtgccaac 600 caggagcaca tctttaagaa gttcgatggt ccttgtgacc cctgccaggg cagcatgtca 660 gacctgaatc atatttgccg ggtgaaccca cgtacacggc acccagaaat gcttctgcgg 720 cctgagaact gccccgccca acacacct atctgtggag atgatggggt cacctatgaa 780 aacgactgtg tcatgagccg tataggtgca gcccgtggcc tgcttctcca gaaagtgcgc 840 tctggtcaat gccagactcg agaccagtgc ccggagacct gccagtttaa ctctgtatgc 900 ctgtcccgcc gcggccgtcc ccactgttcc tgcgatcgcg tcacctgtga tggggcttac 960 aggccagtgt gtgcccagga tgggcacacg tatgacaatg actgttggcg ccaacaggcc 1020 gagtgtcgac aacagcagac cattcccccc aagcaccagg gcccgtgtga ccagacccca 1080 tccccgtgcc gtggagcgca gtgtgcattt ggggcaacat gcacagtgaa gaatgggaaa 1140 gctgtgtgcg agtgccagcg ggtgtgctcg ggcggctacg atcctgtgg cggcagtgat 1200 ggtgtcactt acggcagtgt gtgcgagctg gaatccatgg cctgtaccct tgggcgggaa 1260 atccgagtgg cccgcagagg accgtgtgac cgatgtgggc agtgccggtt tggatccttg 1320 tgcgaggtgg agactggacg ctgtgtgtgc ccctctgagt gtgtggagtc agcccagccc 1380 gtatgtggct ctgacggaca cacatatgct agtgaatgtg agctgcatgt ccacgcctgt 1440 acacaccaga tcagcctata cgtggcctca gccggacact gccagacctg tggagaaaca 1500 gtttgtacct ttggggctgt gtgctcagct ggacagtgtg tatgtccccg ttgtgagcac 1560 cccccacctg gccctgtgtg cggcagtgat ggcgtcacct acctcagtgc ctgtgagctc 1620 cgagaggctg cctgtcagca gcaggtacaa attgaggagg cccgtgcagg gccgtgtgag 1680 ccggctgagt gtggctcagg gggctctggg tctggggaag acaatgcgtg tgagcaggag 1740 ctgtgtcggc agcatggtgg tgtctgggat gaggactcag aagacgggcc gtgtgtctgt 1800 gactttagtt gccagagtgt ccttaaaagc ccagtgtgtg gctcagatgg agtcacctat 1860 agcacggagt gccatctgaa gaaggccaga tgtgaagcgc ggcaagagct gtacgtcgct 1920 gctcagggag cctgccgggg ccctaccttg gctccactgc tacctatggc ctccccacac 1980 tgtgcccaaa ccccctatgg ctgctgccag gacaatgtca ctgctgccca gggtgtggggc 2040 ttggctggct gtcccagcac ctgccattgc aacccacacg gctcctatag cggcacttgt 2100 gacccagtca cagggcagtg ctcctgccga ccagggtgtag gaggcctcag gtgtgatcgc 2160 tgtgagcctg gcttctggaa cttccgtggc attgtcaccg atggacatag tggttgcact 2220 ccctgcagct gtgaccctcg gggtgctgta agagatgact gtgagcagat gactggattg 2280 tgttcctgta gacctggtgt ggctggtccc aagtgtgggc agtgtccaga tggtcaagcc 2340 ctgggccatc ttggctgtga agcagatccc acaacaccag tgacttgtgt ggaaatgcac 2400 tgtgagtttg gcgcctcctg cgtagaggag gctggttttg cccagtgtgt ctgcccaact 2460 ctcacatgtc cagaggctaa ctctaccaag gtctgtggat cagatggtgt cacatacggc 2520 aatgaatgcc agctgaagac cattgcctgc cgccagcgtc tggacatctc cattcagagt 2580 cttggtccat gccgggagag tgttgctcct ggggtttccc ctacatctgc atctatgacc 2640 accccaaggc atatcctgag caggacactg gcgtctcccc acagcagcct tcctctgtct 2700 cccagcacta ctgcccatga ttggcccacc ccattaccca catcacctca gaccgtagtc 2760 ggcaccccca ggagcactgc agccacaccc tctgatgtgg ccagtcttgc tacagcgatc 2820 ttcagggaat ctggcagcac caacggcagt ggcgatgagg agctcagtgg cgatgaggag 2880 gccagtgggg gcgggtctgg gggacttgag cccccggtgg gcagcgttgt ggtgacccac 2940 gggccaccca tcgagagggc ttcctgttac aactcacctt tgggctgctg ctcagatggc 3000 aagacaccct cactggactc agaaggctcc aactgtccag ctaccaaggc attccagggc 3060 gtgctggagc ttgagggggt cgagggacag gaactgttct acacaccaga gatggctgac 3120 cccaagtcag agttgtttgg ggagactgca aggagcattg agagcacgct ggacgacctg 3180 ttccggaatt cggatgttaa gaaggacttc tggagcatcc gcctacggga actggggcct 3240 ggcaaattag tccgtgccat tgtggatgtt cactttgacc ccaccacagc cttccaggca 3300 ccagatgtgg gtcaggcctt gctccaacag atccaggtat ccaggccgtg ggccctggca 3360 gtgagggaggc ctctgcggga gcatgtgcga ttcttggact ttgactggtt tcccactttt 3420 tttacgggag ctgcaacagg aaccacagct gctgtggcca cagccagagc caccactgtg 3480 agccgactgt ctgcctcttc tgtcacccca cgagtctacc ccagttacac cagccggcct 3540 gttggcagaa ctacggcacc gctaaccact cgccggccac caaccactac cgccagtatt 3600 gaccgacctc ggactccagg cccgcaacgg cccccaaagt cctgtgattc ccagccttgc 3660 ctccacggag gtacctgcca ggacctggat tctggcaagg gtttcagctg cagctgtact 3720 gcaggcaggg ctggcactgt ctgtgagaaa gtgcagctcc cctctgtgcc agcttttaag 3780 ggccactcct tcttggcctt ccccaccctc cgagcctacc acacgctgcg tctggcacta 3840 gaattccggg cgctggagac agagggactg ctgctctaca atggcaatgc acgtggcaaa 3900 gatttcctgg ctctggctct gttggatggt catgtacagt tcaggttcga cacgggctca 3960 gggccggcgg tgctaacaag cttagtgcca gtggaaccgg gacggtggca ccgcctcgag 4020 ttgtcacggc attggcggca gggcacactt tctgtggatg gcgaggctcc tgttgtaggt 4080 gaaagtccga gtggcactga tggcctcaac ttggacacga agctctatgt gggtggtctc 4140 ccagaagaac aagttgccac ggtgcttgat cggacctctg tgggcatcgg cctgaaagga 4200 tgcattcgta tgttggacat caacaaccag cagctggagc tgagcgattg gcagagggct 4260 gtggttcaaa gctctggtgt gggggaatgc ggagaccatc cctgctcacc taacccctgc 4320 catggcgggg ccctctgcca ggccctggag gctggcgtgt tcctctgtca gtgcccacct 4380 ggccgctttg gcccaacttg tgcagatgaa aagaacccct gccaaccgaa cccctgccac 4440 gggtcagccc cctgccatgt gctttccagg ggtggggcca agtgtgcgtg ccccctggga 4500 cgcagtggtt ccttctgtga gacagtcctg gagaatgctg gctcccggcc cttcctggct 4560 gactttaatg gcttctccta cctggaactg aaaggcttgc acaccttcga gagagaccta 4620 ggggagaaga tggcgctgga gatggtgttc ttggctcgtg ggcccagtgg cttactcctc 4680 tacaatgggc agaagacgga tggcaagggg gactttgtat ccctggccct gcataaccgg 4740 cacctagagt tccgctatga ccttggcaag ggggctgcaa tcatcaggag caaagagccc 4800 atagccctgg gcacctgggt tagggtattc ctggaacgaa atggccgcaa gggtgccctt 4860 caagtgggtg atgggccccg tgtgctaggg gaatctccga aatcccgcaa ggtcccgcac 4920 accatgctca acctcaagga gcccctctat gtggggggag ctcctgactt cagcaagctg 4980 gctcggggcg ctgcagtggc ctccggcttt gatggtgcca tccagctggt gtctctaaga 5040 ggccatcagc tgctgactca ggagcatgtg ttgcgggcag tagatgtagc gccttttgca 5100 ggccaccctt gtacccaggc cgtggacaac ccctgcctta atgggggctc ctgtatcccg 5160 agggaagcca cttatgagtg cctgtgtcct gggggcttct ctgggctgca ctgcgagaag 5220 gggatagttg agaagtcagt gggggaccta gaaacactgg cctttgatgg gcggacctac 5280 atcgagtacc tcaatgctgt gactgagagc gagctgacca atgagatccc agcccccgaa 5340 actctggatt cccgggccct tttcagtgag aaagcgctgc agagcaacca ctttgagctg 5400 agcttacgca ctgaggccac gcaggggctg gtgctgtgga ttggaaaggt tggagaacgt 5460 gcagactaca tggctctggc cattgtggat gggcacctac aactgagcta tgacctaggc 5520 tcccagccag ttgtgctgcg ctccactgtg aaggtcaaca ccaaccgctg gcttcgagtc 5580 agggctcaca gggagcacag ggaaggttcc cttcaggtgg gcaatgaagc ccctgtgact 5640 ggctcttccc cgctgggtgc cacacaattg gacacagatg gagccctgtg gcttggaggc 5700 ctacagaagc ttcctgtggg gcaggctctc cccaaggcct atggcacggg ttttgtgggc 5760 tgtctgcggg acgtggtagt gggccatcgc cagctgcatc tgctggagga cgctgtcacc 5820 aaaccagagc taagaccctg ccccactctc tga 5853 <210> 113 <211> 1949 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 113 Met Pro Pro Leu Pro Leu Glu His Arg Pro Arg Gln Gln Pro Gly Ala 1 5 10 15 Ser Val Leu Val Arg Tyr Phe Met Ile Pro Cys Asn Ile Cys Leu Ile 20 25 30 Leu Leu Ala Thr Ser Thr Leu Gly Phe Ala Val Leu Leu Phe Leu Ser 35 40 45 Asn Tyr Lys Pro Gly Ile His Phe Thr Ala Ala Pro Ser Met Pro Pro 50 55 60 Asp Val Cys Arg Gly Met Leu Cys Gly Phe Gly Ala Val Cys Glu Pro 65 70 75 80 Ser Val Glu Asp Pro Gly Arg Ala Ser Cys Val Cys Lys Lys Asn Val 85 90 95 Cys Pro Ala Met Val Ala Pro Val Cys Gly Ser Asp Ala Ser Thr Tyr 100 105 110 Ser Asn Glu Cys Glu Leu Gln Arg Ala Gln Cys Asn Gln Gln Arg Arg 115 120 125 Ile Arg Leu Leu Arg Gln Gly Pro Cys Gly Ser Arg Asp Pro Cys Ala 130 135 140 Asn Val Thr Cys Ser Phe Gly Ser Thr Cys Val Pro Ser Ala Asp Gly 145 150 155 160 Gln Thr Ala Ser Cys Leu Cys Pro Thr Thr Cys Phe Gly Ala Pro Asp 165 170 175 Gly Thr Val Cys Gly Ser Asp Gly Val Asp Tyr Pro Ser Glu Cys Gln 180 185 190 Leu Leu Arg His Ala Cys Ala Asn Gln Glu His Ile Phe Lys Lys Phe 195 200 205 Asp Gly Pro Cys Asp Pro Cys Gln Gly Ser Met Ser Asp Leu Asn His 210 215 220 Ile Cys Arg Val Asn Pro Arg Thr Arg His Pro Glu Met Leu Leu Arg 225 230 235 240 Pro Glu Asn Cys Pro Ala Gln His Thr Pro Ile Cys Gly Asp Asp Gly 245 250 255 Val Thr Tyr Glu Asn Asp Cys Val Met Ser Arg Ile Gly Ala Ala Arg 260 265 270 Gly Leu Leu Leu Leu Gln Lys Val Arg Ser Gly Gln Cys Gln Thr Arg Asp 275 280 285 Gln Cys Pro Glu Thr Cys Gln Phe Asn Ser Val Cys Leu Ser Arg Arg 290 295 300 Gly Arg Pro His Cys Ser Cys Asp Arg Val Thr Cys Asp Gly Ala Tyr 305 310 315 320 Arg Pro Val Cys Ala Gln Asp Gly His Thr Tyr Asp Asn Asp Cys Trp 325 330 335 Arg Gln Gln Ala Glu Cys Arg Gln Gln Gln Thr Ile Pro Pro Lys His 340 345 350 Gln Gly Pro Cys Asp Gln Thr Pro Ser Pro Cys Arg Gly Ala Gln Cys 355 360 365 Ala Phe Gly Ala Thr Cys Thr Val Lys Asn Gly Lys Ala Val Cys Glu 370 375 380 Cys Gln Arg Val Cys Ser Gly Gly Tyr Asp Pro Val Cys Gly Ser Asp 385 390 395 400 Gly Val Thr Tyr Gly Ser Val Cys Glu Leu Glu Ser Met Ala Cys Thr 405 410 415 Leu Gly Arg Glu Ile Arg Val Ala Arg Arg Gly Pro Cys Asp Arg Cys 420 425 430 Gly Gln Cys Arg Phe Gly Ser Leu Cys Glu Val Glu Thr Gly Arg Cys 435 440 445 Val Cys Pro Ser Glu Cys Val Glu Ser Ala Gln Pro Val Cys Gly Ser 450 455 460 Asp Gly His Thr Tyr Ala Ser Glu Cys Glu Leu His Val His Ala Cys 465 470 475 480 Thr His Gln Ile Ser Leu Tyr Val Ala Ser Ala Gly His Cys Gln Thr 485 490 495 Cys Gly Glu Thr Val Cys Thr Phe Gly Ala Val Cys Ser Ala Gly Gln 500 505 510 Cys Val Cys Pro Arg Cys Glu His Pro Pro Pro Gly Pro Val Cys Gly 515 520 525 Ser Asp Gly Val Thr Tyr Leu Ser Ala Cys Glu Leu Arg Glu Ala Ala 530 535 540 Cys Gln Gln Gln Val Gln Ile Glu Glu Ala Arg Ala Gly Pro Cys Glu 545 550 555 560 Pro Ala Glu Cys Gly Ser Gly Gly Ser Gly Ser Gly Glu Asp Asn Ala 565 570 575 Cys Glu Gln Glu Leu Cys Arg Gln His Gly Gly Val Trp Asp Glu Asp 580 585 590 Ser Glu Asp Gly Pro Cys Val Cys Asp Phe Ser Cys Gln Ser Val Leu 59 5 600 605 Lys Ser Pro Val Cys Gly Ser Asp Gly Val Thr Tyr Ser Thr Glu Cys 610 615 620 His Leu Lys Lys Ala Arg Cys Glu Ala Arg Gln Glu Leu Tyr Val Ala 625 630 635 640 Ala Gln Gly Ala Cys Arg Gly Pro Thr Leu Ala Pro Leu Leu Pro Met 645 650 655 Ala Ser Pro His Cys Ala Gln Thr Pro Tyr Gly Cys Cys Gln Asp Asn 660 665 670 Val Thr Ala Ala Gln Gly Val Gly Leu Ala Gly Cys Pro Ser Thr Cys 675 680 685 His Cys Asn Pro His Gly Ser Tyr Ser Gly Thr Cys Asp Pro Val Thr 690 695 700 Gly Gln Cys Ser Cys Arg Pro Gly Val Gly Gly Leu Arg Cys Asp Arg 705 710 715 720 Cys Glu Pro Gly Phe Trp Asn Phe Arg Gly Ile Val Thr Asp Gly His 725 730 735 Ser Gly Cys Thr Pro Cys Ser Cys Asp Pro Arg Gly Ala Va l Arg Asp 740 745 750 Asp Cys Glu Gln Met Thr Gly Leu Cys Ser Cys Arg Pro Gly Val Ala 755 760 765 Gly Pro Lys Cys Gly Gln Cys Pro Asp Gly Gln Ala Leu Gly His Leu 770 775 780 Gly Cys Glu Ala Asp Pro Thr Thr Pro Val Thr Cys Val Glu Met His 785 790 795 800 Cys Glu Phe Gly Ala Ser Cys Val Glu Glu Ala Gly Phe Ala Gln Cys 805 810 815 Val Cys Pro Thr Leu Thr Cys Pro Glu Ala Asn Ser Thr Lys Val Cys 820 825 830 Gly Ser Asp Gly Val Thr Tyr Gly Asn Glu Cys Gln Leu Lys Thr Ile 835 840 845 Ala Cys Arg Gln Arg Leu Asp Ile Ser Ile Gln Ser Leu Gly Pro Cys 850 855 860 Arg Glu Ser Val Ala Pro Gly Val Ser Pro Thr Ser Ala Ser Met Thr 865 870 875 880 Thr Pro Arg His Ile Leu Ser Arg Thr Leu Al a Ser Pro His Ser Ser 885 890 895 Leu Pro Leu Ser Pro Ser Thr Thr Thr Ala His Asp Trp Pro Thr Pro Leu 900 905 910 Pro Thr Ser Pro Gln Thr Val Val Gly Thr Pro Arg Ser Thr Ala Ala 915 920 925 Thr Pro Ser Asp Val Ala Ser Leu Ala Thr Ala Ile Phe Arg Glu Ser 930 935 940 Gly Ser Thr Asn Gly Ser Gly Asp Glu Glu Leu Ser Gly Asp Glu Glu 945 950 955 960 Ala Ser Gly Gly Gly Ser Gly Gly Leu Glu Pro Pro Val Gly Ser Val 965 970 975 Val Val Thr His Gly Pro Pro Ile Glu Arg Ala Ser Cys Tyr Asn Ser 980 985 990 Pro Leu Gly Cys Cys Ser Asp Gly Lys Thr Pro Ser Leu Asp Ser Glu 995 1000 1005 Gly Ser Asn Cys Pro Ala Thr Lys Ala Phe Gln Gly Val Leu Glu 1010 1015 1020 Leu Glu Gly Val Glu Gly Gln Glu Leu Phe Tyr Thr Pro Glu Met 1025 1030 1035 Ala Asp Pro Lys Ser Glu Leu Phe Gly Gl u Thr Ala Arg Ser Ile 1040 1045 1050 Glu Ser Thr Leu Asp Asp Leu Phe Arg Asn Ser Asp Val Lys Lys 1055 1060 1065 Asp Phe Trp Ser Ile Arg Leu Arg Glu Leu Gly Pro Gly Lys Leu 1070 1075 1080 Val Arg Ala Ile Val Asp Val His Phe Asp Pro Thr Thr Ala Phe 1085 1090 1095 Gln Ala Pro Asp Val Gly Gln Ala Leu Leu Gln Gln Ile Gln Val 1100 1105 1110 Ser Arg Pro Trp Ala Leu Ala Val Arg Arg Pro Leu Arg Glu His 1115 1120 1125 Val Arg Phe Leu Asp Phe Asp Trp Phe Pro Thr Phe Phe Thr Gly 