A drug combination and its application

Abstract

Provided are a drug combination and its application. The drug combination is used to prepare a drug for treating hyperglobulinemia, and comprises an immunoglobulin degrading enzyme and a protein containing Fc. The drug combination reduces the effect of globulin on treatment by combining the immunoglobulin degrading enzyme with an Fc agent for hyperglobulinemia, so that the Fc agent can play a better role, and can also reduce the clinical dosage of some Fc agents, which can reduce the side effects of the therapeutic agent on the one hand, and reduce the economic burden of medication on the other hand.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a drug combination and its application, in particular to its application in the preparation of a therapeutic drug for diseases with abnormally elevated blood IgG levels. Background Art

[0002] Hyperglobulinemia is characterized by higher-than-normal levels of immunoglobulins in the patient's body. Immunoglobulins include IgA, IgD, IgE, IgM, and IgG, with excess levels of γ-immunoglobulin IgG being the most common. M-protein is an abnormal immunoglobulin produced in large quantities by the malignant proliferation of a monoclonal plasma cell or B lymphocyte. It is essentially an immunoglobulin or immunoglobulin fragment and is also called monoclonal protein, monoclonal immunoglobulin, myeloma protein, or M-spike.

[0003] Because it is commonly found in multiple myeloma, macroglobulinemia, and malignant lymphoma, all diseases beginning with "M," it is called "M-protein." M-protein positivity is seen in malignant monoclonal gammopathy, such as multiple myeloma, heavy chain disease, malignant lymphoma, chronic lymphocytic leukemia, and macroglobulinemia; secondary monoclonal gammopathy, such as non-lymphoreticular tumors, monocytic leukemia, and cryoglobulinemia; and benign M-proteinemia, with an incidence of approximately 3% in people over 70 years old.

[0004] Multiple myeloma is a blood cancer caused by the cancerous transformation of plasma cells in the bone marrow. Abnormal plasma cells accumulate in the bone marrow and form tumors in multiple bones in the body. Not only do these cells fail to perform their normal functions, they also cause the bone marrow to be unable to produce healthy blood cells. The abnormal proliferation of bone marrow plasma cells is accompanied by excessive production of non-functional monoclonal immunoglobulins or light chains (M proteins). The level of this abnormal immunoglobulin can be as high as 30g / L or higher in most patients (normal human blood IgG levels are around 10g / L), and approximately 50% of patients have M-proteins of the IgG subtype. Current antibodies for the treatment of multiple myeloma include daratumumab and isatuximab. The inventors unexpectedly discovered that by pre-clearing pathological immunoglobulins through immunoglobulin degrading enzymes, the amount of monoclonal antibody treatment can be reduced while enhancing the antibody treatment effect. Summary of the Invention

[0005] In response to the shortcomings of the existing technology, the purpose of the present invention is to reduce the impact of globulin on treatment by combining immunoglobulin degrading enzymes with Fc agents for hyperglobulinemia, so that the Fc agents can play a better role. At the same time, it can also reduce the clinical dosage of some Fc agents, which can reduce the side effects of the therapeutic agents on the one hand and the economic burden of medication on the other.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] 1. Drug Combinations

[0008] In a first aspect, a pharmaceutical combination is provided, which can be used to prepare a drug for treating hyperglobulinemia, wherein the pharmaceutical combination comprises: 1) an immunoglobulin degrading enzyme, and 2) an Fc-containing protein. The pharmaceutical combination allows for separate administration of the degrading enzyme and the immunoglobulin. Preferably, the pharmaceutical combination comprises a therapeutically effective amount of the immunoglobulin degrading enzyme and the immunoglobulin. Preferably, the pharmaceutical combination is a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier or diluent, which is a lyophilized powder or a liquid.

[0009] 1.1 Immunoglobulin degrading enzyme

[0010] As used herein, the term "immunoglobulin degrading enzyme" preferably refers to a protease drug or agent that reduces blood immunoglobulin levels to 60% or less of the original level, and its amino acid sequence is generally derived from bacteria, or contains a portion of a bacterial-derived sequence. Preferably, the drug or agent reduces blood immunoglobulin levels to at most 60% of the original level, at most 50% of the original level, at most 40% of the original level, at most 30% of the original level, at most 20% of the original level, at most 10% of the original level, or at most 0% of the original level. More preferably, the drug or agent reduces blood immunoglobulin levels to at most 20% of the original level, at most 10% of the original level, or at most 0% of the original level.

[0011] The agent is typically a protein that has IgG cysteine ​​protease activity, preferably cleaving the hinge region of an immunoglobulin molecule. An example of such a protein is IdeE (immunoglobulin G degrading enzyme from Streptococcus pyogenes). IdeE is a streptococcal protease with a unique degree of specificity; it cleaves immunoglobulin G (IgG) antibodies but not any of its other substrates (including IgA, IgD, IgE, and IgM). IdeE cleaves human IgG into F(ab')2 fragments and Fc fragments at a specific site at the COOH-terminus of the hinge region. The mature sequence of IdeE is shown in SEQ ID NO: 5. The agent may be a protein comprising or consisting of the amino acid sequence of SEQ ID NO: 5, or may be a homolog thereof from an alternative bacterium.

[0012] Preferably, in the drug combination as described above, the immunoglobulin degrading enzyme is an IgG degrading enzyme, and the IgG degrading enzyme is selected from the IgG cysteine ​​protease of Streptococcus pyogenes or its variants or fragments or human-derived MMP protease or its variants or fragments, and the variants or fragments retain the activity of enzymatic cleavage of IgG; preferably, the IgG degrading enzyme is selected from IdeS, MAC2, IdeZ, IdeZ2, IdeE, IdeE2, IdeP, MMP.

[0013] A variant of the ideE protein may comprise or consist of an amino acid sequence that has 1, 2, 3, 4, 5, 10, 20, 30 or more amino acid substitutions, insertions or deletions relative to the amino acid sequence of SEQ ID NO: 5, provided that the variant has IgG cysteine ​​protease activity. All amino acid substitutions are preferably conservative. Conservative substitutions replace an amino acid with another amino acid having a similar chemical structure, similar chemical properties or similar side chain volume. The introduced amino acid may have similar polarity, hydrophilicity, hydrophobicity, basicity, acidity, neutrality or charge as the substituted amino acid. Alternatively, conservative substitutions may introduce another aromatic or aliphatic amino acid in the place of a previously existing aromatic or aliphatic amino acid. Conservative amino acid changes are well known in the art.

[0014] A variant of the IdeE protein is obtained by replacing at least one or more of positions 8, 10, 24, 59, 97 and 280 of the amino acid sequence of the immunoglobulin degrading enzyme IdeE; the function of the mutant at least includes the function of the immunoglobulin degrading enzyme IdeE.

[0015] "At least comprising" the function of the immunoglobulin degrading enzyme IdeE means that the mutant may contain other functions while retaining the immunoglobulin degrading enzyme IdeE, or the mutant is more efficient than IdeS in cleaving human IgG, or the mutant is as efficient as IdeS in cleaving human IgG.

[0016] Alternatively, the immunoglobulin degrading enzyme may be a protein comprising or consisting of a fragment of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, and may have IgG cysteine ​​protease activity. Preferably, the fragment is 100 to 300 amino acids, 150 to 300 amino acids, or 200 to 300 amino acids in length. The fragment may be generated by deleting one or more amino acid residues from the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. The deletion may be of up to 1, 2, 3, 4, 5, 10, 20, 30, 40, or 50 residues, or more. The deleted residues may be contiguous.

[0017] Preferably, the IgG degrading enzyme comprises the amino acid sequence of Table 1 or a variant thereof having the same function, or is a protein consisting of the amino acid sequence or a fragment thereof. In one embodiment, the IgG degrading enzyme comprises the amino acid sequence of Table 1 and may further include: 1) the amino acid sequences of SEQ ID NOs: 1-42, 59, 60, 61-95; 2) a variant thereof, wherein the variant has at least 50% identity with the amino acid sequences of SEQ ID NOs: 1-42, 59, 60, 61-95 and has IgG degrading enzyme activity; or a fragment of 1) or 2) having IgG degrading enzyme activity.

[0018] Table 1. Sequences of immunoglobulin degrading enzymes

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026] The mutant of the present invention is preferably produced by genetic engineering recombination.

[0027] Preferably, the mutant comprises or consists of any amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical to the sequence shown in SEQ ID NO: 5, and has IgG cysteine ​​protease activity.

[0028] A modified immunoglobulin degrading enzyme, which is modified by a modification selected from the group consisting of glycosylation, sialylation, albumination, farnesylation, carboxylation, hydroxylation, phosphorylation and conjugation to a polymer.

[0029] A modified immunoglobulin degrading enzyme, wherein the modified polypeptide is modified by conjugation with dextran, PEG, a multimerization domain, a toxin, a detectable label or a drug.

[0030] A modified immunoglobulin degrading enzyme that is an HSA fusion protein or an Fc fusion protein.

[0031] 1.2 Fc agent (i.e., protein or preparation containing Fc, the following description uses protein containing Fc as an example)

[0032] Preferably, in the pharmaceutical combination as described above, the Fc-containing protein is selected from one or more of an antibody, an immunoglobulin, an immunoadhesin, a therapeutic agent, a diagnostic agent, an imaging agent, and an antibody-drug conjugate.

[0033] Preferably, the drug combination as described above further comprises a leukocyte depletion agent. The leukocytes are preferably B cells. The leukocyte depletion agent preferably binds to CD4, CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD69, CD70, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, CD86, HLA-DRA, TNFRSF5, TNFRSF6, TNFSF5, TNFSF6, BLR1, HDAC4, HDAC5, HDAC7A, HDAC9, ICOSL, IGBP1, MS4A1, RGS1, Antibodies that specifically bind to SLA2, CD81, IFNB1, IL10, TNFRSF5, TNFRSF7, TNFSF5, AICDA, BLNK, GALNAC4S-6ST, HDAC4, HDAC5, HDAC7A, HDAC9, IL4, INHA, INHBA, KLF6, TNFRSF7, DPP4, FCER2, IL2RA, TNFRSF8, TNFSF7, CR2, IL1R2, ITGA2, ITGA3, MS4A1, ST6GAL1, CD1C, CHST10, HLA-A, HLA-DRA, or NT5E.

[0034] Preferably, the pharmaceutical combination as described above, wherein the Fc-containing protein is an antibody against CD3, CD11a, CD14, CD25, CD28, CD30, CD33, CD36, CD38, CD40, CD44, CD52, CD55, CD59, CD56, CD103, CD134, CD137, CD138, CD152, CD3, IL-1β, IL-2R, IL-6, IL-12, IL-23, C5, BAFF, BLyS, BCMA, CXCR-4, ICAM-1, SLAMF7 / CS1, TNFα and IgE.

[0035] Preferably, the drug combination as described above, wherein the Fc-containing protein is an antibody against IL1β, IL2, IL2R, IL4, IL6, IL10, IL11, IL12, IL23, C5, BAFF, BLyS, BCMA, CXCR-4, ICAM-1, SLAMF7 / CS1, TNFα, IgE, B7.1 / B7.2.

[0036] Preferably, the drug combination as described above, wherein the Fc-containing protein is rituximab (CD20), daclizumab (IL2R), basiliximab (IL2R), muromonab-CD3, infliximab (TNFα), adalimumab (TNFα), omalizumab (IgE), efalizumab (CD11a), natalizumab (Integrinα4), tocilizumab (IL6), eculizumab (C5), golimumab (TNFα), canakinumab (IL1β), ustekinumab (IL12 / IL23), belimumab (BLyS), cetuximab, bevacizumab, elotuzumab (SLAMF7), or a combination thereof.

[0037] The antibody that specifically recognizes CD38 has binding specificity to human effector cells, and / or the antibody is capable of killing cells expressing CD38 by apoptosis, and / or antibody-dependent cell-mediated cytotoxicity, and / or complement-dependent cytotoxicity.

[0038] The immunoconjugate of the CD38 antibody, wherein the antibody is a monomeric IgM antibody linked to a cytotoxic agent, a radioisotope or a drug.

[0039] The CD38 antibody has binding specificity to CD3, CD4, CD138, IL-15R, membrane-bound or receptor-bound TNF-α, human Fc receptor, or membrane-bound or receptor-bound IL-15.

[0040] The CD38 antibody is selected from daratumumab, isatuximab, MOR202, TAK-079, TAK-573, SAR442085, TAK-169, T-007, AMG424, GBR1324, Hexabody-CD38, TSK011010, STI-5171, anti-CD38 / IGF-1RbsAb, Anti-CD38 SIFbody, Actinium-225dara, STI-6129, Anti-CD38 / anti-CD3, CD38 TCE and Y-150.

[0041] The CD38 antibody is characterized in that the antibody comprises at least one heavy chain and at least one light chain, wherein the light chain comprises three consecutive complementarity determining regions as shown in the amino acid sequences of SEQ ID NO: 43, SEQ ID NO: 44 and SEQ ID NO: 45, or three consecutive complementarity determining regions as shown in the amino acid sequences of SEQ ID NO: 49 to 51, and the heavy chain comprises three consecutive complementarity determining regions as shown in the amino acid sequences of SEQ ID NO: 46 to 48, or three consecutive complementarity determining regions as shown in the amino acid sequences of SEQ ID NO: 52, SEQ ID NO: 53 and SEQ ID NO: 54; wherein the epitope-binding fragment is Fab, Fab' and F(ab')2, scFv or disulfide-linked Fv fragment.

[0042] Preferably, the light chain comprises the amino acid sequence shown in SEQ ID NO. 55 or 57, and the heavy chain comprises the amino acid sequence shown in SEQ ID NO. 56 or 58;

[0043] More preferably, the amino acid sequence of the light chain is shown as SEQ ID NO.55, and the amino acid sequence of the heavy chain is shown as SEQ ID NO.56; or the amino acid sequence of the light chain is shown as SEQ ID NO.57, and the amino acid sequence of the heavy chain is shown as SEQ ID NO.58.

[0044] Table 2. Antibody-related sequences

[0045]

[0046]

[0047] The Fc-containing protein further comprises an antibody that binds to one or more immune checkpoint targets selected from the following. The immune checkpoint is selected from CTLA-4, PD-1, TIM-3, LAG3, Siglec15, 4-1BB, GITR, OX40, CD40L, CD28, TIGIT, and VISTA; the immune checkpoint antibody is selected from anti-CTLA-4 antibody, anti-PD-1 antibody, anti-TIM-3 antibody, anti-LAG3 antibody, anti-Siglec15 antibody, anti-4-1BB antibody, anti-GITR antibody, anti-OX40 antibody, anti-CD40L antibody, anti-CD28 antibody, anti-TIGIT antibody, and anti-VISTA antibody.

[0048] 1.3 Other reagents included

[0049] The pharmaceutical composition described above further comprises a chemotherapeutic agent, a hormone agent, or a targeted small molecule agent. The combined use can induce immunogenic cell death, enhance tumor cell antigenicity or susceptibility to immune cells, and inhibit negatively regulating Treg cells and myeloid-derived suppressor cells (MDSC).

[0050] The chemotherapy drug is selected from immunosuppressants, proteasome inhibitors, cytotoxic drugs and cell cycle non-specific agents; the immunosuppressants are such as cyclophosphamide, thalidomide, pomalidomide, lenalidomide; the proteasome inhibitors are such as bortezomib; the cytotoxic drugs are such as gemcitabine, temozolomide, cisplatin; the cell cycle non-specific drugs are such as melphalan, mitoxantrone, vincristine, doxorubicin.

[0051] The hormonal agents include dexamethasone and prednisone.

[0052] The targeted small molecule formulation is selected from epigenetic drugs, inhibitors targeting the PI3K / Akt / mTOR signaling pathway, and tyrosine kinase inhibitors. Tyrosine kinase (PTKs) inhibitors have multiple effects of inhibiting tumor angiogenesis and anti-tumor cell growth. For example, gefitinib is an oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor. Inhibition of EGFR-TK can hinder tumor growth, metastasis, and angiogenesis, and increase tumor cell apoptosis.

[0053] Other therapeutic agents are also included, including pamidronate, zoledronic acid, clodronate, risedronate, ibandronate, etidronate, alendronate, tiludronate, arsenic trioxide, filgrastim, pegylated filgrastim, sargramostim, suberoylanilide hydroxamic acid and SCIO-469, all-trans retinoic acid (ATRA), cytarabine, phenylalanine mustard, vascular endothelial growth factor inhibitors, immunosuppressive antibodies that bind to CD40, TOR inhibitors, immunosuppressive antibodies that bind to IL-6, and IGF-IR inhibitors.

[0054] Other therapeutic agents are also included, including antagonists of epidermal growth factor (EGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP) or vascular endothelial growth factor (VEGF), or antagonists of receptors for epidermal growth factor (EGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP) or vascular endothelial growth factor (VEGF).

[0055] Other therapeutic agents are also included, including analgesics, anti-inflammatory agents, antimicrobials, anti-amoebic agents, trichomonascides, anti-Parkinson's agents, anti-dysentery agents, anticonvulsants, antidepressants, anti-rheumatic agents, antifungals, antihypertensives, antipyretics, antiparasitics, antihistamines, alpha-adrenergic agonists, alpha blockers, anesthetics, bronchodilators, biocides, bactericides, antibacterials, beta-adrenergic blockers, calcium channel blockers, cardiovascular agents, Pregnancy drugs, decongestants, diuretics, sedatives, diagnostic reagents, electrolyte reagents, hypnotic drugs, hormones, hyperglycemic drugs, muscle relaxants, muscle contractants, ophthalmic drugs, parasympathomimetics, psychiatric drugs, tranquilizers, sympathomimetics, tranquilizers, urinary drugs, vaginal drugs, viricides, vitamin drugs, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, peptides, proteins, nucleic acids, drugs, organic molecules and sleep-inducing agents.

[0056] 1.4 Carriers or excipients of the composition

[0057] The pharmaceutical carrier can be a liquid, and the pharmaceutical composition can be in the form of a solution. Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture thereof, or a pharmaceutically acceptable oil or fat.

[0058] Pharmaceutical compositions for parenteral administration are sterile, substantially isotonic, pyrogen-free, and prepared in accordance with GMPs of the FDA or similar agencies. Viral vector drugs can be administered as injectable dosage forms of solutions or suspensions of the substance, wherein the substance is in a physiologically acceptable diluent and pharmaceutical carrier (which can be a sterile liquid such as water, oil, saline, glycerol, or ethanol). In addition, auxiliary substances such as wetting agents or emulsifiers, surfactants, and pH buffering substances may be present in the composition. Other components of the pharmaceutical composition include components of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. Generally, glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially for injectable solutions. Fc-containing proteins can be administered in the form of depot injections or implants, which can be formulated to allow for sustained release of the active ingredient. Typically, the composition is prepared as an injectable, i.e., a liquid solution or suspension; it can also be prepared as a solid form suitable for dissolution or suspension in a liquid carrier prior to injection.

[0059] A combination product wherein the immunoglobulin is immobilized on a surface and the pharmaceutically active agent is free in solution.

[0060] 1.5 Preparation of the composition and application of the obtained product

[0061] The present invention also provides a product comprising an agent for reducing blood IgG levels, including an immunoglobulin degrading enzyme and an Fc-containing protein, for use as a combined preparation, either simultaneously, separately, or sequentially, in the treatment of hypergammaglobulinemia and / or the prevention of infection. Preferably, the combined preparation is used in a method for treating hypergammaglobulinemia.

[0062] 1.6 Kits or kits containing a third therapeutic component other than immunoglobulin degrading enzymes and Fc-containing proteins

[0063] The present invention also provides a kit or pharmaceutical kit for preventing or treating hyperglobulinemia, comprising: 1) a therapeutically effective amount of an immunoglobulin degrading enzyme; and 2) a therapeutically effective amount of an Fc-containing protein. The kit may further include other active ingredients in addition to 1) and 2).

[0064] The kit includes Kit A and Kit B, wherein Kit A includes a therapeutically effective amount of a drug for reducing blood immunoglobulin levels, including an IgG degrading enzyme, and Kit B includes a therapeutically effective amount of a viral vector drug. The kit may also include Kit C. Kit C may also include other active ingredients in addition to 1) and 2).

[0065] The kit may include instructions for administering a therapeutically effective amount of a drug that reduces blood immunoglobulin levels and a therapeutically effective amount of a viral vector drug (eg, dosage information, dosing interval information).

[0066] The present invention also provides, for example, but not limited to, a package and kit for preventing or treating hyperglobulinemia, comprising: 1) an immunoglobulin degrading enzyme; and 2) a therapeutically effective amount of a pharmaceutically active agent comprising a CD38 antibody; and 3) a label with instructions for performing the methods disclosed herein. In certain embodiments, 1) and 2) are in separate or identical containers.

[0067] 2. Use of the combination in the preparation of a composition for treating hyperglobulinemia

[0068] In a preferred embodiment, any one of the modified immunoglobulin degrading enzymes is used in combination with an Fc-containing protein for the preparation of a drug for treating hyperglobulinemia.

[0069] In a preferred embodiment, any one of the modified immunoglobulin degrading enzymes and an Fc-containing protein is used in combination for preparing a medicament for treating multiple myeloma.

[0070] In a preferred embodiment, any one of the kits or drug kits is used to prepare a drug for treating hyperglobulinemia.

[0071] 2.1 Hyperglobulinemia

[0072] Hyperglobulinemia (abnormal increase in IgG) is characterized by higher than normal levels of immunoglobulins in the patient's body. Immunoglobulins include IgA, IgD, IgE, IgM and IgG, among which excess γ immunoglobulin IgG is the most common. Excess immunoglobulins are produced by white blood cells, and the white blood cells are selected from B cells, abnormal B cells, cells that produce IgM, cells that produce IgE, and cells that produce IgA; the globulins include γ globulins; the hyperglobulinemia includes malignant monoclonal gammopathy (such as multiple myeloma, heavy chain disease, malignant lymphoma, chronic lymphocytic leukemia, macroglobulinemia, etc.), primary monoclonal gammopathy, secondary monoclonal gammopathy (such as non-lymphoreticular tumors, mononuclear cells, etc.), and so on. leukemia, cryoglobulinemia, etc.), benign M-proteinemia, monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom's macroglobulinemia, AL amyloidosis, solitary plasmacytoma (bone or extraskeletal), POMES syndrome, reactive plasmacytosis, osteolytic lesions of metastatic cancer, plasmablastic lymphoma, monoclonal immunoglobulin-related renal damage (MGRS), etc. MGRS is renal damage caused by monoclonal immunoglobulins or their fragments, and its hematological changes are more similar to MGUS. It also includes connective tissue diseases, such as systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjögren's syndrome, etc.; liver diseases, chronic viral active hepatitis, latent cirrhosis, lupus hepatitis, etc.; infectious diseases, tuberculosis, leprosy, kala-azar, infectious mononucleosis, venereal diseases, lymphogranuloma, actinomycosis, malaria, trypanosomiasis, etc.; others, sarcoidosis, myasthenia gravis, Hodgkin's disease, monocytic leukemia, Behcet's disease, nephritis, Henoch-Schonlein purpura, immune (or spontaneous) thrombocytopenia, etc.

[0073] 2.2CD38-related cancers or autoimmune diseases

[0074] CD38 is a therapeutic target for multiple myeloma and other hyperglobulinemia blood tumors. CD38-related cancers or autoimmune diseases also include leukemias and lymphomas, such as B-cell chronic lymphocytic leukemia, T-cell and B-cell acute lymphocytic leukemia, Waldenstrom's macroglobulinemia, primary systemic amyloidosis, mantle cell lymphoma, prolymphocytic / myeloid leukemia, acute myeloid leukemia, chronic myeloid leukemia, follicular lymphoma, Burkitt lymphoma, large granular lymphocyte (LGL) leukemia, NK cell leukemia and plasma cell leukemia, Diffuse Large B-Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle-Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), Acute Myeloid Leukemia (AML). Multiple myeloma is a blood cancer caused by the cancerous transformation of plasma cells in the bone marrow. Currently, there are a variety of Fc agents targeting CD38, including but not limited to daratumumab, isatuximab, and MOR202.