1130 1135 1140 Ala Ala Thr Gly Thr Thr Ala Ala Val Ala Thr Ala Arg Ala Thr 1145 1150 1155 Thr Val Ser Arg Leu Ser Ala Ser Ser Val Thr Pro Arg Val Tyr 1160 1165 1170 Pro Ser Tyr Thr Ser Arg Pro Val Gly Arg Thr Thr Ala Pro Leu 1175 1180 1185 Thr Thr Arg Arg Pro Pro Thr Thr Thr Ala Ser Ile Asp Arg Pro 1190 1195 1200 Arg Thr Pro Gly Pro Gln Arg Pro Pro Lys Ser Cys Asp Ser Gln 1205 1210 1215 Pro Cys Leu His Gly Gly Thr Cys Gln Asp Leu Asp Ser Gly Lys 1220 1225 1230 Gly Phe Ser Cys Ser Cys Thr Ala Gly Arg Ala Gly Thr Val Cys 123 5 1240 1245 Glu Lys Val Gln Leu Pro Ser Val Pro Ala Phe Lys Gly His Ser 1250 1255 1260 Phe Leu Ala Phe Pro Thr Leu Arg Ala Tyr His Thr Leu Arg Leu 1265 1270 1275 Ala Leu Glu Phe Arg Ala Leu Glu Thr Glu Gly Leu Leu Leu Tyr 1280 1285 1290 Asn Gly Asn Ala Arg Gly Lys Asp Phe Leu Ala Leu Ala Leu Leu 1295 1300 1305 Asp Gly His Val Gln Phe Arg Phe Asp Thr Gly Ser Gly Pro Ala 1310 1315 1320 Val Leu Thr Ser Leu Val Pro Val Glu Pro Gly Arg Trp His Arg 1325 1330 1335 Leu Glu Leu Ser Arg His Trp Arg Gln Gly Thr Leu Ser Val Asp 1340 1345 1350 Gly Glu Ala Pro Val Val Gly Glu Ser Pro Ser Gly Thr Asp Gly 1355 1360 1365 Leu Asn Leu Asp Thr Lys Leu Tyr Val Gly Gly Leu Pro Glu Glu 1370 1375 1380 Gln Val Ala Thr Val Leu Asp Arg Thr Ser Val Gly Ile Gly Leu 1385 1390 1395 Lys Gly Cys Ile Arg Met Leu Asp Ile Asn Asn Gln Gln Leu Glu 1400 1405 1410 Leu Ser Asp Trp Gln Arg Ala Val Val Gln Ser Ser Gly Val Gly 1415 1420 1425 Glu Cys Gly Asp His Pro Cys Ser Pro Asn Pro Cys His Gly Gly 1430 1435 1440 Ala Leu Cys G ln Ala Leu Glu Ala Gly Val Phe Leu Cys Gln Cys 1445 1450 1455 Pro Pro Gly Arg Phe Gly Pro Thr Cys Ala Asp Glu Lys Asn Pro 1460 1465 1470 Cys Gln Pro Asn Pro Cys His Gly Ser Ala Pro Cys His Val Leu 1475 1480 1485 Ser Arg Gly Gly Ala Lys Cys Ala Cys Pro Leu Gly Arg Ser Gly 1490 1495 1500 Ser Phe Cys Glu Thr Val Leu Glu Asn Ala Gly Ser Arg Pro Phe 1505 1510 1515 Ala Asp Phe Asn Gly Phe Ser Tyr Leu Glu Leu Lys Gly Leu His 1520 1525 1530 Thr Phe Glu Arg Asp Leu Gly Glu Lys Met Ala Leu Glu Met Val 1535 1540 1545 Phe Leu Ala Arg Gly Pro Ser Gly Leu Leu Leu Leu Tyr Asn Gly Gly Gln 1550 1555 1560 Lys Thr Asp Gly Lys Gly Asp Phe Val Ser Leu Ala Leu His Asn 1565 1570 1575 Arg His Leu Glu Phe Arg Tyr Asp Leu Gly Lys Gly Ala Ala Ile 1580 1585 1590 Ile Arg Ser Lys Glu Pro Ile Ala Leu Gly Thr Trp Val Arg Val 1595 1600 1605 Phe Leu Glu Arg Asn Gly Arg Lys Gly Ala Leu Gln Val Gly Asp 1610 1615 1620 Gly Pro Arg Val Leu Gly Glu Ser Pro Lys Ser Arg Lys Val Pro 1625 1630 1635 His Thr Met Leu Asn Leu Lys Glu Pro Le u Tyr Val Gly Gly Ala 1640 1645 1650 Pro Asp Phe Ser Lys Leu Ala Arg Gly Ala Ala Val Ala Ser Gly 1655 1660 1665 Phe Asp Gly Ala Ile Gln Leu Val Ser Leu Arg Gly His Gln Leu 1670 1675 1680 Leu Thr Gln Glu His Val Leu Arg Ala Val Asp Val Ala Pro Phe 1685 1690 1695 Ala Gly His Pro Cys Thr Gln Ala Val Asp Asn Pro Cys Leu Asn 1700 1705 1710 Gly Gly Ser Cys Ile Pro Arg Glu Ala Thr Tyr Glu Cys Leu Cys 1715 1720 1725 Pro Gly Gly Phe Ser Gly Leu His Cys Glu Lys Gly Ile Val Glu 1730 1735 1740 Lys Ser Val Gly Asp Leu Glu Thr Leu Ala Phe Asp Gly Arg Thr 1745 1750 1755 Tyr Ile Glu Tyr Leu Asn Ala Val Thr Glu Ser Glu Leu Thr Asn 1760 1765 1770 Glu Ile Pro Ala Pro Glu Thr Leu Asp Ser Arg Ala Leu Phe Ser 1775 1780 1785 Glu Lys Ala Leu Gln Ser Asn His Phe Glu Leu Ser Leu Arg Thr 1790 1795 1800 Glu Ala Thr Gln Gly Leu Val Leu Trp Ile Gly Lys Val Gly Glu 1805 1810 1815 Arg Ala Asp Tyr Met Ala Leu Ala Ile Val Asp Gly His Leu Gln 1820 1825 1830 Leu Ser Tyr Asp Leu Gly Ser Gln Pro Val Val Leu Arg Ser Thr 183 5 1840 1845 Val Lys Val Asn Thr Asn Arg Trp Leu Arg Val Arg Ala His Arg 1850 1855 1860 Glu His Arg Glu Gly Ser Leu Gln Val Gly Asn Glu Ala Pro Val 1865 1870 1875 Thr Gly Ser Ser Pro Leu Gly Ala Thr Gln Leu Asp Thr Asp Gly 1880 1885 1890 Ala Leu Trp Leu Gly Gly Leu Gln Lys Leu Pro Val Gly Gln Ala 1895 1900 1905 Leu Pro Lys Ala Tyr Gly Thr Gly Phe Val Gly Cys Leu Arg Asp 1910 1915 1920 Val Val Val Gly His Arg Gln Leu His Leu Leu Glu Asp Ala Val 1925 1930 1935Thr Lys Pro Glu Leu Arg Pro Cys Pro Thr Leu 1940 1945 <210> 114 <211> 537 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 114 atgcctggct cagcactgct atgctgcctg ctcttactga ctggcatgag gatcagcagg 60 ggccagtaca gccgggaaga caataactgc acccacttcc cagtcggcca gagccacatg 120 ctcctagagc tgcggactgc cttcagccag gtgaagactt tctttcaaac aaaggaccag 180 ctggacaaca tactgctaac cgactcctta atgcaggact ttaagggtta cttgggttgc 240 caagccttat cggaaatgat ccagttttac ctggtagaag tgatgcccca ggcagagaag 300 catggcccag aaatcaagga gcatttgaat tccctgggtg agaagctgaa gaccctcagg 360 atgcggctga ggcgctgtca tcgatttctc ccctgtgaaa ataagagcaa ggcagtggag 420 caggtgaaga gtgattttaa taagctccaa gaccaaggtg tctacaaggc catgaatgaa 480 tttgacatct tcatcaactg catagaagca tacatgatga tcaaaatgaa aagctaa 537 <210> 115 <211> 178 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 115 Met Pro Gly Ser Ala Leu Leu Cys Cys Leu Leu Leu Leu Thr Gly Met 1 5 10 15 Arg Ile Ser Arg Gly Gln Tyr Ser Arg Glu Asp Asn Asn Cys Thr His 20 25 30 Phe Pro Val Gly Gln Ser His Met Leu Leu Glu Leu Arg Thr Ala Phe 35 40 45 Ser Gln Val Lys Thr Phe Phe Gln Thr Lys Asp Gln Leu Asp Asn Ile 50 55 60 Leu Leu Thr Asp Ser Leu Met Gln Asp Phe Lys Gly Tyr Leu Gly Cys 65 70 75 80 Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Val Glu Val Met Pro 85 90 95 Gln Ala Glu Lys His Gly Pro Glu Ile Lys Glu His Leu Asn Ser Leu 100 105 110 Gly Glu Lys Leu Lys Thr Leu Arg Met Arg Leu Arg Arg Cys His Arg 115 120 125 Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Ser 130 135 140 Asp Phe Asn Lys Leu Gln Asp Gln Gly Val Tyr Lys Ala Met Asn Glu 145 150 155 160 Phe Asp Ile Phe Ile Asn Cys Ile Glu Ala Tyr Met Met Ile Lys Met 165 170 175 Lys Ser <210> 116 <211> 501 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 116 atggcagccc ccagcggagg cttctggact gcggtggtcc tggcggccgc agcgctgaaa 60 ttggccgccg ctgtgtccga gcccaccacc gtgccatttg acgtgaggcc cggagggggtc 120 gtgcattcgt tctcccagga cgtaggaccc gggaacaagt ttacatgtac attcacctac 180 gcttcccaag gagggaccaa cgagcaatgg cagatgagcc tggggacaag tgaagacagc 240 cagcacttta cctgtaccat ctggaggccc caggggaaat cctacctcta cttcacacag 300 ttcaaggctg agttgcgagg tgctgagatc gagtatgcca tggcctactc caaagccgca 360 tttgagagag agagtgatgt ccccctgaaa agtgaggagt ttgaagtgac caagacagca 420 gtgtctcaca ggcctggggc cttcaaagct gagctctcca agctggtgat cgtagccaag 480 gcggcacgct cggagctgtg a 501 <210> 117 <211> 166 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 117 Met Ala Ala Pro Ser Gly Gly Phe Trp Thr Ala Val Val Leu Ala Ala 1 5 10 15 Ala Ala Leu Lys Leu Ala Ala Ala Val Ser Glu Pro Thr Thr Val Pro 20 25 30 Phe Asp Val Arg Pro Gly Gly Val Val His Ser Phe Ser Gln Asp Val 35 40 45 Gly Pro Gly Asn Lys Phe Thr Cys Thr Phe Thr Tyr Ala Ser Gln Gly 50 55 60 Gly Thr Asn Glu Gln Trp Gln Met Ser Leu Gly Thr Ser Glu Asp Ser 65 70 75 80 Gln His Phe Thr Cys Thr Ile Trp Arg Pro Gln Gly Lys Ser Tyr Leu 85 90 95 Tyr Phe Thr Gln Phe Lys Ala Glu Leu Arg Gly Ala Glu Ile Glu Tyr 100 105 110 Ala Met Ala Tyr Ser Lys Ala Ala Phe Glu Arg Glu Ser Asp Val Pro 115 120 125 Leu Lys Ser Glu Glu Phe Glu Val Thr Lys Thr Ala Val Ser His Arg 130 135 140 Pro Gly Ala Phe Lys Ala Glu Leu Ser Lys Leu Val Ile Val Ala Lys 145 150 155 160 Ala Ala Arg Ser Glu Leu 165 <210> 118 <211> 2412 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 118 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta ggtcagccca aggccaaccc cactgtcact 360 ctgttcccgc cctcctctga ggagctccaa gccaacaagg ccacactagt gtgtctgatc 420 agtgacttct acccgggagc tgtgacagtg gcctggaagg cagatggcag ccccgtcaag 480 gcgggagtgg agaccaccaa accctccaaa cagagcaaca acaagtacgc ggccagcagc 540 tacctgagcc tgacgcccga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600 catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttcagg cgccggatct 660 ggtggaaact ggaggtcatcc ccaattcgag aagggcggaa gcggtgggag tggcgggtcc 720 ggtggaagca actggtcaca cccacaattc gagaaaggcg gttctggcgg atctggtgga 780 tctggcggaa gtaactggtc tcatcctcaa ttcgaaaagg gcggaagcgg tggcggcagg 840 ctaggtggag gctcagtgca ggtgcagctg gtggagtctg ggggaggctt ggtacagcct 900 ggggggtccc tgagactctc ctgtgcagcc tctggattca cctttagcag ctatgccatg 960 agctgggtcc gccaggctcc agggaagggg ctggagtggg tctcagttat ttatagcggt 1020 ggtagtagca catactatgc agactccgtg aagggccggt tcaccatctc cagagataat 1080 tccaagaaca cgctgtatct gcaaatgaac agcctgagag ccgaggacac ggccgtatat 1140 tactgtgcgc gcacttctta cctgaaccat ggtgattact ggggtcaagg tactctggtg 1200 accgtgtcta gcgcctccac caagggccca tcggtcttcc ccctggcacc ctcctccaag 1260 agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 1320 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 1380 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 1440 ggcacccaga cctacatctg caacgtgaac cacaagccca gcaacaccaa ggtggacaag 1500 agagtggagc ccaagagctg cgacaagacc cacacctgcc ccccctgccc agccccagag 1560 ctgctgggcg gaccctccgt gttcctgttc ccccccaagc ccaaggacac cctgatgatc 1620 agcaggaccc ccgaggtgac ctgcgtggtg gtggacgtga gccacgagga cccagaggtg 1680 aagttcaact ggtacgtgga cggcgtggag gtgcacaacg ccaagaccaa gcccagagag 1740 gagcagtaca acagcaccta cagggtggtg tccgtgctga ccgtgctgca ccaggactgg 1800 ctgaacggca aggaatacaa gtgcaaggtc tccaacaagg ccctgccagc ccccatcgaa 1860 aagaccatca gcaaggccaa gggccagcca cgggagcccc aggtgtacac cctgcccccc 1920 tcccgggagg agatgaccaa gaaccaggtg tccctgacct gtctggtgaa gggcttctac 1980 cccagcgaca tcgccgtgga gtgggagagc aacggccagc ccgagaacaa ctacaagacc 2040 acccccccag tgctggacag cgacggcagc ttcttcctgt acagcaagct gaccgtggac 2100 aagtccaggt ggcagcaggg caacgtgttc agctgcagcg tgatgcacga ggccctgcac 2160 aaccactaca cccagaagag cctgagcctg tcccccgagc tgcaactgga ggagagctgt 2220 gcggaggcgc aggacgggga gctggacggg ctgtggacga ccatcaccat cttcatcaca 2280 ctcttcctgt taagcgtgtg ctacagtgcc accgtcacct tcttcaaggt gaagtggatc 2340 ttctcctcgg tggtggacct gaagcagacc atcatccccg actacaggaa catgatcgga 2400 cagggggcct ga 2412 <210> 119 <211> 803 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 119 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser Gly Ala Gly Ser Gly Gly Asn Trp 210 215 220 Ser His Pro Gln Phe Glu Lys Gly Gly Ser Gly Gly Ser Gly Gly Ser 225 230 235 240 Gly Gly Ser Asn Trp Ser His Pro Gln Phe Glu Lys Gly Gly Ser Gly 245 250 255 Gly Ser Gly Gly Ser Gly Gly Ser Asn Trp Ser His Pro Gln Phe Glu 260 265 270 Lys Gly Gly Ser Gly Gly Gly Arg Leu Gly Gly Gly Ser Val Gln Val 275 280 285 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu 290 295 300 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met 305 310 315 320 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val 325 330 335 Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly 340 345 350 Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln 355 360 365 Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 370 375 380 Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val 385 390 395 400 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 405 410 415 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 420 425 430 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 435 440 445 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 450 455 460 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 465 470 475 480 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 485 490 495 Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 500 505 510 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 515 520 525 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 530 535 540 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 545 550 555 560 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 565 570 575 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 580 585 590 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 595 600 605 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 610 615 620 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 625 630 635 640 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 