[0075] Use of the pharmaceutical combination in the preparation of a medicament for a method for inhibiting the growth and / or proliferation of cells expressing CD38, the method comprising administering the pharmaceutical composition, thereby inhibiting the growth and / or proliferation of the cells.

[0076] Use of the pharmaceutical combination in preparing a medicament for treating a disease or symptom in a patient caused by cells expressing CD38, the method comprising administering the pharmaceutical composition to a patient in need of treatment.

[0077] Use of the pharmaceutical combination in the preparation of a medicament for a method for preventing a disease or symptom in a patient in which cells expressing CD38 participate, the method comprising administering the pharmaceutical composition to a patient in need of treatment.

[0078] 2.3 Systemic lupus erythematosus

[0079] A hallmark of the immunopathogenicity of systemic lupus erythematosus (SLE) is polyclonal B cell activation, which leads to hyperglobulinemia, autoantibody production, and immune complex formation. The primary abnormality appears to be due to a generalized T cell dysregulation that results in the inability of T cells to suppress these prohibited B cell clones. In addition, several cytokines (e.g., IL10) and co-stimulatory molecules (e.g., CD40 and CD40L, B7 and CD28, and CTLA-4) that trigger secondary signals also promote B cell-T cell interactions. These interactions, along with impaired phagocytic clearance of immune complexes and apoptotic material, contribute to the maintenance of the immune response and the resulting tissue damage. The combination of the present invention will enhance the therapeutic efficacy of SLE (see Sfikakis PP et al., 2005 Curr Opin Rheumatol 17:550-7; Peng SL (2004) Methods Mol Med.; 102:227-72).

[0080] 3. Combination therapy for hyperglobulinemia

[0081] In a preferred embodiment, the immunoglobulin degrading enzyme and Fc agent are used to prevent and or treat hyperglobulinemia.

[0082] The hyperglobulinemia is selected from the group consisting of the following diseases or the following diseases: malignant monoclonal gammopathy (such as multiple myeloma, heavy chain disease, malignant lymphoma, chronic lymphocytic leukemia, macroglobulinemia, etc.), secondary monoclonal gammopathy (such as non-lymphoreticular tumors, monocytic leukemia, cryoglobulinemia, etc.), benign M proteinemia, monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom's macroglobulinemia, AL amyloidosis, solitary plasmacytoma (bone or extraskeletal), POMES syndrome, reactive plasmacytosis, osteolytic lesions of metastatic cancer, plasmablastic lymphoma, monoclonal immunoglobulin-related renal damage (MGRS), etc. The disease is preferably multiple myeloma.

[0083] When the immunoglobulin degrading enzyme is administered before the Fc agent, the level of immunoglobulins, particularly M protein, in the subject's blood is quantitatively detected before the immunoglobulin degrading enzyme is administered, after the agent is administered, and before the Fc agent is administered, after the Fc agent is administered.

[0084] When the immunoglobulin degrading enzyme is administered after the administration of the Fc agent, the level of immunoglobulins, particularly M protein, in the subject's blood is quantitatively detected before the administration of the Fc agent, after the administration of the Fc agent and before the administration of the immunoglobulin degrading enzyme, and after the administration of the immunoglobulin degrading enzyme.

[0085] Preferably, the immunoglobulin degrading enzyme is administered before the administration of the Fc agent, or the immunoglobulin degrading enzyme is administered after the administration of the Fc agent.

[0086] In the use of the present invention, the immunoglobulin degrading enzyme is present in the Fc agent as a combined preparation for simultaneous, separate or sequential use.

[0087] In some embodiments, the method comprises the following steps: 1) administering the immunoglobulin degrading enzyme to a subject; and subsequently, 2) administering the Fc agent to the subject. Preferably, there is a time interval between the administration of the immunoglobulin degrading enzyme and the Fc agent.

[0088] In some embodiments, the method comprises the following steps: 1) administering the Fc agent to the subject; and subsequently, 2) administering the immunoglobulin degrading enzyme to the subject. Preferably, there is a time interval between the administration of the immunoglobulin degrading enzyme and the Fc agent.

[0089] Preferably, the immunoglobulin degrading enzyme is administered in an amount and at a time interval sufficient to reduce the immunoglobulin level in the subject to 60% of the starting level. More preferably, the agent is administered in an amount and at a time interval sufficient to reduce the immunoglobulin level in the subject to less than 50%, 40%, 30%, 20% or 10% of the starting level in the patient. The agent can be administered at a single time point or over a set period of time.

[0090] The agent and oncolytic virus or viral vaccine can be administered by any suitable route. Preferably, the immunoglobulin degrading enzyme is administered by intravenous infusion or subcutaneous injection, and / or the amount of the agent administered is 0.01 mg / kg body weight to 2 mg / kg body weight, 0.04 to 2 mg / kg body weight, 0.12 mg / kg body weight to 2 mg / kg body weight, 0.24 mg / kg body weight to 2 mg / kg body weight or 1 mg / kg body weight to 2 mg / kg body weight.

[0091] Preferably, the time interval between administration of the immunoglobulin degrading enzyme and the Fc agent is at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 4 hours, at least 5 hours or at least 6 hours; and at most 35 days, at most 28 days, at most 21 days, at most 18 days, at most 14 days, at most 13 days, at most 12 days, at most 11 days, at most 10 days, at most 9 days, at most 8 days, at most 7 days, at most 6 days, at most 5 days, at most 4 days, at most 3 days, at most 2 days, at most 24 hours, at most 18 hours, at most 12 hours, at most 10 hours, at most 8 hours, at most 7 hours or at most 6 hours.

[0092] Preferably, the administration time interval between the immunoglobulin degrading enzyme and the Fc agent is 30 minutes to 1 hour, 30 minutes to 2 hours, 30 minutes to 3 hours, 30 minutes to 4 hours, 30 minutes to 5 hours, 30 minutes to 6 hours, 1 to 2 hours, 1 to 3 hours, 1 to 4 hours, 1 to 5 hours, 1 to 6 hours, 2 to 3 hours, 2 to 4 hours, 2 to 5 hours, 2 to 6 hours, 3 to 4 hours, 3 to 5 hours, 3 to 6 hours, 4 to 5 hours, 4 to 6 hours or 5 to 6 hours.

[0093] In yet another embodiment, the method comprises the steps of: 1) treating blood from the subject ex vivo with the immunoglobulin degrading enzyme; 2) returning the blood to the subject; 3) administering the Fc agent to the subject.

[0094] In yet another embodiment, the method comprises the steps of: 1) administering the Fc agent to the subject; 2) treating blood from the subject ex vivo with the immunoglobulin degrading enzyme; 3) returning the blood to the subject.

[0095] In a preferred embodiment, the immunoglobulin degrading enzyme and Fc agent are used to treat hyperglobulinemia.

[0096] In a preferred embodiment, the immunoglobulin degrading enzyme and Fc agent are used to prevent hyperglobulinemia.

[0097] In any aspect of the present invention, the immunoglobulin degrading enzyme and the Fc agent can be administered simultaneously, separately or sequentially for the treatment and prevention of hyperglobulinemia. The immunoglobulin degrading enzyme and the Fc agent can be provided as separate preparations or as a combined preparation.

[0098] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0099] The reagents and raw materials used in the present invention are commercially available.

[0100] The positive improvement effect of the present invention is that by combining immunoglobulin degrading enzyme with Fc agent for hyperglobulinemia, the influence of globulin on treatment is reduced, so that Fc agent can play a better role. At the same time, the clinical dosage of some Fc agents can also be reduced. On the one hand, the side effects of the therapeutic agent can be reduced, and on the other hand, the economic burden of medication can be reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Figure 1 Figure 2 is the SDS-PAGE gel electrophoresis of the cleavage products of human IgG1 produced by 7 single-point mutants and wild-type IdeE (enzyme: substrate = 1:1000).

[0102] Figure 2 Figure 2 is the SDS-PAGE gel electrophoresis of the cleavage products of human IgG1 produced by 7 single-point mutants and wild-type IdeE (enzyme: substrate = 1:2000).

[0103] Figure 3 Figure 2 shows the SDS-PAGE gel electrophoresis of the cleavage products of human IgG1 produced by cleaving five N-terminal truncation mutants (enzyme: substrate = 1:1000).

[0104] Figure 4 This is the SDS-PAGE gel electrophoresis diagram of the cleavage products produced by five N-terminal truncation mutants and wild-type IdeE cleaving human IgG1 after incubation at 50°C for 1 hour (enzyme: substrate = 1:1000).

[0105] Figure 5 Figure 2 shows the SDS-PAGE gel electrophoresis of the cleavage products of human IgG1 produced by two C truncation mutants (enzyme: substrate = 1:1000).

[0106] Figure 6 Figure 2 shows the SDS-PAGE gel electrophoresis of the cleavage products of human IgG1 produced by the five combined mutants (enzyme: substrate = 1:2000).

[0107] Figure 7 This is the SDS-PAGE gel electrophoresis of the cleavage products produced by the five combined mutants cleaving human IgG1 after incubation at 50°C for 1 hour (enzyme: substrate = 1:2000).

[0108] Figure 8 Figure 3 is an SDS-PAGE gel electrophoresis diagram of the cleavage products generated by different concentrations of E97D_del18 mutant and IdeS cleaving human IgG1.

[0109] Figure 9 Figure 3 is an SDS-PAGE gel electrophoresis diagram of the cleavage products generated by cleaving human IgG1 with different concentrations of the E97D_del18 mutant and IdeZ.

[0110] Figure 10A and 10B Figure 2 shows the SDS-PAGE gel electrophoresis of the cleavage products of human IgG1 cleaved by mutants with different mutation combinations and IdeE (enzyme: substrate = 1:2000).

[0111] Figure 11 Figure 3 is an SDS-PAGE gel electrophoresis diagram of the cleavage products generated by the E97D_del18 mutant cleaving human IVIg in mouse serum and plasma.

[0112] Figure 12Figure 3 is the SDS-PAGE gel electrophoresis of the cleavage products produced by the E97D_del18 mutant in mouse and human serum.

[0113] Figure 13 The SDS-PAGE gel electrophoresis diagram shows the cleavage products produced by E97D_del18 cleaving human IVIg at different times in mice.

[0114] Figure 14 In a Daudi cell tumor model, immunoglobulin-degrading enzymes reduce the inhibition of IgG on antibody-induced tumor suppression. DETAILED DESCRIPTION

[0115] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0116] Example 1. Protein preparation

[0117] 1) Preparation of CD38 monoclonal antibody liquid preparation

[0118] Daratumumab is harvested from the cell culture fluid and purified using immobilized protein A affinity chromatography, cation exchange chromatography (e.g., SP Sepharose FF), a filtration step to remove viral contamination, followed by hydrophobic chromatography (e.g., Butyl Sepharose HP) and an ultrafiltration step. To prepare a pharmaceutical composition according to the examples, daratumumab is provided at a concentration of approximately 100 mg / mL in 20 mM histidine buffer (pH approximately 6.0). Isatuximab is prepared using the same method.