645 650 655 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 660 665 670 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 675 680 685 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 690 695 700 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 705 710 715 720 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Glu Leu Gln Leu 725 730 735 Glu Glu Ser Cys Ala Glu Ala Gln Asp Gly Glu Leu Asp Gly Leu Trp 740 745 750 Thr Thr Ile Thr Ile Phe Ile Thr Leu Phe Leu Leu Ser Val Cys Tyr 755 760 765 Ser Ala Thr Val Thr Phe Phe Lys Val Lys Trp Ile Phe Ser Ser Val 770 775 780 Val Asp Leu Lys Gln Thr Ile Ile Pro Asp Tyr Arg Asn Met Ile Gly 785 790 795 800 Gln Gly Ala <210> 120 <211> 645 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 120 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta tcttcagcct ccaccaaggg cccatcggtc 360 ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 420 gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 480 ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 540 gtgaccgtgc cctccagcag cttgggcacc cagacctaca tctgcaacgt gaaccacaag 600 cccagcaaca ccaaggtgga caagagagtg gagcccaaga gctgc 645 <210> 121 <211> 215 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 121 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser Ser 100 105 110 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 115 120 125 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 130 135 140 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 145 150 155 160 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 165 170 175 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 180 185 190 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 195 200 205 Arg Val Glu Pro Lys Ser Cys 210 215 <210> 122 <211> 1566 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 122 caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagtag cacatactat 180 gcagactccg tgaagggccg gttcaccatc tccagagata attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gcgcacttct 300 tacctgaacc atggtgatta ctggggtcaa ggtactctgg tgaccgtgtc tagcgcctcc 360 gtggctgcac catctgtctt catcttcccg ccatctgatg agcagttgaa atctggaact 420 gcctctgttg tgtgcctgct gaataacttc tatcccagag aggccaaagt acagtggaag 480 gtggataacg ccctccaatc gggtaactcc caggagagtg tcacagagca ggacagcaag 540 gacagcacct acagcctcag cagcaccctg acgctgagca aagcagacta cgagaaacac 600 aaagtctacg cctgcgaagt cacccatcag ggcctgagct cgcccgtcac aaagagcttc 660 aacaggggag agtgtgacaa gacccacacc tgccccccct gcccagcccc agagctgctg 720 ggcggaccct ccgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcagg 780 acccccgagg tgacctgcgt ggtggtggac gtgagccacg aggacccaga ggtgaagttc 840 aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag 900 tacaacagca cctacagggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 960 ggcaaggaat acaagtgcaa ggtctccaac aaggccctgc cagcccccat cgaaaagacc 1020 atcagcaagg ccaagggcca gccacggggag ccccaggtgt acaccctgcc cccctcccgg 1080 gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctaccccagc 1140 gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 1200 ccagtgctgg acagcgacgg cagcttcttc ctgtacagca agctgaccgt ggacaagtcc 1260 aggtggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 1320 tacacccaga agagcctgag cctgtccccc gagctgcaac tggaggagag ctgtgcggag 1380 gcgcaggacg gggagctgga cgggctgtgg acgaccatca ccatcttcat cacactcttc 1440 ctgttaagcg tgtgctacag tgccaccgtc accttcttca aggtgaagtg gatcttctcc 1500 tcggtggtgg acctgaagca gaccatcatc cccgactaca ggaacatgat cggacagggg 1560 gcctga 1566 <210> 123 <211> 521 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 123 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro Ser Val Phe Ile 115 120 125 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 130 135 140 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 145 150 155 160 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 165 170 175 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 180 185 190 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 195 200 205 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Glu Leu Gln Leu Glu Glu Ser Cys Ala Glu Ala Gln Asp Gly 450 455 460 Glu Leu Asp Gly Leu Trp Thr Thr Ile Thr Ile Phe Ile Thr Leu Phe 465 470 475 480 Leu Leu Ser Val Cys Tyr Ser Ala Thr Val Thr Phe Phe Lys Val Lys 485 490 495 Trp Ile Phe Ser Ser Val Val Asp Leu Lys Gln Thr Ile Ile Pro Asp 500 505 510 Tyr Arg Asn Met Ile Gly Gln Gly Ala 515 520 <210> 124 <211> 486 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 124 atgaaaattt tgaaaccata tatgaggaat acatccatct cgtgctactt gtgtttcctt 60 ctaaacagtc actttttaac tgaggctggc attcatgtct tcattttggg ctgtgtcagt 120 gtaggtctcc ctaaaacaga ggccaactgg atagatgtaa gatatgacct ggagaaaatt 180 gaaagcctta ttcaatctat tcatattgac accactttat acactgacag tgactttcat 240 cccagttgca aagttactgc aatgaactgc tttctcctgg aattgcaggt tattttacat 300 gagtacagta acatgactct taatgaaaca gtaagaaacg tgctctacct tgcaaacagc 360 actctgtctt ctaacaagaa tgtagcagaa tctggctgca aggaatgtga ggagctggag 420 gagaaaacct tcacagagtt tttgcaaagc tttatacgca ttgtccaaat gttcatcaac 480 acgtcc 486 <210> 125 <211> 162 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 125 Met Lys Ile Leu Lys Pro Tyr Met Arg Asn Thr Ser Ile Ser Cys Tyr 1 5 10 15 Leu Cys Phe Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His 20 25 30 Val Phe Ile Leu Gly Cys Val Ser Val Gly Leu Pro Lys Thr Glu Ala 35 40 45 Asn Trp Ile Asp Val Arg Tyr Asp Leu Glu Lys Ile Glu Ser Leu Ile 50 55 60 Gln Ser Ile His Ile Asp Thr Thr Leu Tyr Thr Asp Ser Asp Phe His 65 70 75 80 Pro Ser Cys Lys Val Thr Ala Met Asn Cys Phe Leu Leu Glu Leu Gln 85 90 95 Val Ile Leu His Glu Tyr Ser Asn Met Thr Leu Asn Glu Thr Val Arg 100 105 110 Asn Val Leu Tyr Leu Ala Asn Ser Thr Leu Ser Ser Asn Lys Asn Val 115 120 125 Ala Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Thr Phe 130 135 140 Thr Glu Phe Leu Gln Ser Phe Ile Arg Ile Val Gln Met Phe Ile Asn 145 150 155 160 Thr Ser <210> 126 <211> 1185 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 126 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 60 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 120 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 180 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 300 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 360 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggagtctggg 420 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 540 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 600 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 660 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 720 ggtcaaggta ctctggtgac cgtgtctagc gccgctgcag tggtccccgt gctgcagaaa 780 gttaatagca ccaccactaa acctgtcctg aggactccta gtccagtgca cccaacaggg 840 accagtcagc cacagagacc ggaagactgc agaccaagag gttcagtgaa gggaaccggc 900 ctggatttcg cctgcgattt ttgggccctg gtcgtcgtcg caggagtttt gttttgctat 960 ggactgctcg tcacagttgc tttgtgtgtt atctggacaa ggaaacggtg gcaaaatgag 1020 aagtttgggg tggacatgcc agatgactat gaagatgaaa atctctatga gggcctgaac 1080 cttgatgact gttctatgta tgaggacatc tccaggggac tccagggcac ctaccaggat 1140 gtgggcaacc tccacattgg agatgcccag ctggaaaagc catga 1185 <210> 127 <211> 394 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 127 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser 100 105 110 Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175 Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220 Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Val Val Pro 245 250 255 Val Leu Gln Lys Val Asn Ser Thr Thr Thr Lys Pro Val Leu Arg Thr 260 265 270 Pro Ser Pro Val His Pro Thr Gly Thr Ser Gln Pro Gln Arg Pro Glu 275 280 285 Asp Cys Arg Pro Arg Gly Ser Val Lys Gly Thr Gly Leu Asp Phe Ala 290 295 300 Cys Asp Phe Trp Ala Leu Val Val Val Ala Gly Val Leu Phe Cys Tyr 305 310 315 320 Gly Leu Leu Val Thr Val Ala Leu Cys Val Ile Trp Thr Arg Lys Arg 325 330 335 Trp Gln Asn Glu Lys Phe Gly Val Asp Met Pro Asp Asp Tyr Glu Asp 340 345 350 Glu Asn Leu Tyr Glu Gly Leu Asn Leu Asp Asp Cys Ser Met Tyr Glu 355 360 365 Asp Ile Ser Arg Gly Leu Gln Gly Thr Tyr Gln Asp Val Gly Asn Leu 370 375 380 His Ile Gly Asp Ala Gln Leu Glu Lys Pro 385 390 <210> 128 <211> 1152 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 128 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaagtgg tccccgtgct gcagaaagtt aatagcacca ccactaaacc tgtcctgagg 780 actcctagtc cagtgcaccc aacagggacc agtcagccac agagaccgga agactgcaga 840 ccaagaggtt cagtgaaggg aaccggcctg gatttcgcct gcgatttttg ggccctggtc 900 gtcgtcgcag gagttttgtt ttgctatgga ctgctcgtca cagttgcttt gtgtgttatc 960 tggacaagga aacggtggca aaatgagaag tttggggtgg acatgccaga tgactatgaa 1020 gatgaaaatc tctatgaggg cctgaacctt gatgactgtt ctatgtatga ggacatctcc 1080 aggggactcc agggcaccta ccaggatgtg ggcaacctcc acattggaga tgcccagctg 1140 gaaaagccat ga 1152 <210> 129 <211> 383 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 129 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Lys Pro Gly Ser Gly Lys Pro Gly Ser Gly Lys Pro 115 120 125 Gly Ser Gly Lys Pro Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp 130 135 140 Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala 145 150 155 160 Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Asp 165 170 175 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly 180 185 190 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Val Val Pro Val Leu Gln Lys Val Asn Ser Thr Thr Thr Lys 245 250 255 Pro Val Leu Arg Thr Pro Ser Pro Val His Pro Thr Gly Thr Ser Gln 260 265 270 Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly Ser Val Lys Gly Thr 275 280 285 Gly Leu Asp Phe Ala Cys Asp Phe Trp Ala Leu Val Val Val Ala Gly 290 295 300 Val Leu Phe Cys Tyr Gly Leu Leu Val Thr Val Ala Leu Cys Val Ile 305 310 315 320 Trp Thr Arg Lys Arg Trp Gln Asn Glu Lys Phe Gly Val Asp Met Pro 325 330 335 Asp Asp Tyr Glu Asp Glu Asn Leu Tyr Glu Gly Leu Asn Leu Asp Asp 340 345 350 Cys Ser Met Tyr Glu Asp Ile Ser Arg Gly Leu Gln Gly Thr Tyr Gln 355 360 365 Asp Val Gly Asn Leu His Ile Gly Asp Ala Gln Leu Glu Lys Pro 370 375 380 <210> 130 <211> 1344 <212> DNA 213 <213> <400> 130 atgtgtcagt cacgctatct tctcttcctt gctactctgg ccttgctcaa tcacttgtcc 60 cttgctcgtg tgattcctgt gtccggccca gctaggtgtc tctcccagtc acggaatctc 120 ctgaaaacca cggatgacat ggtaaagaca gctagggaga aactcaagca ctactcctgc 180 acagctgagg atatcgatca tgaggacatc accagggacc agacatccac tctgaaaact 240 tgcctgcctt tggaactcca caagaacgaa tcttgtctgg caacgcgtga aacgagttct 300 actacaagag ggtcctgtct tccccctcaa aagacaagcc ttatgatgac cttgtgtctc 360 ggtagcattt atgaggacct aaagatgtat caaaccgagt ttcaggctat caatgcagcg 420 ctccagaatc ataaccatca gcagatcatt cttgacaaag gaatgctcgt ggccattgat 480 gaactaatgc agagcctaaa ccacaatggc gagactcttc gacagaaacc gcctgtggggc 540 gaggccgatc catatagagt caaaatgaaa ctgtgtattc tcctgcatgc atttagtact 600 cgtgtagtga ctattaacag agtgatgggt tacctttcct cagctcccag agggcccaca 660 atcaagccct gtcctccatg caaatgccca gcacctaacc tcttgggtgg accatccgtc 720 ttcatcttcc ctccaaagat caaggatgta ctcatgatct ccctgagccc catagtcaca 780 tgtgtggtgg tggatgtgag cgaggatgac ccagatgtcc agatcagctg gtttgtgaac 840 aacgtggaag tacacacagc tcagacacaa acccatagag aggattacaa cagtactctc 900 cgggtggtca gtgccctccc catccagcac caggactgga tgagtggcaa ggagttcaaa 960 tgcaaggtca acaacaaaga ccctcccagcg cccatcgaga gaaccatctc aaaacccaaa 1020 gggtcagtaa gagctccaca ggtatatgtc ttgcctccac cagaagaaga gatgactaag 1080 aaacaggtca ctctgacctg catggtcaca gacttcatgc ctgaagacat ttacgtggag 1140 tggaccaaca acgggaaaac agagctaaac tacaagaaca ctgaaccagt cctggactct 1200 gatggttctt acttcatgta cagcaagctg agagtggaaa agaagaactg ggtggaaaga 1260 aatagctact cctgttcagt ggtccacgag ggtctgcaca atcaccacac gactaagagc 1320 ttctcccgga ctccgggtaa atag 1344 <210> 131 <211> 447 <212> PRT 213 <213> <400> 131 Met Cys Gln Ser Arg Tyr Leu Leu Phe Leu Ala Thr Leu Ala Leu Leu 1 5 10 15 Asn His Leu Ser Leu Ala Arg Val Ile Pro Val Ser Gly Pro Ala Arg 20 25 30 Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val 35 40 45 Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp 50 55 60 Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr 65 70 75 80 Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg 85 90 95 Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr 100 105 110 Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys 115 120 125 Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His 130 135 140 Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp 145 150 155 160 Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys 165 170 175 Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys 180 185 190 Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val 195 200 205 Met Gly Tyr Leu Ser Ser Ala Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445 <210> 132 <211> 1704 <212> DNA 213 <213> <400> 132 atgtgcccac agaaactcac aatttcttgg ttcgcaatcg tcctgctggt gtcacccctg 60 atggcaatgt ggggagttgga aaaggatgta tacgtcgtcg aggtcgactg gacacctgac 120 gctccgggtg aaactgtcaa cctcacttgc gatactcctg aagaggacga catcacgtgg 180 acgagcgacc agcgacatgg agtgataggg tctggcaaga cgcttactat cacggttaag 240 gaatttctcg acgcagggca gtacacatgt cacaagggcg gcgagactct gagccactcc 300 catttgctgc tgcacaagaa ggagaatggt atctggtcta ccgaaatcct gaagaatttt 360 aagaacaaga cttttctgaa atgcgaggcc ccaaattatt ccggacgttt cacttgcagt 420 tggctcgttc aaagaaatat ggacttgaaa tttaacatta aatccagctc ttcatctcct 480 gacagcaggg ccgtaacttg tggaatggct tcattgtcag ctgagaaagt tacgcttgac 540 caaagggatt atgagaaata cagcgtgagt tgccaggaag atgtgacatg tccaacggca 600 gaggaaacgt tgccaattga gctcgctttg gaagctcgtc aacaaaacaa gtatgaaaac 660 tatagtacta gcttcttcat acgggacatc atcaaaccag atccacctaa gaatttgcag 720 atgaagcctc tgaagaattc acaagtcgag gtatcctggg aatacccaga ttcatggtcc 780 actcctcata gttactttag cctgaaattc tttgtacgca tacagcggaa gaaggagaaa 840 atgaaggaga cggaagaagg ctgcaatcag aaaggcgctt ttcttgttga aaagacgagc 900 actgaggttc aatgcaaagg cgggaatgta tgtgttcaag cccaagatag gtattataat 960 agctcctgct ctaagtgggc ttgcgtacca tgcagagtta gaagtcccag agggcccaca 1020 atcaagccct gtcctccatg caaatgccca gcacctaacc tcttgggtgg accatccgtc 1080 ttcatcttcc ctccaaagat caaggatgta ctcatgatct ccctgagccc catagtcaca 1140 tgtgtggtgg tggatgtgag cgaggatgac ccagatgtcc agatcagctg gtttgtgaac 1200 aacgtggaag tacacacagc tcagacacaa acccatagag aggattacaa cagtactctc 1260 cgggtggtca gtgccctccc catccagcac caggactgga tgagtggcaa ggagttcaaa 1320 tgcaaggtca acaacaaaga ccctcccagcg cccatcgaga gaaccatctc aaaacccaaa 1380 gggtcagtaa gagctccaca ggtatatgtc ttgcctccac cagaagaaga gatgactaag 1440 aaacaggtca ctctgacctg catggtcaca gacttcatgc ctgaagacat ttacgtggag 1500 tggaccaaca acgggaaaac agagctaaac tacaagaaca ctgaaccagt cctggactct 1560 gatggttctt acttcatgta cagcaagctg agagtggaaa agaagaactg ggtggaaaga 1620 aatagctact cctgttcagt ggtccacgag ggtctgcaca atcaccacac gactaagagc 1680 ttctcccgga ctccgggtaa atag 1704 <210> 133 <211> 567 <212> PRT 213 <213> <400> 133 Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu 1 5 10 15 Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu 35 40 45 Thr Cys Asp Thr Pro Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys 65 70 75 80 Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr 85 90 95 Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp 100 105 110 Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys 115 120 125 Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln 130 135 140 Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro 145 150 155 160 Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys 165 170 175 Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln 180 185 190 Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu 195 200 205 Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser 210 215 220 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 225 230 235 240 Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro 245 250 255 Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val 260 265 270 Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys 275 280 285 Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln 290 295 300 Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn 305 310 315 320 Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser Pro 325 330 335 Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro 340 345 350 Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys 355 360 365 Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val 370 375 380 Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn 385 390 395 400 Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr 405 410 415 Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp 420 425 430 Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu 435 440 445 Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg 450 455 460 Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys 465 470 475 480 Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp 485 490 495 Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys 500 505 510 Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser 515 520 525 Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser 530 535 540 Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser 545 550 555 560 Phe Ser Arg Thr Pro Gly Lys 565 <210> 134 <211> 1344 <212> DNA 213 <213> <400> 134 atgtgtcagt cacgctatct tctcttcctt gctactctgg ccttgctcaa tcacttgtcc 60 cttgctcgtg tgattcctgt gtccggccca gctaggtgtc tctcccagtc acggaatctc 120 ctgaaaacca cggatgacat ggtaaagaca gctagggaga aactcaagca ctactcctgc 180 acagctgagg atatcgatca tgaggacatc accagggacc agacatccac tctgaaaact 240 tgcctgcctt tggaactcca caagaacgaa tcttgtctgg caacgcgtga aacgagttct 300 actacaagag ggtcctgtct tccccctcaa aagacaagcc ttatgatgac cttgtgtctc 360 ggtagcattt atgaggacct aaagatgtat caaaccgagt ttcaggctat caatgcagcg 420 ctccagaatc ataaccatca gcagatcatt cttgacaaag gaatgctcgt ggccattgat 480 gaactaatgc agagcctaaa ccacaatggc gagactcttc gacagaaacc gcctgtggggc 540 gaggccgatc catatagagt caaaatgaaa ctgtgtattc tcctgcatgc atttagtact 600 cgtgtagtga ctattaacag agtgatgggt tacctttcct cagctcccag agggcccaca 660 atcaagccct gtcctccatg caaatgccca gcacctaacg ctgccggtgg accatccgtc 720 ttcatcttcc ctccaaagat caaggatgta ctcatgatct ccctgagccc catagtcaca 780 tgtgtggtgg tggatgtgag cgaggatgac ccagatgtcc agatcagctg gtttgtgaac 840 aacgtggaag tacacacagc tcagacacaa acccatagag aggattacaa cagtactctc 900 cgggtggtca gtgccctccc catccagcac caggactgga tgagtggcaa ggagttcaaa 960 tgcaaggtca acaacaaaga cctcggagcg cccatcgaga gaaccatctc aaaacccaaa 1020 gggtcagtaa gagctccaca ggtatatgtc ttgcctccac cagaagaaga gatgactaag 1080 aaacaggtca ctctgacctg catggtcaca gacttcatgc ctgaagacat ttacgtggag 1140 tggaccaaca acgggaaaac agagctaaac tacaagaaca ctgaaccagt cctggactct 1200 gatggttctt acttcatgta cagcaagctg agagtggaaa agaagaactg ggtggaaaga 1260 aatagctact cctgttcagt ggtccacgag ggtctgcaca atcaccacac gactaagagc 1320 ttctcccgga ctccgggtaa atga 1344 <210> 135 <211> 447 <212> PRT 213 <213> <400> 135 Met Cys Gln Ser Arg Tyr Leu Leu Phe Leu Ala Thr Leu Ala Leu Leu 1 5 10 15 Asn His Leu Ser Leu Ala Arg Val Ile Pro Val Ser Gly Pro Ala Arg 20 25 30 Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val 35 40 45 Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp 50 55 60 Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr 65 70 75 80 Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg 85 90 95 Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr 100 105 110 Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys 115 120 125 Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His 130 135 140 Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp 145 150 155 160 Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys 165 170 175 Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys 180 185 190 Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val 195 200 205 Met Gly Tyr Leu Ser Ser Ala Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Gly Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445 <210> 136 <211> 1704 <212> DNA 213 <213> <400> 136 atgtgcccac agaaactcac aatttcttgg ttcgcaatcg tcctgctggt gtcacccctg 60 atggcaatgt ggggagttgga aaaggatgta tacgtcgtcg aggtcgactg gacacctgac 120 gctccgggtg aaactgtcaa cctcacttgc gatactcctg aagaggacga catcacgtgg 180 acgagcgacc agcgacatgg agtgataggg tctggcaaga cgcttactat cacggttaag 240 gaatttctcg acgcagggca gtacacatgt cacaagggcg gcgagactct gagccactcc 300 catttgctgc tgcacaagaa ggagaatggt atctggtcta ccgaaatcct gaagaatttt 360 aagaacaaga cttttctgaa atgcgaggcc ccaaattatt ccggacgttt cacttgcagt 420 tggctcgttc aaagaaatat ggacttgaaa tttaacatta aatccagctc ttcatctcct 480 gacagcaggg ccgtaacttg tggaatggct tcattgtcag ctgagaaagt tacgcttgac 540 caaagggatt atgagaaata cagcgtgagt tgccaggaag atgtgacatg tccaacggca 600 gaggaaacgt tgccaattga gctcgctttg gaagctcgtc aacaaaacaa gtatgaaaac 660 tatagtacta gcttcttcat acgggacatc atcaaaccag atccacctaa gaatttgcag 720 atgaagcctc tgaagaattc acaagtcgag gtatcctggg aatacccaga ttcatggtcc 780 actcctcata gttactttag cctgaaattc tttgtacgca tacagcggaa gaaggagaaa 840 atgaaggaga cggaagaagg ctgcaatcag aaaggcgctt ttcttgttga aaagacgagc 900 actgaggttc aatgcaaagg cgggaatgta tgtgttcaag cccaagatag gtattataat 960 agctcctgct ctaagtgggc ttgcgtacca tgcagagtta gaagtcccag agggcccaca 1020 atcaagccct gtcctccatg caaatgccca gcacctaacg ctgccggtgg accatccgtc 1080 ttcatcttcc ctccaaagat caaggatgta ctcatgatct ccctgagccc catagtcaca 1140 tgtgtggtgg tggatgtgag cgaggatgac ccagatgtcc agatcagctg gtttgtgaac 1200 aacgtggaag tacacacagc tcagacacaa acccatagag aggattacaa cagtactctc 1260 cgggtggtca gtgccctccc catccagcac caggactgga tgagtggcaa ggagttcaaa 1320 tgcaaggtca acaacaaaga cctcggagcg cccatcgaga gaaccatctc aaaacccaaa 1380 gggtcagtaa gagctccaca ggtatatgtc ttgcctccac cagaagaaga gatgactaag 1440 aaacaggtca ctctgacctg catggtcaca gacttcatgc ctgaagacat ttacgtggag 1500 tggaccaaca acgggaaaac agagctaaac tacaagaaca ctgaaccagt cctggactct 1560 gatggttctt acttcatgta cagcaagctg agagtggaaa agaagaactg ggtggaaaga 1620 aatagctact cctgttcagt ggtccacgag ggtctgcaca atcaccacac gactaagagc 1680 ttctcccgga ctccgggtaa atga 1704 <210> 137 <211> 567 <212> PRT 213 <213> <400> 137 Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu 1 5 10 15 Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu 35 40 45 Thr Cys Asp Thr Pro Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys 65 70 75 80 Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr 85 90 95 Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp 100 105 110 Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys 115 120 125 Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln 130 135 140 Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro 145 150 155 160 Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys 165 170 175 Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln 180 185 190 Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu 195 200 205 Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser 210 215 220 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 225 230 235 240 Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro 245 250 255 Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val 260 265 270 Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys 275 280 285 Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln 290 295 300 Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn 305 310 315 320 Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser Pro 325 330 335 Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro 340 345 350 Asn Ala Ala Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys 355 360 365 Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val 370 375 380 Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn 385 390 395 400 Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr 405 410 415 Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp 420 425 430 Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu 435 440 445 Gly Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg 450 455 460 Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys 465 470 475 480 Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp 485 490 495 Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys 500 505 510 Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser 515 520 525 Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser 530 535 540 Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser 545 550 555 560 Phe Ser Arg Thr Pro Gly Lys 565 <210> 138 <211> 113 <212> PRT <213> Homo sapiens <400> 138 Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 1 5 10 15 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 20 25 30 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 35 40 45 Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 50 55 60 Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu 65 70 75 80 Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 85 90 95 Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 100 105 110 Arg <210> 139 <211> 342 <212> DNA <213> Homo sapiens <400> 139 agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60 tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120 cgggaccctg agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac 180 aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240 cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300 acctacgacg cccttcacat gcaggccctg ccccctcgct aa 342 <210> 140 <211> 570 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 140 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala 20 25 30 Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn 35 40 45 Ile Gly Ser Asp Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala 50 55 60 Pro Lys Leu Leu Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro 65 70 75 80 Asp Arg Phe Ser Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile 85 90 95 Thr Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp 100 105 110 Asp Tyr Thr Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 115 120 125 Val Leu Gly Ser Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly 145 150 155 160 Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 165 170 175 Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala 180 185 190 Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser 195 200 205 Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg 210 215 220 Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala 225 230 235 240 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His 245 250 255 Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Pro Lys 260 265 270 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 275 280 285 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 290 295 300 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 305 310 315 320 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 325 330 335 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 340 345 350 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 355 360 365 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 370 375 380 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 385 390 395 400 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 405 410 415 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 420 425 430 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 435 440 445 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 450 455 460 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 465 470 475 480 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 485 490 495 Leu Ser Pro Glu Leu Gln Leu Glu Glu Ser Cys Ala Glu Ala Gln Asp 500 505 510 Gly Glu Leu Asp Gly Leu Trp Thr Thr Ile Thr Ile Phe Ile Thr Leu 515 520 525 Phe Leu Leu Ser Val Cys Tyr Ser Ala Thr Val Thr Phe Phe Lys Val 530 535 540 Lys Trp Ile Phe Ser Ser Val Val Asp Leu Lys Gln Thr Ile Ile Pro 545 550 555 560 Asp Tyr Arg Asn Met Ile Gly Gln Gly Ala 565 570 <210> 141 <211> 1713 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 141 atggaaaccg atacactgct gctgtgggtg ctgctgctgt gggtgccagg atctaccggt 60 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 120 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 180 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 240 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 300 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 360 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 420 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggaggtctggg 480 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 540 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 600 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 660 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 720 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 780 ggtcaaggta ctctggtgac cgtgtctagc cccaagagct gcgacaagac ccacacctgc 840 cccccctgcc cagccccaga gctgctgggc ggaccctccg tgttcctgtt cccccccaag 900 cccaaggaca ccctgatgat cagcaggacc cccgaggtga cctgcgtggt ggtggacgtg 960 agccacgagg acccagaggt gaagttcaac tggtacgtgg acggcgtgga ggtgcacaac 1020 gccaagacca agcccagaga ggagcagtac aacagcacct acagggtggt gtccgtgctg 1080 accgtgctgc accaggactg gctgaacggc aaggaataca agtgcaaggt ctccaacaag 1140 gccctgccag cccccatcga aaagaccatc agcaaggcca agggccagcc acgggagccc 1200 caggtgtaca ccctgcccccc ctcccggggag gagatgacca agaaccaggt gtccctgacc 1260 tgtctggtga agggcttcta ccccagcgac atcgccgtgg agtggggagag caacggccag 1320 cccgagaaca actacaagac caccccccca gtgctggaca gcgacggcag cttcttcctg 1380 tacagcaagc tgaccgtgga caagtccagg tggcagcagg gcaacgtgtt cagctgcagc 1440 gtgatgcacg aggccctgca caaccactac acccagaaga gcctgagcct gtcccccgag 1500 ctgcaactgg aggagagctg tgcggaggcg caggacgggg agctggacgg gctgtggacg 1560 accatcacca tcttcatcac actcttcctg ttaagcgtgt gctacagtgc caccgtcacc 1620 ttcttcaagg tgaagtggat cttctcctcg gtggtggacc tgaagcagac catcatcccc 1680 gactacagga acatgatcgg acagggggcc tga 1713 <210> 142 <211> 236 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 142 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala 20 25 30 Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn 35 40 45 Ile Gly Ser Asp Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala 50 55 60 Pro Lys Leu Leu Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro 65 70 75 80 Asp Arg Phe Ser Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile 85 90 95 Thr Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp 100 105 110 Asp Tyr Thr Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 115 120 125 Val Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro 130 135 140 Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile 145 150 155 160 Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly 165 170 175 Ser Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser 180 185 190 Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln 195 200 205 Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser 210 215 220 Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 225 230 235 <210> 143 <211> 711 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 143 atggaaaccg atacactgct gctgtgggtg ctgctgctgt gggtgccagg atctaccggt 60 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 120 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 180 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 240 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 300 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 360 ttcggcggag ggaccaagct gaccgtccta ggtcagccca aggccaaccc cactgtcact 420 ctgttcccgc cctcctctga ggagctccaa gccaacaagg ccacactagt gtgtctgatc 480 agtgacttct acccgggagc tgtgacagtg gcctggaagg cagatggcag ccccgtcaag 540 gcgggagtgg agaccaccaa accctccaaa cagagcaaca acaagtacgc ggccagcagc 600 tacctgagcc tgacgcccga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 660 catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttcata g 711 <210> 144 <211> 537 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 144 Met Val Phe Thr Pro Gln Ile Leu Gly Leu Met Leu Phe Trp Ile Ser 1 5 10 15 Ala Ser Arg Gly Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 20 25 30 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 35 40 45 Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 50 55 60 Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr 65 70 75 80 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 85 90 95 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 100 105 110 Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 225 230 235 240 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 245 250 255 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 260 265 270 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 275 280 285 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 290 295 300 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 305 310 315 320 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 325 330 335 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 340 345 350 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 355 360 365 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 370 375 380 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 385 390 395 400 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 405 410 415 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 420 425 430 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 435 440 445 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 450 455 460 Ser Pro Glu Leu Gln Leu Glu Glu Ser Cys Ala Glu Ala Gln Asp Gly 465 470 475 480 Glu Leu Asp Gly Leu Trp Thr Thr Ile Thr Ile Phe Ile Thr Leu Phe 485 490 495 Leu Leu Ser Val Cys Tyr Ser Ala Thr Val Thr Phe Phe Lys Val Lys 500 505 510 Trp Ile Phe Ser Ser Val Val Asp Leu Lys Gln Thr Ile Ile Pro Asp 515 520 525 Tyr Arg Asn Met Ile Gly Gln Gly Ala 530 535 <210> 145 <211> 1614 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 145 atggtgttta caccgcaaat attggggctc atgcttttct ggatcagtgc aagcagggga 60 caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 120 tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 180 ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagtag cacatactat 240 gcagactccg tgaagggccg gttcaccatc tccagagata attccaagaa cacgctgtat 300 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gcgcacttct 360 tacctgaacc atggtgatta ctggggtcaa ggtactctgg tgaccgtgtc tagcgcctcc 420 accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 480 gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 600 tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 660 tgcaacgtga accacaagcc cagcaacacc aaggtggaca agagagtgga gcccaagagc 720 tgcgacaaga cccacacctg ccccccctgc ccagccccag agctgctggg cggaccctcc 780 gtgttcctgt tcccccccaa gcccaaggac accctgatga tcagcaggac ccccgaggtg 840 acctgcgtgg tggtggacgt gagccacgag gacccagagg tgaagttcaa ctggtacgtg 900 gacggcgtgg aggtgcacaa cgccaagacc aagcccagag aggagcagta caacagcacc 960 tacagggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaggaatac 1020 aagtgcaagg tctccaacaa ggccctgcca gcccccatcg aaaagaccat cagcaaggcc 1080 aagggccagc cacgggagcc ccaggtgtac accctgcccc cctcccggga ggagatgacc 1140 aagaaccagg tgtccctgac ctgtctggtg aagggcttct accccagcga catcgccgtg 1200 gagtggggaga gcaacggcca gcccgagaac aactacaaga ccaccccccc agtgctggac 1260 agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaagtccag gtggcagcag 1320 ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacccagaag 1380 agcctgagcc tgtccccccga gctgcaactg gaggagagct gtgcggaggc gcaggacggg 1440 gagctggacg ggctgtggac gaccatcacc atcttcatca cactcttcct gttaagcgtg 1500 tgctacagtg ccaccgtcac cttcttcaag gtgaagtgga tcttctcctc ggtggtggac 1560 ctgaagcaga ccatcatccc cgactacagg aacatgatcg gacagggggc ctga 1614 <210> 146 <211> 404 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 146 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala 20 25 30 Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn 35 40 45 Ile Gly Ser Asp Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala 50 55 60 Pro Lys Leu Leu Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro 65 70 75 80 Asp Arg Phe Ser Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile 85 90 95 Thr Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp 100 105 110 Asp Tyr Thr Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 115 120 125 Val Leu Gly Ser Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly 145 150 155 160 Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 165 170 175 Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala 180 185 190 Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser 195 200 205 Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg 210 215 220 Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala 225 230 235 240 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His 245 250 255 Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala 260 265 270 Ala Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala 275 280 285 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 290 295 300 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 305 310 315 320 Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly 325 330 335 Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile 340 345 350 Phe Trp Val Leu Asp Lys Asp Asp Ser Lys Ala Gly Met Glu Glu Asp 355 360 365 His Thr Tyr Glu Gly Leu Asp Ile Asp Gln Thr Ala Thr Tyr Glu Asp 370 375 380 Ile Val Thr Leu Arg Thr Gly Glu Val Lys Trp Ser Val Gly Glu His 385 390 395 400 Pro Gly Gln Glu <210> 147 <211> 1215 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 147 atggaaaccg atacactgct gctgtgggtg ctgctgctgt gggtgccagg atctaccggt 60 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 120 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 180 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 240 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 300 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 360 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 420 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggaggtctggg 480 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 540 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 600 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 660 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 720 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 780 ggtcaaggta ctctggtgac cgtgtctagc gccgctgcat tcgtgcctgt gttcctccca 840 gctaagccca ctaccacccc cgctccaagg ccgcccacgc ccgctcctac tattgctagt 900 cagcctttaa gtttacgacc cgaagcttgc aggcccgccg ccggcggcgc tgtgcacacc 960 agggggcttg attttgcctg cgacttttgg gtattggtag tggtgggcgg agttttagcc 1020 tgctacagcc tcctggtaac agtggctttt atcatctttt ggggtgctgga caaggatgac 1080 agcaaggctg gcatggagga agatcacacc tacgagggcc tggacattga ccagacagcc 1140 acctatgagg acatagtgac gctgcggaca ggggaagtga agtggtctgt aggtgagcac 1200 ccaggccagg agtga 1215 <210> 148 <211> 416 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 148 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala 20 25 30 Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn 35 40 45 Ile Gly Ser Asp Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala 50 55 60 Pro Lys Leu Leu Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro 65 70 75 80 Asp Arg Phe Ser Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile 85 90 95 Thr Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp 100 105 110 Asp Tyr Thr Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 115 120 125 Val Leu Gly Ser Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly 145 150 155 160 Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 165 170 175 Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala 180 185 190 Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser 195 200 205 Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg 210 215 220 Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala 225 230 235 240 Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His 245 250 255 Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala 260 265 270 Ala Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala 275 280 285 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 290 295 300 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 305 310 315 320 Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly 325 330 335 Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile 340 345 350 Phe Trp Val Arg Lys Arg Trp Gln Asn Glu Lys Leu Gly Leu Asp Ala 355 360 365 Gly Asp Glu Tyr Glu Asp Glu Asn Leu Tyr Glu Gly Leu Asn Leu Asp 370 375 380 Asp Cys Ser Met Tyr Glu Asp Ile Ser Arg Gly Leu Gln Gly Thr Tyr 385 390 395 400 Gln Asp Val Gly Ser Leu Asn Ile Gly Asp Val Gln Leu Glu Lys Pro 405 410 415 <210> 149 <211> 1251 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 149 atggaaaccg atacactgct gctgtgggtg ctgctgctgt gggtgccagg atctaccggt 60 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagag ggtcaccatc 120 tcctgctctg gaaccaggtc caacattggg agtgattatg tttcctggta ccaacacctc 180 ccaggaacag cccccaaact cctcgtttat ggcgataatc tgcgaccctc agggattcct 240 gaccgattct ctgcctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 300 actggggacg aggccgatta ttactgcggc acatgggatt acaccctgaa tggtgtggtg 360 ttcggcggag ggaccaagct gaccgtccta ggttctagag gtggtggtgg tagcggcggc 420 ggcggctctg gtggtggtgg atccctcgag atggcccagg tgcagctggt ggaggtctggg 480 ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 540 tttagcagct atgccatgag ctgggtccgc caggctccag ggaaggggct ggaggtgggtc 600 tcagttattt atagcggtgg tagtagcaca tactatgcag actccgtgaa gggccggttc 660 accatctcca gagataattc caagaacacg ctgtatctgc aaatgaacag cctgagagcc 720 gaggacacgg ccgtatatta ctgtgcgcgc acttcttacc tgaaccatgg tgattactgg 780 ggtcaaggta ctctggtgac cgtgtctagc gccgctgcat tcgtgcctgt gttcctccca 840 gctaagccca ctaccacccc cgctccaagg ccgcccacgc ccgctcctac tattgctagt 900 cagcctttaa gtttacgacc cgaagcttgc aggcccgccg ccggcggcgc tgtgcacacc 960 agggggcttg attttgcctg cgacttttgg gtattggtag tggtgggcgg agttttagcc 1020 tgctacagcc tcctggtaac agtggctttt atcatctttt gggtgaggaa acgatggcag 1080 aacgagaagc tcgggttgga tgccggggat gaatatgaag atgaaaacct ttatgaaggc 1140 ctgaacctgg acgactgctc catgtatgag gacatctccc ggggcctcca gggcacctac 1200 caggatgtgg gcagcctcaa cataggagat gtccagctgg agaagccgtg a 1251 <210> 150 <211> 1389 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 150 gaggttcaac ttgttcaatc tggggcagaa gtgaagaagc ccggggcatc tgtgaaagta 60 tcatgcaaaa catccggcta tacgtttacc gaatacacca ttcactgggt cagacaggct 120 cccggtcaaa gcctcgaatg gatgggaaat attaacccta acaatggcgg aaccacatat 180 aatcagaaat tccaaggccg agtgacgata actgtcgata agagtacgtc cacagcttac 240 atggaactca gctctttgag atccgaagac actgcagttt attattgtgc agctggatgg 300 aacttcgact attggggaca agggactctt gttacggtgt ccagtggcaa accaggtagt 360 ggtaaacccg gaagcggcaa gcccgggagc ggtaaacctg gtagcgacat cgtcatgact 420 caaagccctg actcactcgc cgtgagcctg ggagagcgtg caacgctatc ttgtcgggcc 480 tctcaggatg tcggaactgc tgtagactgg tatcaacaga aacctgacca atcaccaaaa 540 ctcctgattt attgggcctc aacacgtcac acaggagtgc cagataggtt cacaggtagt 600 ggcagtgggaa ctgattttac tttgacaatt agcagcctgc aagccgaaga tgtagccgtt 660 tacttctgtc aacaatataa ctcataccca ctaacgttcg gtgccgggac gaaggtagag 720 attaaattcg tgcctgtgtt cctcccagct aagcccacta ccacccccgc tccaaggccg 780 cccacgcccg ctcctactat tgctagtcag cctttaagtt tacgacccga agcttgcagg 840 cccgccgccg gcggcgctgt gcacaccagg gggcttgatt ttgcctgcga cttttgggta 900 ttggtagtgg tgggcggagt tttagcctgc tacagcctcc tggtaacagt ggcttttatc 960 atcttttggg tgaagaaggt tgcaaaaaaa cctactaata aggctcccca tcctaagcaa 1020 gagccccaag aaattaactt tcccgatgat cttccgggtt ctaacacggc agccccggtg 1080 caggagaccc tgcatggttg tcaacccgtc actcaggagg acgggaaaga gtctcgtatc 1140 tccgtccagg agagacagcg caaaaaacgt ataagcgcaa actctacaga tccagtaaaa 1200 gccgcgcaat tcgagcctcc cggccgccag atgattgcaa tacggaaacg tcaactggag 1260 gaaactaata atgactatga gacggccgac ggtggataca tgacccttaa tccccgcgcg 1320 ccaaccgacg atgataagaa catatatctg acgctccccc ctaacgatca cgttaacagt 1380 aaataattaa 1389

Claims (150)

An isolated transformed B cell capable of expressing a chimeric receptor (CAR-B), which chimeric receptor
a) an extracellular domain comprising an extracellular binding domain and a hinge domain;
b) a transmembrane domain; and
c) an isolated modified B cell comprising a cytoplasmic domain comprising at least one signaling domain. The isolated transformed B cell of claim 1 , wherein said extracellular binding domain recognizes at least one antigen or protein expressed on the surface of a target cell. The isolated modified B cell of claim 1 , wherein the extracellular binding domain recognizes at least one antigen that is a secreted protein. 4. The isolated modified B cell of claim 3, wherein the secreted protein accumulates in the extracellular matrix. The method of claim 2, wherein the target cells consist of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells, endothelial cells, liver cells, lung epithelial cells, and fibroblasts. An isolated modified B cell selected from the group. The isolated modified B cell of claim 1 , wherein the B cell expresses more than one CAR-B receptor construct. The isolated modified B cell of claim 1 , wherein the CAR-B receptor comprises more than one extracellular binding domain. The isolated modified B cell of claim 1 , wherein the extracellular binding domain is a single chain variable fragment (scFv), or a full-length antibody or antibody fragment, or an extracellular domain of a receptor or ligand. The method of claim 1, wherein the extracellular binding domain is selected from the group consisting of PSMA, GPC3, ASGR1, ASGR2, sarcoglycan, Corin, FAP, MUC1, CEA153, JAM-1, LAF-1 and Her2. An isolated transformed B cell capable of binding. The isolated modified B cell of claim 1 , wherein said hinge domain is derived from the group consisting of immunoglobulins (eg, IgG, IgM), CD28 and CD8. The isolated transformed B cell of claim 1 , wherein said cytoplasmic domain comprises at least one signaling domain unique to a B cell receptor. The isolated modified B cell of claim 1 , wherein the cytoplasmic domain comprises at least one signaling domain that is an immunoglobulin. The method of claim 1, wherein the cytoplasmic domain is selected from the group consisting of CD79a (immunoglobulin α), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ and BLNK An isolated transformed B cell comprising the domain. 14. The isolated modified B cell of claim 13, wherein said cytoplasmic domain comprises a domain that is CD79a. 14. The isolated transformed B cell of claim 13, wherein said cytoplasmic domain further comprises a costimulatory domain. An isolated modified B cell, wherein the B cell is capable of expressing and secreting a payload, wherein the payload is not naturally expressed in the B cell or is expressed at a higher level than is naturally expressed in the B cell. Isolated modified B cells. 17. The isolated modified B cell of claim 16, wherein the payload is an antibody or fragment thereof. 18. The isolated modified B cell of claim 17, wherein the antibody is a secreted antibody or fragment thereof. 18. The isolated modified B cell of claim 17, wherein the antibody is membrane bound. 17. The method of claim 16, wherein the payload comprises cytokines, chemokines, T cell costimulatory molecules, and IL-1, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, IL-21, interferon α, interferon β, interferon γ, TSLP, CCL21, FLT3L, XCL1, LIGHT (TNFSF14), OX40L, CD137L, CD40L, ICOSL, anti-CD3 antibody, CD47, TIM4-FC, CXCL13 , CCL21, CD80, CD40L, IFNα A2, LIGHT, 4-1BBL, MDGF (C19orf10), FGF10, PDGF, Agrin, TNF-α, GM-CSF, anti-FAP antibody, anti-TGF-β antibody; TGF-β traps, decoys or other inhibitory molecules; anti-BMP antibodies; A modified B cell selected from the group consisting of gateway molecules consisting of BMP traps, decoys or other inhibitory molecules. 17. The modified B cell of claim 16, wherein the B cell is capable of expressing more than one payload. 17. The modified B cell of claim 16, wherein the B cell is capable of expressing more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 payloads. A method of treating a patient comprising administering the modified B cell of claim 14 . 24. The method of claim 23, wherein the modified B cells are administered intratumorally, intravenously, subcutaneously, intradermally, or within an inflammatory lesion. 24. The method of claim 23, further comprising administering one or more checkpoint inhibitors with or without the additional chemotherapeutic agent. 26. The method of claim 25, wherein the checkpoint inhibitor is capable of inhibiting a checkpoint molecule selected from the group consisting of PD-1, PD-L1, CTLA-4, LAG3, TIM-3 and NKG2A. 24. The method of claim 23, further comprising administering a T cell costimulatory molecule. 28. The method of claim 27, wherein the T cell costimulatory molecule is selected from the group consisting of CD80, CD86, ICOSL, 4-1BBL, OX40L, CD27, and LIGHT. An isolated transformed B cell capable of expressing a chimeric receptor, which chimeric receptor