[0119] 2) Preparation of IdeS and IdeZ

[0120] Nanjing GenScript Biotechnology Co., Ltd. was commissioned to synthesize polynucleotide sequences encoding SEQ ID NO: 1 to SEQ ID NO: 5 after optimizing codons preferred by E. coli. An N-terminal methionine and a C-terminal 6× histidine tag were added. After sequence synthesis, the sequences were inserted into the pET32a expression vector. After correct sequencing, a recombinant plasmid for polypeptide expression was obtained. The prepared recombinant plasmid was electroporated into E. coli BL21 Star (DE3) and inoculated onto LB agarose plates containing 100 μg / mL ampicillin. The plates were cultured overnight at 37°C until colonies grew. A single colony was picked and inoculated into 3 ml of LB medium containing 100 μg / mL ampicillin and incubated overnight at 37°C at 250 rpm. The overnight culture was inoculated into 50 mL of LB medium containing 100 μg / mL ampicillin and incubated at 37°C until the OD600 reached 0.4–0.6. 0.1 mM IPTG was added and the culture continued overnight at 20°C. Overnight cultures were pelleted by centrifugation, resuspended in PBS to 100 g / L, and then disrupted by sonication. The supernatant was collected by centrifugation and purified using IDA-Ni magnetic agarose beads. Following purification, the eluted protein was transferred to PBS buffer using an ultrafiltration centrifuge tube. The purity of each protein was assessed using SDS-PAGE.

[0121] Example 2. Comparison of the cleavage activity of single-point mutants on human IgG1

[0122] According to the method of Example 1, seven single-point mutants of IdeE T8D (SEQ D NO: 63), T8W (SEQ D NO: 65), T24A (SEQ D NO: 69), A59L (SEQ ID NO: 73), A59V (SEQ ID NO: 74), E97D (SEQ ID NO: 75) and R280H (SEQ ID NO: 76) were synthesized to show activity in cleaving human IgG1.

[0123] The cleavage activity of the mutants relative to wild-type IdeE was further evaluated by visualizing the cleavage products generated by different concentrations of each mutant on human IgG1 on SDS-PAGE. Purified mutants or wild-type IdeE were diluted to 0.002 mg / mL and 0.001 mg / mL, respectively. The cleavage reaction was initiated by adding 50 μl of each mutant or wild-type IdeE at different concentrations to 50 μl of trastuzumab at 2 mg / mL. The reaction was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C for 5 minutes. The cleavage products were then analyzed by SDS-PAGE.

[0124] Figure 1Shown are the electrophoretic patterns of cleavage products generated by 7 single-point mutants and wild-type IdeE cleaving human IgG1 (enzyme: substrate = 1:1000). Figure 2 The electrophoresis diagrams of the cleavage products of seven single-point mutants and wild-type IdeE cleaving human IgG1 are shown (enzyme:substrate = 1:2000). The cleavage efficiency of the seven single-point mutants at a concentration of 0.001 mg / ml was no less than that of 0.002 mg / ml wild-type IdeE, indicating that the cleavage activity of the seven single-point mutants on human IgG1 was at least twice that of wild-type IdeE.

[0125] Example 3. Comparison of the activity and thermal stability of N-terminal truncation mutants in cleaving human IgG1

[0126] Based on the wild-type IdeE, the first 15 (D1-V15), first 16 (D1-P16), first 17 (D1-H17), first 18 (D1-Q18) and first 19 amino acids (D1-I19) of the N-terminus were deleted to construct five N-terminal truncation mutants (see Table 3).

[0127] Table 3. Sequence design of truncation mutants

[0128] mutant Modifications relative to wild-type or mutant sequences SEQ ID NO: WT_del15 Delete the first 15 amino acids of SEQ ID NO: 62 78 WT_del16 Delete the first 16 amino acids of SEQ ID NO: 62 79 WT_del17 Delete the first 17 amino acids of SEQ ID NO: 62 80 WT_del18 Delete the first 18 amino acids of SEQ ID NO: 62 81 WT_del19 Delete the first 19 amino acids of SEQ ID NO: 62 82

[0129] 1. Expression and purification of mutants

[0130] The mutant polynucleotide sequences in Table 3 were synthesized according to the method of Example 1, mutant expression recombinant plasmids were constructed, Escherichia coli BL21 Star (DE3) were transformed, and mutant purified proteins were prepared.

[0131] 2. Comparison of the mutants' activity in cleaving human IgG1

[0132] Purified mutant or wild-type IdeE was diluted to 0.002 mg / mL. 50 μl of each diluted mutant or wild-type IdeE was added to 50 μl of trastuzumab (2 mg / mL) to initiate the cleavage reaction. The reaction was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C for 5 minutes. Cleavage products were then analyzed by SDS-PAGE.

[0133] Figure 3 The electrophoresis diagram of the cleavage products of human IgG1 produced by the five truncation mutants is shown (enzyme: substrate = 1: 1000). The cleavage activities of the five truncation mutants were not significantly different from those of wild-type IdeE.

[0134] 3. Comparison of thermal stability of mutants

[0135] Purified mutant or wild-type IdeE was diluted to 0.1 mg / mL and incubated at 50°C for 1 hour. After incubation, the sample was diluted to 0.002 mg / mL. The cleavage reaction was initiated by adding 50 μl of each diluted mutant or wild-type IdeE to 50 μl of trastuzumab containing 2 mg / mL. The reaction was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C for 5 minutes. The cleavage products were then analyzed by SDS-PAGE.

[0136] Figure 4 Shown are electrophoretic images of the cleavage products of human IgG1 produced by five truncation mutants and wild-type IdeE after incubation at 50°C for 1 hour (enzyme:substrate = 1:1000). After heat treatment at 50°C, the residual activity of the five truncation mutants was significantly higher than that of the wild-type, indicating that the thermal stability of the five truncation mutants was significantly improved compared to the wild-type.

[0137] Example 4. Comparison of C-terminal truncation mutants' cleavage activity on human IgG1

[0138] Based on the wild-type IdeE, the last 5 (W311-S315) and last 10 amino acids (S306-S315) of the C-terminus were deleted, respectively, to construct two C-terminal truncation mutants (see Table 4).

[0139] Table 4. Sequence design of truncation mutants

[0140] mutant Modifications relative to wild-type or mutant sequences SEQ ID NO: WT_delC5 Delete the last 5 amino acids of SEQ ID NO: 62 83 WT_delC10 Delete the last 10 amino acids of SEQ D NO: 62 84

[0141] 1. Expression and purification of mutants

[0142] The mutant polynucleotide sequences in Table 4 were synthesized according to the method of Example 1, mutant expression recombinant plasmids were constructed, Escherichia coli BL21 Star (DE3) were transformed, and mutant purified proteins were prepared.

[0143] 2. Comparison of the mutants' activity in cleaving human IgG1

[0144] Purified mutant or wild-type IdeE was diluted to 0.002 mg / mL. 50 μl of each diluted mutant or wild-type IdeE was added to 50 μl of trastuzumab (2 mg / mL) to initiate the cleavage reaction. The reaction was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C for 5 minutes. Cleavage products were then analyzed by SDS-PAGE.

[0145] Figure 5 The electrophoresis diagram of the cleavage products of human IgG1 produced by two C-terminal truncation mutants (enzyme: substrate = 1:1000) is shown. The cleavage activities of the two truncation mutants are more than 2 times higher than that of wild-type IdeE.

[0146] Example 5. Comparison of human IgG1 cleavage activity and thermal stability of combined mutants

[0147] Based on the five single-point mutants T24A, A59L, A59V, E97D and R280H, the first 18 amino acids (D1-Q18) were deleted respectively to construct five combined mutants (see Table 5).

[0148] Table 5. Combination mutant sequence design

[0149] mutant Modifications relative to wild-type or mutant sequences SEQ D NO: T24A_del18 Delete the first 18 amino acids of SEQ ID NO: 69 85 A59L_de118 Delete the first 18 amino acids of SEQ ID NO: 73 86 A59V_del18 Delete the first 18 amino acids of SEQ ID NO: 74 87 E97D_del18 Delete the first 18 amino acids of SEQ ID NO: 75 88 R280H_del18 Delete the first 18 amino acids of SEQ ID NO: 76 89

[0150] 1. Expression and purification of mutants

[0151] The mutant polynucleotide sequences in Table 5 were synthesized according to the method of Example 1, mutant expression recombinant plasmids were constructed, Escherichia coli BL21Star (DE3) were transformed, and mutant purified proteins were prepared.

[0152] 2. Comparison of the mutants' activity in cleaving human IgG1

[0153] Purified mutants were diluted to 0.001 mg / mL. 50 μl of each diluted mutant or wild-type IdeE was added to 50 μl of trastuzumab (2 mg / mL) to initiate the cleavage reaction. The reaction was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C for 5 minutes. The cleavage products were then analyzed by SDS-PAGE.

[0154] Figure 6 The electrophoresis diagram of the cleavage products of human IgG1 produced by the five combined mutants is shown (enzyme: substrate = 1:2000). Figure 6 and Figure 2 There was no significant difference in the cleavage activity between the five truncated mutants and the single-point combination mutants, indicating that the activity of the combination mutants in cleaving human IgG1 was no less than 2 times that of the wild-type IdeE.

[0155] 3. Comparison of thermal stability of mutants

[0156] Purified mutants were diluted to 0.1 mg / ml and incubated at 50°C for 1 hour. After incubation, the mixture was diluted again to 0.001 mg / mL. The cleavage reaction was initiated by adding 50 μl of the diluted mutant or wild-type IdeE to 50 μl of trastuzumab at 2 mg / ml. The reaction was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C for 5 minutes. The cleavage products were then analyzed by SDS-PAGE.

[0157] Figure 7The electrophoresis diagram of the cleavage products of human IgG1 produced by the five combined mutants after incubation at 50°C for 1 hour (enzyme: substrate = 1:2000) is shown. Figure 7 and Figure 2 The cutting effect of the five combined mutants was significant, and the activity of the five combined mutants was only slightly decreased after heat treatment at 50°C, indicating that the thermal stability of the five combined mutants was significantly improved compared with the wild type.

[0158] Example 6. Comparison of the activity of the E97D_del18 mutant with IdeS and IdeZ

[0159] The E97D_del18 mutant purified in Example 5 was diluted to 20 μg / mL, 10 μg / mL, 5 μg / mL, 2.5 μg / mL and 1.25 μg / mL in sequence. Catalog number: A0-FRI-020, Genovis) were diluted to 2U / μl, 1U / μl, 0.5U / μl, 0.25U / μl and 0.125U / μl according to the label. Catalog number: A0-FRZ-020, Genovis) were diluted to 0.4 U / μl, 0.2 U / μl, 0.1 U / μl, 0.05 U / μl, and 0.025 U / μl, respectively. The cleavage reaction was initiated by adding 50 μl of each mutant, IdeS, or IdeZ at different concentrations to 50 μl of a reaction system containing 2 mg / ml trastuzumab. The reaction system was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C in a water bath for 5 minutes. The cleavage products were then analyzed by SDS-PAGE.

[0160] Figure 8 The electrophoresis diagrams show the cleavage products of human IgG1 produced by different concentrations of the E97D_del18 mutant and IdeS. The enzyme protein bands in the electrophoresis diagram indicate that the IdeS concentration in lane 1 lies between the concentrations of the E97D_del18 mutant in lanes 7 and 8. This, in turn, infers that the IdeS concentration in lane 3 lies between the concentrations of the E97D_del18 mutant in lanes 9 and 10. Furthermore, the IgG1 cleavage activity in lane 3 lies between that in lanes 10 and 11. Therefore, it can be inferred that the E97D_del18 mutant has nearly twice the activity of IdeS in cleaving human IgG1.

[0161] Figure 9The electrophoresis diagrams show the cleavage products of human IgG1 produced by different concentrations of the E97D_del18 mutant and IdeZ. The enzyme protein bands in the electrophoresis diagram indicate that the IdeZ enzyme concentration in lane 1 is higher than that in lane 7 compared to the E97D_del18 mutant enzyme. This indicates that the IdeZ enzyme concentration in lane 3 is higher than that in lane 9 compared to the E97D_del18 mutant enzyme, which is four times higher than the E97D_del18 mutant enzyme concentration in lane 11. Furthermore, the IgG1 cleavage activity in lane 3 is similar to that in lane 11, indicating that the E97D_del18 mutant has a four-fold higher activity than IdeZ in cleaving human IgG1.