a) an extracellular domain comprising an extracellular binding domain and a hinge domain;
b) a transmembrane domain; and
c) comprises a cytoplasmic domain comprising at least one signaling domain;
wherein the modified B cell is capable of further expressing a payload, wherein the payload is not naturally expressed in the B cell. 30. The isolated modified B cell of claim 29, wherein said extracellular binding domain recognizes an antigen or protein expressed on the surface of a target cell. 30. The isolated transformed B cell of claim 29, wherein said extracellular binding domain recognizes a secreted antigen or protein. 30. The method of claim 29, wherein the target cell is a group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells, endothelial cells, liver cells, lung epithelial cells and fibroblasts. An isolated modified B cell selected from. 30. The isolated modified B cell of claim 29, wherein the B cell expresses more than one CAR-B receptor construct. 30. The isolated modified B cell of claim 29, wherein said CAR-B receptor comprises more than one extracellular binding domain. 30. The isolated modified B cell of claim 29, wherein the extracellular binding domain is a single chain variable fragment (scFv), a full length antibody, an antibody fragment or an extracellular domain of a receptor or ligand. 30. The method of claim 29, wherein the extracellular binding domain is an antigen selected from the group consisting of PSMA, GP3, ASGR1, ASGR2, Sarcoglycan, Corin, and Her2, FAP, MUC1, CEA153, JAM-1, and LFA-1, or An isolated modified B cell that is capable of binding a protein. 30. The isolated modified B cell of claim 29, wherein said hinge domain is from the group consisting of an immunoglobulin (eg, IgG or IgM), CD28 and CD8. 30. The isolated transformed B cell of claim 29, wherein said cytoplasmic domain comprises at least one signaling domain native to a B cell. 30. The isolated transformed B cell of claim 29, wherein said cytoplasmic domain comprises at least one signaling domain that is an immunoglobulin. 30. The method of claim 29, wherein the cytoplasmic domain is a domain selected from the group consisting of CD79a (immunoglobulin α), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ and BLNK An isolated modified B cell comprising a. 41. The isolated modified B cell of claim 40, wherein said cytoplasmic domain comprises a domain that is CD79a (immunoglobulin a). 42. The isolated modified B cell of claim 41, wherein said cytoplasmic domain further comprises a costimulatory domain. 30. The isolated modified B cell of claim 29, wherein the payload is a secreted or membrane bound antibody or fragment thereof. 30. The method of claim 29, wherein the payload comprises cytokines, chemokines, T cell costimulatory molecules, and IL-1, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, IL-21, interferon α, interferon β, interferon γ, TSLP, CCL21, FLT3L, XCL1, LIGHT (TNFSF14), OX40L, CD137L, CD40L, ICOSL, anti-CD3 antibody, CD47, TIM4-FC, CXCL13 , CCL21, CD80, CD40L, IFNα A2, LIGHT, 4-1BBL, MDGF (C19orf10), FGF10, PDGF, Agrin, TNF-α, GM-CSF, anti-FAP antibody, anti-TGF-β antibody; TGF-β traps, decoys or other inhibitory molecules; anti-BMP antibodies; A modified B cell selected from the group consisting of gateway molecules consisting of BMP traps, decoys or other inhibitory molecules. 30. The isolated modified B cell of claim 29, wherein the B cell is capable of expressing more than one payload. 30. The isolated modified B cell of claim 29, wherein the B cell is capable of expressing more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 payloads. The method of claim 29, wherein the modified B cells add at least one protein selected from the group consisting of CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, CD3ζ and the cytoplasmic domain of MyD88. An isolated transformed B cell that encodes with. A method of treating a patient comprising administering the modified B cell of claim 29 . 49. The method of claim 48, further comprising administering a checkpoint inhibitor. 49. The method of claim 48, wherein the checkpoint inhibitor is capable of inhibiting a checkpoint molecule selected from the group consisting of PD-1, PD-L1, CTLA-4, LAG3, TIM-3 and NKG2A. 51. The method of claim 50, wherein said checkpoint inhibitor is a monoclonal antibody. An isolated transformed B cell capable of expressing a chimeric receptor, the chimeric receptor comprising an extracellular domain, the extracellular domain comprising a hinge domain and an extracellular binding domain, the extracellular binding domain comprising a B cell is not naturally expressed on the An isolated modified B cell wherein said extracellular binding domain is capable of recognizing a target of interest. 53. The isolated modified B cell of claim 52, wherein said binding domain is an extracellular domain of a single chain variable fragment (scFv), full-length antibody, antibody fragment, ligand or receptor. 54. The isolated modified B cell of claim 53, wherein said binding domain is a scFv. 53. The isolated modified B cell of claim 52, wherein the B cell is capable of expressing more than one chimeric receptor. 53. The isolated modified B cell of claim 52, wherein the B cell is further capable of expressing a payload. A method of treating a patient comprising administering the modified B cell of claim 52 . A nucleic acid capable of expressing a chimeric B cell receptor, said chimeric receptor comprising:
a) an extracellular domain comprising an extracellular binding domain and a hinge domain;
b) a transmembrane domain; and
c) a cytoplasmic domain comprising at least one signaling domain. 59. The nucleic acid of claim 58, wherein the extracellular binding domain recognizes an antigen or protein expressed on the surface of a target cell. 59. The nucleic acid of claim 58, wherein the extracellular binding domain recognizes an antigen or protein that is a secreted protein. 59. The nucleic acid of claim 58, wherein the secreted protein accumulates in the extracellular matrix. 59. The nucleic acid of claim 58, wherein said extracellular binding domain is a single chain variable fragment (scFv), full-length antibody, antibody fragment or extracellular domain of a receptor or ligand. 59. The method of claim 58, wherein the target cell is from the group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells, endothelial cells, hepatocytes, lung epithelial cells, or fibroblasts. A nucleic acid that is selected. 59. The nucleic acid of claim 58, wherein the vector expresses more than one CAR-B receptor. 59. The nucleic acid of claim 58, wherein the CAR-B receptor expresses more than one extracellular binding domain. 59. The method of claim 58, wherein the extracellular binding domain is an antigen or protein selected from the group consisting of PSMA, GP3, ASGR1, AGSR2, Sarcoglycan, Corin, Her2, PAF1, MUC1, CEA153, JAM-1, and LFA-1 A nucleic acid capable of binding to. 59. The nucleic acid of claim 58, wherein the hinge domain is from the group consisting of an immunoglobulin domain (eg, IgG or IgM), CD28 and CD8. 59. The nucleic acid of claim 58, wherein said cytoplasmic domain comprises at least one signaling domain unique to the B cell receptor. 59. The method of claim 58, wherein the cytoplasmic domain is CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ and A nucleic acid comprising a domain selected from the group consisting of BLNK. 70. The nucleic acid of claim 69, wherein the cytoplasmic domain comprises a domain that is CD79a (immunoglobulin a). 70. The nucleic acid of claim 69, wherein said cytoplasmic domain further comprises a costimulatory domain. A vector containing a nucleic acid capable of expressing a chimeric B cell receptor, wherein the chimeric receptor
a) an extracellular domain comprising an extracellular binding domain and a hinge domain;
b) a transmembrane domain; and
c) a vector comprising a cytoplasmic domain comprising at least one signaling domain. 73. The vector of claim 72, wherein the extracellular binding domain recognizes an antigen or protein expressed on the surface of a target cell. 73. The vector of claim 72, wherein the extracellular binding domain recognizes an antigen or protein that is a secreted protein. 73. The vector of claim 72, wherein the secreted protein accumulates in the extracellular matrix. 73. The method of claim 72, wherein the target cell is from the group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells, endothelial cells, hepatocytes, lung epithelial cells, or fibroblasts. The vector to be selected. 73. The vector of claim 72, wherein the vector expresses more than one CAR-B receptor. 73. The vector of claim 72, wherein the CAR-B expresses more than one extracellular binding domain. 73. The vector of claim 72, wherein the extracellular binding domain is a single chain variable fragment (scFv), an extracellular domain of a full-length antibody, antibody fragment, receptor or ligand. 73. The method of claim 72, wherein the extracellular binding domain is an antigen or protein selected from the group consisting of PSMA, GPC3, ASGR1, AGSR2, Sarcoglycan, Corin, Her2, PAF1, MUC1, CEA153, JAM-1, and LFA-1 A vector that can be concatenated to . 73. The vector of claim 72, wherein the hinge domain is from the group consisting of an immunoglobulin domain (eg, IgG or IgM), CD28 and CD8. 73. The vector of claim 72, wherein the cytoplasmic domain comprises at least one signaling domain native to a B cell. 73. The method of claim 72, wherein the cytoplasmic domain is CD79a (immunoglobulin α), CD79b (immunoglobulin β), CD40, CD19, CD137, Fcγr2a, MyD88, CD21, Syk, FYN, LYN, PI3K, BTK, PLCγ2, CD3ζ and A vector comprising a signaling domain selected from the group consisting of BLNK. 73. The vector of claim 72, wherein the cytoplasmic domain further comprises a costimulatory domain. An isolated modified B cell capable of expressing an integrin, homing antibody, protein, receptor, or combination thereof, wherein the integrin, homing antibody, protein, or receptor is not naturally expressed in B cells or is naturally expressed in B cells. expressed at higher levels than wherein said integrin, homing antibody, protein, receptor, or combination thereof is directed to a region or target of interest. 