[0162] Example 7. Comparison of the activity of combined mutants in cleaving human IgG1

[0163] Based on the E97D_del18 mutant, the last 5 (W311-S315) and the last 10 amino acids (S306-S315) of the C-terminus were deleted to construct two C-terminal truncation mutants and a triple mutation combination (see Table 6).

[0164] Table 6. Combination mutant sequence design

[0165] mutant Modifications relative to wild-type or mutant sequences SEQ ID NO: E97D_del18_delC5 Delete the last 5 amino acids of SEQ ID NO: 88 90 E97D_del18_delC10 Delete the last 10 amino acids of SEQ ID NO: 88 91 A59V_del18_delC5 Delete the last 5 amino acids of SEQ ID NO: 87 92 A59L_del18_delC5 Delete the last 5 amino acids of SEQ ID NO: 86 93 R280H_del18_delC5 Delete the last 5 amino acids of SEQ ID NO: 89 94 E97D_A59V_R280H E97D, A59V, R280H triple mutation combination 95

[0166] 1. Expression and purification of mutants

[0167] The mutant polynucleotide sequences in Table 6 were synthesized according to the method of Example 1, mutant expression recombinant plasmids were constructed, Escherichia coli BL21 Star (DE3) were transformed, and mutant purified proteins were prepared.

[0168] 2. Comparison of the mutants' activity in cleaving human IgG1

[0169] Purified mutants were diluted to 0.001 mg / mL. 50 μl of each diluted mutant or wild-type IdeE was added to 50 μl of trastuzumab (2 mg / mL) to initiate the cleavage reaction. The reaction was incubated at 37°C for 30 minutes. The sample was mixed with an equal volume of 2× SDS loading buffer and incubated at 75°C for 5 minutes. The cleavage products were then analyzed by SDS-PAGE.

[0170] Figure 10A and 10B Shown are the electrophoretic patterns of cleavage products generated by cleavage of human IgG1 by the six combined mutants (enzyme: substrate = 1:2000).

[0171] Example 7. In vitro detection of the activity of the E97D_del18 mutant in cleaving human IgG1

[0172] The in vitro cleavage activity of the E97D_del18 mutant against human IgG1 was evaluated by measuring the amount of intact or single-cleaved IVIg in the serum or plasma of mice treated with the E97D_del18 mutant and human IVIg. The enzymatic cleavage system of different groups of mouse serum or plasma was prepared according to Table 7.

[0173] Table 7. Mouse serum or plasma enzymatic digestion system

[0174]

[0175] The role of iodoacetic acid in the iodoacetic acid treatment group was to inhibit the activity of IgG degrading enzymes.

[0176] The system was incubated at 37°C for 30 min. 20 μl of the sample was mixed with an equal volume of 2× SDS non-reducing loading buffer and incubated at 75°C for 5 min. The cleavage products were detected by SDS-PAGE.

[0177] Figure 11 The electrophoresis of the cleavage products produced by the E97D_del18 mutant in mouse serum and plasma shows that E97D_del18 can effectively cleave human IVIg in both mouse serum and plasma.

[0178] The in vitro cleavage activity of the E97D_del18 mutant against human IgG1 was evaluated by testing mouse or human serum treated with the E97D_del18 mutant. Different groups of mouse or human serum enzyme cleavage systems were prepared according to Table 8.

[0179] Table 8. Mouse or human serum enzyme digestion system

[0180]

[0181] The system was incubated at 37°C for 24 hours. 20 μl of the sample was mixed with an equal volume of 2× SDS reducing loading buffer, then diluted 20-fold with 1× SDS reducing loading buffer. The sample was incubated at 75°C in a water bath for 5 minutes, and the cleavage products were detected by SDS-PAGE.

[0182] Figure 12 Electrophoresis of the cleavage products produced by the E97D_del18 mutant in mouse and human serum is shown. The results show that E97D_del18 cleaves a clearly visible 25kD Fc fragment in human serum, but not in mouse serum. This indicates that E97D_del18 can effectively and specifically cleave IgG1 in human serum, while having little or no cleavage activity against IgG1 in mouse serum.

[0183] Example 8. Low pre-existing antibodies against the E97D_del18 mutant in humans

[0184] The assay is based on competition between the E97D_del18 mutant and IdeS for binding to anti-E97D_del18 / IdeS antibodies. Pre-incubation of the test enzyme with human serum will enable binding of the anti-E97D_del18 / IdeS antibodies to the E97D_del18 mutant and IdeS.

[0185] The E97D_del18 mutant and IdeS were coated onto microplates overnight, then washed with PBST and blocked in 2% BSA blocking buffer for 1 hour. A mixed plate was prepared with serially diluted test mutants, IdeS, and human serum. The plate was incubated with shaking at room temperature for 1 hour. After washing with PBST, biotinylated E97D_del18 mutant and IdeS were added, followed by SA-HRP, and color development with TMB and reading. The presence of pre-existing antibodies to E97D_del18 and IdeS in approximately 80 human blood samples was compared in parallel.

[0186] The results, as shown in Table 9, showed that the proportion of pre-existing antibodies to IdeS in normal human serum was as high as approximately 90%, while that to the E97D_del18 mutant was only approximately 20%. The E97D_del18 mutant produced significantly fewer pre-existing antibodies in vivo than IdeS, demonstrating that the E97D_del18 mutant is less immunogenic and more suitable for in vivo administration.

[0187] Table 9. Comparison of pre-existing antibodies against E97D_del18 mutant and IdeS in human blood samples

[0188] E97D_del18 mutant IdeS Total number of human blood samples (cases) 76 76 Proportion of pre-existing antibody positive samples (%) 18.4 89.5

[0189] Example 9. In vivo detection of the activity of the E97D_del18 mutant in cleaving human IgG1

[0190] Under sterile conditions, two mice (two mice were used in parallel, mice numbered 1 and 2) were intraperitoneally injected with human IVIg (intravenous human immunoglobulin) at a dose of 1 g / kg. Twenty-four hours after IVIg injection, IgG degrading enzyme (E97D_del18) was intravenously injected at a dose of 5 mg / kg. Serum samples were collected from both mice at 0, 15, 2, 6, and 24 hours after E97D del18 injection. Twenty microliters of serum sample was mixed with an equal volume of 2× SDS non-reducing loading buffer, diluted 20-fold with 1× SDS non-reducing loading buffer, and analyzed by SDS-PAGE. Serum samples were incubated at 75°C for 5 minutes before analysis.

[0191] Figure 13 The electrophoresis images of the cleavage products produced by E97D_del18 at different times during in vivo cleavage of human IVIg in mice are shown. The results show that E97D_del18 is highly effective in cleaving IVIg in mice, achieving near-complete cleavage within 15 minutes.

[0192] Example 10. Immunoglobulin degrading enzyme effectively eliminates the negative impact of high immunoglobulin on the anti-tumor effect of monoclonal antibodies ring

[0193] The Daudi mouse model was used to evaluate the efficacy of KJ103 against CD38 monoclonal antibodies. Four groups were designed: 1) solvent control; 2) anti-CD38 monoclonal antibody; 3) anti-CD38 monoclonal antibody + IVIg; and 4) anti-CD38 monoclonal antibody + immunoglobulin degrading enzyme + IVIg. Specifically, cells were collected from logarithmically growing mice and inoculated subcutaneously. Each CB-17 SCID mouse was inoculated subcutaneously in the right axilla under sterile conditions with 5×10 6 Daudi cells were inoculated with 0.1 mL / cell. A single intraperitoneal injection of 1 g / kg IVIg was administered on the day of cell inoculation. Twenty-four hours later, a single intravenous injection of 5 mg / kg of the immunoglobulin degrading enzyme E97D_del18 was given. Ten days after IVIg administration, 10 mg / kg of anti-CD38 monoclonal antibody was administered intraperitoneally, once weekly for a total of four doses. Following the initiation of CD38 administration, tumor volume was measured twice weekly for a total of four weeks.

[0194] The experimental results show that ( Figure 14 The presence of IgG (IVIg) can inhibit the efficacy of anti-CD38 monoclonal antibodies in treating tumors. Immunoglobulin degrading enzymes can reduce the inhibitory effect of IgG on the efficacy of antibodies and enhance the therapeutic effect of therapeutic antibodies.

[0195] The applicant states that the present invention is intended to illustrate the detailed methods of the present invention through the above-described embodiments, but the present invention is not limited to the above-described detailed methods, that is, it does not mean that the present invention must rely on the above-described detailed methods in order to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions for various raw materials in the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., are all within the scope of protection and disclosure of the present invention. SEQUENCE LISTING <110> Shanghai Baoji Pharmaceutical Co., Ltd. <120> A drug combination and its application <130> P20014925C <160> 60 <170> PatentIn version 3.5 <210> 1 <211> 339 <212> PRT <213> Artificial Sequence <220> <223> IdeS <400> 1 Met Arg Lys Arg Cys Tyr Ser Thr Ser Ala Ala Val Leu Ala Ala Val 1 5 10 15 Thr Leu Phe Val Leu Ser Val Asp Arg Gly Val Ile Ala Asp Ser Phe 20 25 30 Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro Tyr His Val 35 40 45 Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn Phe Thr Gln 50 55 60 Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln Gly Trp Tyr 65 70 75 80 Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu Cys Gly Ala 85 90 95 Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn Lys Asp 100 105 110 Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln Lys Ile Asn 115 120 125 Phe Asn Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile Asp Thr Lys 130 135 140 Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys Glu Lys Ala 145 150 155 160 Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro Asp His Val 165 170 175 Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr Asn His Gly 180 185 190 Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly Gly Ile Phe 195 200 205 Asp Ala Val Phe Thr Arg Gly Asp Gln Ser Lys Leu Leu Thr Ser Arg 210 215 220 His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp Leu Ile Lys 225 230 235 240 Lys Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu Ser His Thr Tyr Ala 245 250 255 Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala Asp Phe Asp 260 265 270 Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser Asp Ser Asn 275 280 285 Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn Ser Ala Gly 290 295 300 Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn Ile Gly Ala 305 310 315 320 Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp Ser Trp Asn 325 330 335 Gln Thr Asn <210> 2 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> IdeZ <400> 2 Met Lys Thr Ile Ala Tyr Pro Asn Lys Pro His Ser Leu Ser Ala Gly 1 5 10 15 Leu Leu Thr Ala Ile Ala Ile Phe Ser Leu Ala Ser Ser Asn Ile Thr 20 25 30 Tyr Ala Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu 35 40 45 Val Pro His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu 50 55 60 Thr Pro Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro 65 70 75 80 Tyr Leu Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly 85 90 95 Lys Asp Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His 100 105 110 Trp Trp Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys 115 120 125 His Pro Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp 130 135 140 Leu Lys Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu 145 150 155 160 Phe Asn Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln 165 170 175 Leu Gly Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr 180 185 190 Tyr Leu Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr 195 200 205 Gln Asp Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg 210 215 220 Gly Asp Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys 225 230 235 240 Gly Leu Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly 245 250 255 Arg Ala Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His 260 265 270 Val Ile Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu 275 280 285 Ala Ile Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys 290 295 300 Lys Tyr Phe Val Gly Ile Asn Ala His Gly His Val Ala Ile Ser Ala 305 310 315 320 Lys Lys Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe 325 330 335 Thr Leu Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 340 345 <210> 3 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> IdeZ <400> 3 Met Lys Thr Ile Ala Tyr Pro Asn Lys Pro His Ser Leu Ser Ala Gly 1 5 10 15 Leu Leu Thr Ala Ile Ala Ile Phe Ser Leu Ala Ser Ser Asn Ile Thr 20 25 30 Tyr Ala Asp Asp Tyr Gln Arg Asn Ala Ala Glu Val Tyr Ala Lys Glu 35 40 45 Val Pro His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu 50 55 60 Thr Pro Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro 65 70 75 80 Tyr Leu Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Val Phe Asp Gly 85 90 95 Lys Asp Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His 100 105 110 Trp Trp Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys 115 120 125 His Pro Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp 130 135 140 Leu Lys Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu 145 150 155 160 Phe Asn Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln 165 170 175 Leu Gly Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr 180 185 190 Tyr Leu Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr 195 200 205 Gln Asp Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg 210 215 220 Gly Asp Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys 225 230 235 240 Gly Leu Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly 245 250 255 Arg Ala Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His 260 265 270 Val Ile Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu 275 280 285 Ala Ile Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys 290 295 300 Lys Tyr Phe Val Gly Ile Asn Ala His Gly His Val Ala Ile Ser Ala 305 310 315 320 Lys Lys Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe 325 330 335 Thr Leu Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 340 345 <210> 4 <211> 392 <212> PRT <213> Artificial Sequence <220> <223> IdeZ2 <400> 4 Met Met Lys Lys Gln Ser Phe Thr His Ser Arg Lys Pro Lys Phe Gly 1 5 10 15 Met Arg Lys Leu Ser Ile Gly Leu Ala Ser Cys Met Leu Gly Met Met 20 25 30 Phe Leu Thr Thr Ser His Val Ser Gly Glu Val Val Glu Val Trp Pro 35 40 45 Tyr Gly Gln Asp Pro Asn Asp Lys Ile Glu Val Leu Ser Gln Ser Glu 50 55 60 Tyr Ser Glu Tyr Leu Gln Arg Leu His Asp Val Glu Asp Phe Gln Ala 65 70 75 80 Glu Lys Lys Lys Glu Gly Val Val Arg Thr Gln Trp Leu Glu Gly Val 85 90 95 Asn Val Thr Asp His Asp Phe Arg Lys Ile Thr Asp Gly Gly Ser Val 100 105 110 Tyr Tyr Ala Thr Pro Leu Leu Asn Asp Arg Gly Tyr Tyr Asp Ile Asn 115 120 125 Lys Asn Phe Asn Gln Asp Ser Asp Lys Cys Ala Ala Ala Val Ala Val 130 135 140 Asn Met Phe His Tyr Trp Leu Asp Arg Asn Lys Asp Asn Val Ala Lys 145 150 155 160 Phe Leu Ser Gln Ser Pro Asp His Gly Phe Val Glu Gly Glu Pro Thr 165 170 175 Phe Asn Leu Val Asp Phe Gln Tyr Thr Tyr Ala Ser Pro Tyr Glu Glu 180 185 190 Gly Gly Tyr Arg Asp Asn Ser Lys Leu Phe Asp Phe Ile Ser Lys Ala 195 200 205 Phe Asn Lys Pro Leu Trp Ala Asn Lys Leu Leu Asp Ala Tyr Ile Asn 210 215 220 Gly Tyr Gly Tyr Ile Asp Arg Tyr Val Lys Asn Thr Pro His Ser Gly 225 230 235 240 Gln Asn Asn Ser Lys Phe Asn Phe Phe Lys Lys Val Phe Asp Gly Lys 245 250 255 Leu Leu Thr Asp Ile Gln Gln Ile Phe Asp Tyr Tyr Thr Leu Ser Ser 260 265 270 Glu Leu Arg Glu Ala Leu Asp Thr Gly Lys Ala Ile Gly Leu Ala Tyr 275 280 285 Gly Pro Gly Asp Leu Arg Arg Ser Leu Gly His Ile Ile Ser Val Trp 290 295 300 Gly Ala Asp Ile Asn Glu Asp Gly Asn Val Val Ala Ile Tyr Val Thr 305 310 315 320 Asp Ser Asp Asp Lys Lys Leu Thr Ile Gly Asn Lys Lys Asp Arg Ile 325 330 335 Gly Leu Lys Arg Tyr Lys Leu Tyr Ser Asp Asn Val Gly Arg Ala Arg 340 345 350 Leu Thr Ala Tyr Ala Thr Glu Asn Gln Gln Thr Gly Gly Glu Val Arg 355 360 365 Gly Ile Glu Thr Leu Asp Met Ala Thr Gln Asp Trp Ala Asp Tyr Phe 370 375 380 Ser Arg Thr Asp Glu Ala Glu Gln 385 390 <210> 5 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> IdeE <400> 5 Met Lys Thr Ile Ala Tyr Pro Asn Lys Pro His Ser Leu Ser Ala Gly 1 5 10 15 Leu Leu Thr Ala Ile Ala Ile Phe Ser Leu Ala Ser Ser Asn Ile Thr 20 25 30 Tyr Ala Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu 35 40 45 Val Pro His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu 50 55 60 Thr Pro Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro 65 70 75 80 Tyr Leu Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly 85 90 95 Lys Asp Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His 100 105 110 Trp Trp Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys 115 120 125 His Pro Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp 130 135 140 Leu Lys Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu 145 150 155 160 Phe Asn Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln 165 170 175 Leu Gly Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr 180 185 190 Tyr Leu Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr 195 200 205 Gln Asp Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg 210 215 220 Gly Asp Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys 225 230 235 240 Gly Leu Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly 245 250 255 Arg Ala Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His 260 265 270 Val Ile Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu 275 280 285 Ala Ile Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys 290 295 300 Lys Tyr Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala 305 310 315 320 Lys Lys Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe 325 330 335 Thr Leu Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 340 345 <210> 6 <211> 385 <212> PRT <213> Artificial Sequence <220> <223> IdeE2 <400> 6 Met Met Lys Lys Gln Ser Phe Thr His Ser Arg Lys Pro Lys Phe Gly 1 5 10 15 Met Arg Lys Leu Ser Ile Gly Leu Ala Ser Cys Met Leu Gly Met Met 20 25 30 Phe Leu Thr Thr Gly His Val Ser Gly Glu Val Val Glu Val Trp Pro 35 40 45 Asn Gly Gln Asn Pro Asn Gly Lys Ile Glu Ile Leu Ser Gln Thr Glu 50 55 60 His Ser Glu His Leu Gln Lys Leu Arg Asp Ile Glu Asp Phe Gln Ala 65 70 75 80 Gln Lys Gln Ala Asp His Val Arg Tyr Thr Lys Trp Leu Asp Gly Val 85 90 95 Thr Val Asp Glu His Glu Phe Arg Lys Ile Lys Glu Tyr Asp Thr Glu 100 105 110 Tyr Tyr Val Thr Pro Leu Leu Ser Gly Lys Gly Tyr Tyr Asp Ile Asn 115 120 125 Lys Asp Phe Asn Gln Asp Ser Asp Lys Cys Ala Ala Ala Val Ala Ala 130 135 140 Asn Met Phe His Tyr Trp Phe Asp Arg Asn Arg Asp Ser Ile Asn Arg 145 150 155 160 Phe Leu Ser Gln Ser Pro Gly Glu Asn Gly Val Ile Lys Leu Glu Asn 165 170 175 Glu Lys Thr Ile Glu Val Ser Lys Phe Leu Glu Thr Tyr Arg Ser Asp 180 185 190 Gly Asp Tyr Leu Asp Lys Ser Pro Phe Phe Asp Leu Ile Ser Asn Ser 195 200 205 Phe Lys Gly Pro Val Trp Ala Asn Lys Leu Leu Asp Ala Tyr Ile Asn 210 215 220 Gly Tyr Gly Tyr Ile His Lys Phe Ala Lys Asn Thr Pro His Ser Lys 225 230 235 240 Asn Asn Asn Ser Lys Phe Asn Phe Phe Lys Lys Val Phe Asp Gly Asn 245 250 255 Leu Leu Thr Asp Ile His Gln Ile Phe Asp Tyr Asn Thr Phe Ser Asp 260 265 270 Lys Leu Ser Glu Ala Leu Tyr Thr Gly Lys Ala Ile Gly Leu Ala Tyr 275 280 285 Gly Pro Gly Asp Leu Arg Arg Ser Leu Gly His Ile Ile Ser Val Trp 290 295 300 Gly Ala Asp Leu Asp Asp Gln Asn Arg Val Val Ala Ile Tyr Val Thr 305 310 315 320 Asp Ser Asp Asp Lys Lys Leu Thr Ile Gly Asn Glu Arg Val Gly Leu 325 330 335 Lys Arg Tyr Lys Val Ser Ser Asp Asp Gln Gly Arg Ala Arg Leu Thr 340 345 350 Thr Arg Asp Lys Asp Asn Thr Gly Gly Glu Ile Arg Ser Ile Glu Thr 355 360 365 Leu Asp Met Gly Thr Gln Glu Trp Ala Asp Tyr Phe Asn Lys Thr Glu 370 375 380 Lys 385 <210> 7 <211> 372 <212> PRT <213> Artificial Sequence <220> <223> IdeP <400> 7 Met Asn Lys Lys Asn Ser Lys Gly Leu Pro Arg Tyr Phe Arg Ile Ser 1 5 10 15 Ala Arg Thr Leu Leu Leu Gly Ala Leu Leu Ser Gly Gly Leu Leu Ser 20 25 30 Val Pro Glu Lys Ala His Ala Asp Asn Arg Ser Ala Ser Thr Ile Ser 35 40 45 Val Ser Ile Asp Ser Asn Gln Asn Glu Thr Asn Leu Val Thr Ala Glu 50 55 60 Asn Val Gln Thr Ala Asn Leu Ser Asp Pro Asp Thr Lys Val Asn Thr 65 70 75 80 Val Trp Thr Ala Gly Met Ser Glu Leu Asp Thr Lys Gln Phe Thr Pro 85 90 95 His Pro Asp Gly Phe Leu His Tyr Pro Tyr Gln Ser Asn Gln Gly Trp 100 105 110 Tyr Asn Ile Thr Lys Ser Phe Asn Gly Arg Asp Asn Leu Leu Cys Ala 115 120 125 Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn Lys 130 135 140 Glu Gln Ile Asp Arg Tyr Leu Lys Glu His Pro Glu Lys Ala Asn Ile 145 150 155 160 Ser Phe Arg Gly Glu Asn Phe Leu Ser Ile Lys Glu Leu Ile Asn Thr 165 170 175 Lys Gly Lys Gln Lys Asp Ser Ala Leu Phe Thr Tyr Phe Gln Glu Lys 180 185 190 Ala Phe Pro Asp Ile Ser Arg Arg Asn Thr Gly Leu Ile Val Asp Arg 195 200 205 Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Ser Ile Asn Asp Leu 210 215 220 Ser Glu Thr Asn Thr Ser Asn Thr Arg Lys Asp Asn Arg Gly Gly Val 225 230 235 240 Phe Asp His Val Phe Gly Arg Gly Asp Ser His Lys Lys Leu Thr Ser 245 250 255 Arg Tyr Glu Leu Gln Asp Gln Ser Ile Glu Glu Ile Gly Gln Leu Ile 260 265 270 Arg Arg Glu Leu Glu Ala Gly Lys Ala Leu Ala Ile Ser Tyr Thr Tyr 275 280 285 Ala Ser Ile Gly Met Ala His Val Val Asn Leu Trp Gly Ala Asp Phe 290 295 300 Asp Gln Ala Gly Gln Leu Val Ala Ile Tyr Val Ala Asp Ser Asp Asn 305 310 315 320 Ser Thr Asp Val Gly Met Lys Lys Tyr Tyr Val Gly Lys Asn Lys Glu 325 330 335 Gly His Val Ala Ile Ser Ala Gln Lys Val Glu Gly Asp Val Leu Gly 340 345 350 Ser Arg Leu Leu Arg Leu Gly Ser Leu Ser Ser Gly Lys Asp Met Trp 355 360 365 Pro Ala Gln Tyr 370 <210> 8 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART152 <400> 8 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Arg Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Lys Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 9 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART183 <400> 9 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Lys Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Arg Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Lys Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 10 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART184 <400> 10 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Arg Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Lys Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Lys Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Lys Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 11 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART185 <400> 11 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Arg Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Asn Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Lys Glu Leu Asp Glu Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 12 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART186 <400> 12 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Lys Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Asn Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Arg Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Lys Glu Leu Glu Glu Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Lys Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 13 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART187 <400> 13 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Glu Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Asn Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Glu Glu Leu Thr Lys Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Lys Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Lys 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 14 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART188 <400> 14 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Lys Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Arg Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Arg Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Ser Glu Leu Glu Asn Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Lys Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 