86. The method of claim 85, wherein the integrins, homing antibodies, proteins, and receptors are CLA (PSGL-1 glycotype), CLA (PSGL-1 glycotype), CCR10, CCR3, CCR4, CCR5, CCR6, CCR9, CD43E, CD44, c -Met, CXCR3, CXCR4, LFA-1, LFA-1 (αLβ2), selectin ligand, VLA-4, VLA-4 (α4β1), and α4β7, or a combination thereof. 87. The isolated transformed B cell of claim 86, wherein the site of interest is a homing or target tissue, an inflammatory site of a specific site or tissue, or a tumor or tumor microenvironment in which delivery of a payload is desired. 88. The method of claim 87, wherein the home or target tissue is skin, stomach (gut, colon, mesenteric lymph node (mLN), Peyer's Patch (PP), small intestine), liver, lung, bone marrow, heart, peripheral lymph node (LN), CNS , an isolated modified B cell selected from thymus and bone marrow. 89. The method of claim 88, wherein the target of interest is CXCL16, CCL17, CCL17(22), CCL20 (MIP-3α), CCL21, CCL25, CCL27, CCL28, CCL4, CCL5, CD62E, CD62P, CXCL10, CXCL12, CXCL13, CXCL16, CXCL9/CXCL10, CXCR3, E/P-selectin, E-selectin, GPR15L, HGF, hyaluronic acid, ICAM-1, CCR1, 2, 5, MAdCAM, MAdCAM-1, PNAd, VAP-1, VCAM, and VCAM- A ligand for 1, or a combination thereof. A method of treating a patient comprising administering the isolated modified B cell of claim 82 . 91. The method of claim 90, further comprising administering a compound or derivative thereof, wherein the compound or derivative thereof is capable of modulating expression of integrins, homing antibodies, proteins, and receptors, or combinations thereof. 92. The method of claim 91, wherein the compound or derivative thereof is capable of altering the trafficking of B cells to a site or target of interest in the patient. 93. The method of claim 92, wherein the compound is all-trans-retinoic acid (ATRA) or a derivative thereof. An isolated modified B cell capable of expressing an immunosuppressive molecule, wherein the immunosuppressive molecule is not naturally expressed in B cells or is expressed at a higher level than is naturally expressed in B cells. cell. 95. The isolated transformed B cell of claim 94, wherein said immune suppressive molecule is selected from IL-10, TGF-β, PD-L1, PD-L2, LAG-3, and TIM-3, or a combination thereof. . 96. The isolated modified B cell of claim 95, wherein said immune suppressive molecule is capable of reducing inflammatory and autoimmune activity of B cells at a site or target of interest in a patient. A method of treating a patient comprising administering the isolated modified B cell of claim 94 . 98. The method of claim 97, wherein the immunosuppressive molecule is selected from IL-10, TGF-β, PD-L1, PD-L2, LAG-3, and TIM-3, or a combination thereof. 99. The method of claim 98, wherein the immunosuppressive molecule is capable of reducing inflammation and autoimmune activity of B cells at a site or target of interest in the patient. 100. The method of claim 99, further comprising administering a compound or derivative thereof capable of increasing expression of an integrin, homing antibody, protein, receptor, or combination thereof in a B cell. 101. The method of claim 100, wherein the compound or derivative thereof is capable of altering the trafficking of B cells to a site or target of interest in the patient. 102. The method of claim 101, wherein the compound is all-trans-retinoic acid (ATRA) or a derivative thereof. An isolated modified B cell, wherein said isolated modified B cell is treated with a compound or derivative thereof, said compound or derivative thereof capable of increasing expression of an integrin, homing antibody, protein, receptor, or combination thereof in a B cell. isolated transformed B cells. 104. The isolated modified B cell of claim 103, wherein said compound or derivative thereof is capable of altering the trafficking of B cells to a site or target of interest in a patient. 105. The isolated modified B cell of claim 104, wherein the compound is all-trans-retinoic acid (ATRA) or a derivative thereof. 101. A method of treating a patient comprising administering the isolated modified B cell of claim 100, wherein the compound or derivative thereof (i) inhibits expression of an integrin, homing antibody, protein, receptor, or combination thereof in a B cell. and (ii) alter the trafficking of B cells to a region or target of interest in the patient. 107. The method of claim 106, wherein the compound is all-trans-retinoic acid (ATRA) or a derivative thereof. An isolated transformed B cell capable of expressing at least one constitutively active toll-like receptor (TLR), which TLR is not naturally expressed on B cells or at a higher level than is naturally expressed on B cells. An isolated modified B cell wherein expression is expressed. 109. The isolated modified B cell of claim 108, wherein the TRL is selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. . 110. The isolated modified B cell of claim 109, wherein the TLRs are capable of enhancing B cells to increase an immune response in a patient. 111. The isolated modified B cell of claim 110, wherein the TLRs are capable of generating potent effector B cells to increase the patient's immune response. 109. A method of treating a patient comprising administering the isolated modified B cell of claim 108, wherein the immunosuppressive molecule is capable of reducing inflammation and autoimmune activity of B cells at a site or target of interest in the patient. . 113. The method of claim 112, wherein the TLR is selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. 114. The method of claim 113, wherein the TLR is capable of (i) enhancing B cells and (ii) generating potent effector B cells to increase an immune response in the patient. 115. The method of claim 114, further comprising administering to the patient at least one or more TLR agonists. An isolated modified B cell, wherein the isolated modified B cell is treated with at least one TLR agonist. 117. The isolated modified B cell of claim 116, wherein the TLR agonist is capable of (i) enhancing B cells and (ii) generating potent effector B cells to increase an immune response in a patient. 118. The method of claim 117, wherein the TLR agonist binds to one or more TLRs selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. isolated transformed B cells. 119. The isolated transformed B cell of claim 118, wherein said TLR agonist is selected from CpG-rich oligonucleotides, double-stranded RNA mimics, polyinosinic acid:polycytidylic acid (poly-I:C). 120. The isolated modified B cell of claim 119, wherein said TLR agonist comprises a CpG oligonucleotide. A method of treating a patient comprising administering the isolated modified B cell of claim 116 . 122. The method of claim 121, wherein the TLR agonist is capable of (i) enhancing B cells and (ii) generating potent effector B cells to increase the patient's immune response. 123. The method of claim 122, wherein the TLR agonist binds to one or more TLRs selected from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, or combinations thereof. way of being. 124. The method of claim 123, wherein said TLR agonist is selected from CpG-rich oligonucleotides, double-stranded RNA mimics, polyinosinic acid:polycytidylic acid (poly-I:C). 125. The method of claim 124, wherein the TLR agonist comprises a CpG oligonucleotide. An isolated modified B cell, wherein the B cell is electroporated with mRNA encoding at least one or more of the antigens fused to a targeting signal. 127. The method of claim 126, wherein the antigen is (i) not naturally presented by B cells, (ii) not naturally presented by B cells simultaneously on both HLA class I and class II molecules, or (iii) naturally present by B cells. An isolated modified B cell wherein neither HLA class I nor class II molecules are presented by the B cell with high efficiency. 128. The isolated modified B cell of claim 127, wherein the targeting signal is a targeting signal of a lysosomal protein. 129. The isolated transformed B cell of claim 128, wherein the targeting signal is a targeting signal of lysosomal-associated membrane protein-1 (LAMP1). 130. The isolated modified B cell of claim 129, wherein the antigen is capable of being targeted to lysosomes and efficiently presented on both HLA class I and class II molecules simultaneously. 131. The isolated modified B cell of claim 130, wherein said B cell is capable of increasing an antigen-specific immune response in a patient. A method of treating a patient comprising administering the isolated modified B cell of claim 126 . 133. The method of claim 132, wherein the antigen is (i) not naturally presented by B cells, (ii) not naturally presented by B cells simultaneously on both HLA class I and class II molecules, or (iii) naturally present by B cells. wherein both HLA class I and class II molecules are not presented by B cells with high efficiency. 134. The method of claim 133, wherein the targeting signal is a targeting signal of a lysosomal protein. 135. The method of claim 134, wherein the targeting signal is a targeting signal of lysosome-associated membrane protein-1 (LAMP1). 136. The method of claim 135, wherein the antigen can be targeted to lysosomes and can be efficiently presented on both HLA class I and class II molecules simultaneously. 137. The method of claim 136, wherein the B cells are capable of increasing an antigen-specific immune response in the patient. 138. The method of any one of claims 132-137, wherein the patient is treated with more than one differentially modified B cell. 138. The method of any one of claims 132-137, wherein the patient is treated with more than two differentially modified B cells. An isolated transformed B cell capable of expressing a chimeric receptor (CAR-B), which chimeric receptor
a) an extracellular domain comprising an extracellular binding domain and a hinge domain;
b) a transmembrane domain; and
c) an isolated pathological B cell comprising a cytoplasmic domain. 141. The isolated modified B cell of claim 140, wherein said extracellular domain comprises an immunoglobulin domain. 141. The isolated modified B cell of claim 140, wherein said chimeric receptor is capable of forming homologous dimers. 141. The isolated transformed B cell of claim 140, wherein said extracellular binding domain recognizes an antigen or protein expressed on the surface of a target cell. 144. The isolated transformed B cell of claim 143, wherein said extracellular binding domain recognizes a secreted antigen or protein. 144. The method of claim 143, wherein the target cell is from the group consisting of tumor cells, cardiac muscle cells, skeletal muscle cells, bone cells, blood cells, nerve cells, fat cells, skin cells, endothelial cells, hepatocytes, lung epithelial cells and fibroblasts. An isolated transformed B cell that is selected. 144. The isolated modified B cell of claim 143, wherein said extracellular binding domain is a single chain variable fragment (scFv), full-length antibody, antibody fragment or extracellular domain of a receptor or ligand. 144. The method of claim 143, wherein the extracellular binding domain is an antigen selected from the group consisting of PSMA, GP3, ASGR1, ASGR2, sarcoglycan, Corin, and Her2, FAP, MUC1, CEA153, JAM-1, and LFA-1, or An isolated modified B cell that is capable of binding a protein. 15. The isolated transformed B cell of claim 14, wherein said hinge domain is derived from the group consisting of an immunoglobulin (eg, IgG or IgM), CD28 and CD8. An isolated modified B cell capable of expressing a chimeric receptor (CAR-B), wherein the chimeric receptor comprises the amino acid sequence of SEQ ID NO: 146. An isolated modified B cell capable of expressing a chimeric receptor (CAR-B), wherein the chimeric receptor comprises the amino acid sequence of SEQ ID NO: 142, 144 or both.

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