15 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART189 <400> 15 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Lys Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Arg Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Arg Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Lys Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Lys Glu Leu Glu Glu Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 16 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART190 <400> 16 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Glu Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Arg Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Lys Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Glu Glu Leu Thr Lys Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Lys 290 295 300 Ser Trp Asn Gln Thr Asn 305 310 <210> 17 <211> 306 <212> PRT <213> Artificial Sequence <220> <223> pCART209 <400> 17 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Asn Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Lys Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp 305 <210> 18 <211> 290 <212> PRT <213> Artificial Sequence <220> <223> pCART125 <400> 18 Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn Phe Thr Gln Gly 1 5 10 15 Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln Gly Trp Tyr Asp 20 25 30 Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu Cys Gly Ala Ala 35 40 45 Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn Lys Asp Gln 50 55 60 Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln Lys Ile Asn Phe 65 70 75 80 Asn Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile Asp Thr Lys Asn 85 90 95 His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys Glu Lys Ala Phe 100 105 110 Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro Asp His Val Ile 115 120 125 Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr Asn His Gly Pro 130 135 140 Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly Gly Ile Phe Asp 145 150 155 160 Ala Val Phe Thr Arg Gly Asp Gln Ser Lys Leu Leu Thr Ser Arg His 165 170 175 Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp Leu Ile Lys Lys 180 185 190 Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu Ser His Thr Tyr Ala Asn 195 200 205 Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala Asp Phe Asp Ser 210 215 220 Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser Asp Ser Asn Ala 225 230 235 240 Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn Ser Ala Gly Lys 245 250 255 Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn Ile Gly Ala Gln 260 265 270 Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp Ser Trp Asn Gln 275 280 285 Thr Asn 290 <210> 19 <211> 290 <212> PRT <213> Artificial Sequence <220> <223> pCART213 <400> 19 Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn Phe Thr Gln Gly 1 5 10 15 Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln Gly Trp Tyr Asp 20 25 30 Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu Cys Gly Ala Ala 35 40 45 Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn Lys Asp Gln 50 55 60 Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln Lys Ile Asn Phe 65 70 75 80 Lys Gly Glu Gln Met Phe Asp Val Lys Glu Ala Ile Asp Thr Lys Asn 85 90 95 His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys Glu Lys Ala Phe 100 105 110 Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro Asp His Val Ile 115 120 125 Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr Asn His Gly Pro 130 135 140 Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly Gly Ile Phe Asp 145 150 155 160 Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu Thr Ser Arg His 165 170 175 Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp Leu Ile Lys Lys 180 185 190 Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu Ser His Thr Tyr Ala Asn 195 200 205 Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala Asp Phe Asp Ser 210 215 220 Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser Asp Ser Asn Ala 225 230 235 240 Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn Ser Ala Gly Lys 245 250 255 Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn Ile Gly Ala Gln 260 265 270 Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp Ser Trp Asn Gln 275 280 285 Thr Asn 290 <210> 20 <211> 290 <212> PRT <213> Artificial Sequence <220> <223> pCART214 <400> 20 Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn Phe Thr Gln Gly 1 5 10 15 Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln Gly Trp Tyr Asp 20 25 30 Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu Cys Gly Ala Ala 35 40 45 Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn Lys Asp Gln 50 55 60 Ile Glu Arg Tyr Leu Glu Glu His Pro Glu Lys Gln Lys Ile Asn Phe 65 70 75 80 Lys Gly Glu Gln Met Phe Asp Val Lys Lys Ala Ile Asp Thr Lys Asn 85 90 95 His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys Glu Lys Ala Phe 100 105 110 Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro Asp His Val Ile 115 120 125 Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr Asn His Gly Pro 130 135 140 Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly Gly Ile Phe Asp 145 150 155 160 Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu Thr Ser Arg His 165 170 175 Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp Leu Ile Lys Glu 180 185 190 Glu Leu Thr Lys Gly Lys Ala Leu Gly Leu Ser His Thr Tyr Ala Asn 195 200 205 Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala Asp Phe Asp Ser 210 215 220 Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser Asp Ser Asn Ala 225 230 235 240 Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn Ser Ala Gly Lys 245 250 255 Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn Ile Gly Ala Gln 260 265 270 Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Lys Ser Trp Asn Gln 275 280 285 Thr Asn 290 <210> 21 <211> 319 <212> PRT <213> Artificial Sequence <220> <223> pCART228 <400> 21 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Ala Asn 20 25 30 Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Glu Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Lys Gly Glu Gln Met Phe Asp Val Lys Lys Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile Ser Asp 195 200 205 Leu Ile Lys Glu Glu Leu Thr Lys Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asp Ser Asn Gly Asn Leu Lys Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ser Ala Gly Lys Val Ala Ile Ser Ala Lys Glu Ile Lys Glu Asp Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Lys 290 295 300 Ser Trp Asn Gln Thr Asn Gly Gly Gly His His His His His His 305 310 315 <210> 22 <211> 313 <212> PRT[[ID=3x]] <213> Artificial Sequence <220> <223> Sequence of hybrid IdeS / Z <400> 22 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Phe His Ala Pro Tyr Val 35 40 45 Ala Asn Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro 85 90 95 Glu Lys Gln Lys Ile Asn Phe Asn Gly Asp Asn Met Phe Asp Val Lys 100 105 110 Lys Ala Ile Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Asn 115 120 125 Tyr Phe Lys Glu Lys Ala Phe Pro Gly Leu Ser Ala Arg Arg Ile Gly 130 135 140 Val Phe Pro Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu 145 150 155 160 Ser Leu Thr Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp 165 170 175 Pro Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser 180 185 190 Lys Leu Leu Thr Ser Arg His Asp Phe Lys Asn Lys Asn Leu Asn Asp 195 200 205 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Lys Gly Lys Ala Leu Gly 210 215 220 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Asn His Val Ile Asn Leu 225 230 235 240 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 245 250 255 Thr Asp Ser Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 260 265 270 Gly Val Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu 275 280 285 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr 290 295 300 Gly Gln Asp Ser Trp Gln Lys Leu Ser 305 310 <210> 23 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> pCART197 <400> 23 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala Asn Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Arg Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Glu Ala Ile Arg Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Glu 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Tyr Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Lys Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Glu Glu Leu Thr Lys Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Lys His Gly His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Asn 305 310 315 <210> 24 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> pCART198 <400> 24 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Glu Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Lys Glu Lys Ala Phe Pro Asn Leu Ser Thr Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Phe Lys Glu Lys Gly Leu 195 200 205 Lys Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asp Ala Glu Gly Asn Leu Lys Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Gly Lys Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Gln Leu Ser 305 310 315 <210> 25 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> pCART200 <400> 25 Asp Ser Phe Ser Ala Asn Gln Glu Ile Arg Tyr Ser Glu Val Thr Pro 1 5 10 15 Tyr His Val Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 26 <211> 295 <212> PRT <213> Artificial Sequence <220> <223> pCART201 <400> 26 Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln Phe Arg 1 5 10 15 Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln Gly 20 25 30 Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu Cys 35 40 45 Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn 50 55 60 Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln Lys 65 70 75 80 Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile Asp 85 90 95 Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg Asp 100 105 110 Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro Asp 115 120 125 Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe Lys 130 135 140 Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys Arg 145 150 155 160 Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr Thr Leu 165 170 175 Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile Ser 180 185 190 Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu Ser 195 200 205 His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp Gly 210 215 220 Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr Asp 225 230 235 240 Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Ile 245 250 255 Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly Glu 260 265 270 Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly Lys 275 280 285 Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 27 <211> 314 <212> PRT <213> Artificial Sequence <220> <223> pCART202 <400> 27 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala 35 40 45 His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn 50 55 60 Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe 65 70 75 80 Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu 85 90 95 Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala 100 105 110 Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr 115 120 125 Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val 130 135 140 Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn 145 150 155 160 Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys 165 170 175 Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln 180 185 190 Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn 195 200 205 Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu 210 215 220 Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn 225 230 235 240 Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr 245 250 255 Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe 260 265 270 Val Gly Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile 275 280 285 Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser 290 295 300 Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 28 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART203 <400> 28 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 85 90 95 Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile 100 105 110 Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg 115 120 125 Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro 130 135 140 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 145 150 155 160 Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr Thr 180 185 190 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 290 295 300 Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 29 <211> 313 <212> PRT <213> Artificial Sequence <220> <223> pCART204 <400> 29 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 35 40 45 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 50 55 60 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 65 70 75 80 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 85 90 95 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 100 105 110 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 115 120 125 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 130 135 140 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 145 150 155 160 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 165 170 175 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 180 185 190 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 195 200 205 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 210 215 220 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 225 230 235 240 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 245 250 255 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 260 265 270 Gly Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu 275 280 285 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 290 295 300 Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 30 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART 206 <400> 30 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 85 90 95 Lys Ile Ile Ile Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile 100 105 110 Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg 115 120 125 Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro 130 135 140 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 145 150 155 160 Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr Thr 180 185 190 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 290 295 300 Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 31 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART207 <400> 31 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 85 90 95 Lys Ile Ile Phe Arg Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile 100 105 110 Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg 115 120 125 Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro 130 135 140 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 145 150 155 160 Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr Thr 180 185 190 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 290 295 300 Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 32 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART208 <400> 32 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 85 90 95 Lys Ile Ile Ile Arg Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile 100 105 110 Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg 115 120 125 Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro 130 135 140 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 145 150 155 160 Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr Thr 180 185 190 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 290 295 300 Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 33 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART210 <400> 33 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 85 90 95 Lys Ile Ile Phe Arg Asn Gln Glu Leu Phe Asp Leu Lys Glu Ala Ile 100 105 110 Arg Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Glu Tyr Phe Arg 115 120 125 Asp Lys Ala Phe Pro Tyr Leu Ser Ala Arg Gln Leu Gly Val Met Pro 130 135 140 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 145 150 155 160 Lys Thr Gln Ser Thr Asp Val Lys Arg Pro Tyr Gln Asp Lys Asp Lys 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Thr Thr 180 185 190 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Glu Glu Leu Thr Lys Gly Arg Ala Leu Ala Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Ile Asn Lys His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 290 295 300 Lys Asp Ile Trp Gln Lys Leu Asn 305 310 <210> 34 <211> 292 <212> PRT <213> Artificial Sequence <220> <223> pCART217 <400> 34 Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln Phe Thr Gln Gly 1 5 10 15 Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln Gly Trp Tyr Asp 20 25 30 Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu Cys Gly Ala Ala 35 40 45 Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn Lys Thr Glu 50 55 60 Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln Lys Ile Ile Phe 65 70 75 80 Arg Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile Asp Thr Lys Asp 85 90 95 Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg Asp Lys Ala Phe 100 105 110 Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro Asp Leu Val Leu 115 120 125 Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe Lys Thr Gln Ser 130 135 140 Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys Arg Gly Gly Ile 145 150 155 160 Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Thr Thr Leu Leu Thr Ala 165 170 175 Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile Ser Thr Ile Ile 180 185 190 Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu Ser His Thr Tyr 195 200 205 Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp Gly Ala Asp Phe 210 215 220 Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr Asp Ser Asp Ala 225 230 235 240 Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Ile Asn Ala His 245 250 255 Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly Glu Asn Ile Gly 260 265 270 Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly Lys Asp Ile Trp 275 280 285 Gln Lys Leu Ser 290 <210> 35 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART219 <400> 35 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Ala Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 85 90 95 Lys Ile Ile Phe Arg Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile 100 105 110 Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg 115 120 125 Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro 130 135 140 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 145 150 155 160 Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Thr Thr 180 185 190 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 290 295 300 Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 36 <211> 292 <212> PRT <213> Artificial Sequence <220> <223> pCART226 <400> 36 Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln Phe Thr Gln Gly 1 5 10 15 Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln Gly Trp Tyr Asp 20 25 30 Ile Thr Lys Ala Phe Asp Gly Ala Asp Asn Leu Leu Cys Gly Ala Ala 35 40 45 Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln Asn Lys Thr Glu 50 55 60 Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln Lys Ile Ile Phe 65 70 75 80 Arg Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile Asp Thr Lys Asp 85 90 95 Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg Asp Lys Ala Phe 100 105 110 Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro Asp Leu Val Leu 115 120 125 Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe Lys Thr Gln Ser 130 135 140 Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys Arg Gly Gly Ile 145 150 155 160 Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Thr Thr Leu Leu Thr Ala 165 170 175 Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile Ser Thr Ile Ile 180 185 190 Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu Ser His Thr Tyr 195 200 205 Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp Gly Ala Asp Phe 210 215 220 Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr Asp Ser Asp Ala 225 230 235 240 Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Ile Asn Ala His 245 250 255 Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly Glu Asn Ile Gly 260 265 270 Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly Lys Asp Ile Trp 275 280 285 Gln Lys Leu Ser 290 <210> 37 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART229 <400> 37 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 85 90 95 Lys Ile Ile Phe Arg Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile 100 105 110 Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg 115 120 125 Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro 130 135 140 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 145 150 155 160 Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Thr Thr 180 185 190 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Ile Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 290 295 300 Lys Asp Ile Trp Gln Lys Leu Ser 305 310 <210> 38 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCARTI91 <400> 38 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala 35 40 45 Asn Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn 50 55 60 Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe 65 70 75 80 Asp Gln Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu 85 90 95 Lys Gln Lys Ile Asn Phe Asn Gly Glu Asn Met Phe Asp Val Lys Lys 100 105 110 Ala Ile Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Asn Tyr 115 120 125 Phe Lys Glu Lys Ala Phe Pro Tyr Leu Ser Ala Lys His Leu Gly Val 130 135 140 Phe Pro Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser 145 150 155 160 Leu Thr Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys 180 185 190 Leu Leu Thr Ser Arg His Asp Phe Lys Asn Lys Asn Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Gln Glu Leu Thr Lys Gly Lys Ala Leu Gly Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Val Asn Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly 290 295 300 Gln Asp Ser Trp Gln Lys Leu Ser 305 310 <210> 39 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART192 <400> 39 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala 35 40 45 Asn Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn 50 55 60 Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe 65 70 75 80 Asp Gln Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu 85 90 95 Lys Gln Lys Ile Asn Phe Arg Gly Glu Asn Met Phe Asp Val Lys Glu 100 105 110 Ala Ile Arg Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr 115 120 125 Phe Lys Glu Lys Ala Phe Pro Tyr Leu Ser Ala Lys His Leu Gly Val 130 135 140 Phe Pro Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser 145 150 155 160 Leu Thr Asn His Gly Pro Thr Pro Val Lys Lys Gly Ser Lys Asp Pro 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys 180 185 190 Leu Leu Thr Ser Arg His Asp Phe Lys Asn Lys Asn Leu Asn Asp Ile 195 200 205 Ser Thr Ile Ile Lys Ser Glu Leu Thr Asn Gly Lys Ala Leu Gly Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Val Asn Lys His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly 290 295 300 Gln Asp Ser Trp Gln Lys Leu Asn 305 310 <210> 40 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCARTI93 <400> 40 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala 35 40 45 Asn Gln Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp 50 55 60 Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe 65 70 75 80 Asp Gln Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu 85 90 95 Lys Gln Lys Ile Asn Phe Asn Gly Glu Gln Met Phe Asp Val Lys Glu 100 105 110 Ala Ile Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr 115 120 125 Phe Lys Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val 130 135 140 Phe Pro Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser 145 150 155 160 Leu Thr Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys 180 185 190 Leu Leu Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile 195 200 205 Ser Asp Leu Ile Lys Gln Glu Leu Thr Glu Gly Lys Ala Leu Gly Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asp Ala Glu Gly Asn Leu Lys Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Val Asn Ala Ala Gly Lys Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly 290 295 300 Gln Asp Ser Trp Asn Gln Thr Ser 305 310 <210> 41 <211> 312 <212> PRT <213> Artificial Sequence <220> <223> pCART194 <400> 41 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Thr Gln Gly Glu Asp Val Phe His Ala Pro Tyr Val Ala 35 40 45 Asn Gln Gly Trp Tyr Asp Ile Thr Lys Thr Phe Asn Gly Lys Asp Asp 50 55 60 Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe 65 70 75 80 Asp Gln Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu 85 90 95 Lys Gln Lys Ile Asn Phe Arg Gly Glu Gln Met Phe Asp Val Lys Glu 100 105 110 Ala Ile Arg Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Glu Tyr 115 120 125 Phe Lys Glu Lys Ala Phe Pro Tyr Leu Ser Thr Lys His Leu Gly Val 130 135 140 Phe Pro Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser 145 150 155 160 Leu Thr Asn His Gly Pro Thr Pro Val Lys Lys Gly Ser Lys Asp Pro 165 170 175 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys 180 185 190 Leu Leu Thr Ser Arg His Asp Phe Lys Glu Lys Asn Leu Lys Glu Ile 195 200 205 Ser Asp Leu Ile Lys Glu Glu Leu Thr Lys Gly Lys Ala Leu Gly Leu 210 215 220 Ser His Thr Tyr Ala Asn Val Arg Ile Asn His Val Ile Asn Leu Trp 225 230 235 240 Gly Ala Asp Phe Asp Ala Glu Gly Asn Leu Lys Ala Ile Tyr Val Thr 245 250 255 Asp Ser Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 260 265 270 Val Asn Lys Ala Gly Lys Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 275 280 285 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly 290 295 300 Gln Asp Ser Trp Asn Gln Thr Asn 305 310 <210> 42 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> pCART205 <400> 42 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Pro Glu Gln 20 25 30 Phe Thr Gln Gly Glu Asp Val Ile His Ala Pro Tyr Val Ala Asn Gln 35 40 45 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 50 55 60 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 65 70 75 80 Asn Lys Asp Gln Ile Lys Arg Tyr Leu Glu Glu His Pro Glu Lys Gln 85 90 95 Lys Ile Asn Phe Arg Gly Glu Gln Met Phe Asp Val Lys Lys Ala Ile 100 105 110 Asp Thr Lys Asn His Gln Leu Asp Ser Lys Leu Phe Asn Tyr Phe Lys 115 120 125 Glu Lys Ala Phe Pro Gly Leu Ser Ala Arg Arg Ile Gly Val Phe Pro 130 135 140 Asp His Val Ile Asp Met Phe Ile Asn Gly Tyr Arg Leu Ser Leu Thr 145 150 155 160 Asn His Gly Pro Thr Pro Val Lys Glu Gly Ser Lys Asp Pro Arg Gly 165 170 175 Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asn Gln Ser Lys Leu Leu 180 185 190 Thr Ser Arg His Asp Phe Lys Asn Lys Asn Leu Asn Asp Ile Ser Thr 195 200 205 Ile Ile Lys Gln Glu Leu Thr Lys Gly Lys Ala Leu Gly Leu Ser His 210 215 220 Thr Tyr Ala Asn Val Ser Ile Asn His Val Ile Asn Leu Trp Gly Ala 225 230 235 240 Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr Asp Ser 245 250 255 Asp Ser Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly Val Asn 260 265 270 Ala His Gly His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly Glu Asn 275 280 285 Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Thr Gly Gln Asp 290 295 300 Ser Trp Gln Lys Leu Ser 305 310 <210> 43 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR1 <400> 43 Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala 1 5 10 <210> 44 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR2 <400> 44 Asp Ala Ser Asn Arg Ala Thr 1 5 <210> 45 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR3 <400> 45 Gln Gln Arg Ser Asn Trp Pro Pro Thr Phe 1 5 10 <210> 46 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain CDR1 <400> 46 Ser Phe Ala Met Ser 1 5 <210> 47 <211> 17 <212> PRT <213> Artificial Sequence <220><000已582><223> Heavy chain CDR2 <400> 47 Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 48 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain CDR3 <400> 48 Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr 1 5 10 <210> 49 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR1 <400> 49 Lys Ala Ser Gln Asp Val Ser Thr Val Val Ala 1 5 10 <210> 50 [[ID=3�]]<211> 7 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR2 <400> 50 Ser Ala Ser Tyr Arg Tyr Ile 1 5 <210> 51 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR3 <400> 51 Gln Gln His Tyr Ser Pro Pro Tyr Thr 1 5 <210> 52 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain CDR1 <400> 52 Asp Tyr Trp Met Gln 1 5 <210> 53 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain CDR2 <400> 53 Thr Ile Tyr Pro Gly Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 54 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain CDR3 <400> 54 Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr 1 5 10 <210> 55 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region <400> 55 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 56 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region <400> 56 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asn Ser Phe 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Gly 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 Phe Cys 85 90 95 Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 <210> 57 <211> 108<00​​​​​​​​​​​​​​​​​​​​​​​​​​Ser Gly Ala Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 58 <211> 94 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region <400> 58 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Ala Lys Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Lys Thr Val Tyr 65 70 75 80 Met His Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr 85 90 <210> 59 <211> 173 <212> PRT <213> Artificial Sequence <220> <223> MMP3 <400> 59 Phe Arg Thr Phe Pro Gly Ile Pro Lys Trp Arg Lys Thr His Leu Thr 1 5 10 15 Tyr Arg Ile Val Asn Tyr Thr Pro Asp Leu Pro Lys Asp Ala Val Asp 20 25 30 Ser Ala Val Glu Lys Ala Leu Lys Val Trp Glu Glu Val Thr Pro Leu 35 40 45 Thr Phe Ser Arg Leu Tyr Glu Gly Glu Ala Asp Ile Met Ile Ser Phe 50 55 60 Ala Val Arg Glu His Gly Asp Phe Tyr Pro Phe Asp Gly Pro Gly Asn 65 70 75 80 Val Leu Ala His Ala Tyr Ala Pro Gly Pro Gly Ile Asn Gly Asp Ala 85 90 95 His Phe Asp Asp Asp Glu Gln Trp Thr Lys Asp Thr Thr Gly Thr Asn 100 105 110 Leu Phe Leu Val Ala Ala His Glu Ile Gly His Ser Leu Gly Leu Phe 115 120 125 His Ser Ala Asn Thr Glu Ala Leu Met Tyr Pro Leu Tyr His Ser Leu 130 135 140 Thr Asp Leu Thr Arg Phe Arg Leu Ser Gln Asp Asp Ile Asn Gly Ile 145 150 155 160 Gln Ser Leu Tyr Gly Pro Pro Pro Asp Ser Pro Glu Thr 165 170 <210> 60 <211> 172 <212> PRT <213> Artificial Sequence <220> <223> MMP12 <400> 60 Phe Arg Glu Met Pro Gly Gly Pro Val Trp Arg Lys His Tyr Ile Thr 1 5 10 15 Tyr Arg Ile Asn Asn Tyr Thr Pro Asp Met Asn Arg Glu Asp Val Asp 20 25 30 Tyr Ala Ile Arg Lys Ala Phe Gln Val Trp Ser Asn Val Thr Pro Leu 35 40 45 Lys Phe Ser Lys Ile Asn Thr Gly Met Ala Asp Ile Leu Val Val Phe 50 55 60 Ala Arg Gly Ala His Gly Asp Phe His Ala Phe Asp Gly Lys Gly Gly 65 70 75 80 Ile Leu Ala His Ala Phe Gly Pro Gly Ser Gly Ile Gly Gly Asp Ala 85 90 95 His Phe Asp Glu Asp Glu Phe Trp Thr Thr His Ser Gly Gly Thr Asn 100 105 110 Leu Phe Leu Thr Ala Val His Glu Ile Gly His Ser Leu Gly Leu Gly 115 120 125 His Ser Ser Asp Pro Lys Ala Val Met Phe Pro Thr Tyr Lys Tyr Val 130 135 140 Asp Ile Asn Thr Phe Arg Leu Ser Ala Asp Asp Ile Arg Gly Ile Gln 145 150 155 160 Ser Leu Tyr Gly Asp Pro Lys Glu Asn Gln Arg Leu 165 170 <210> 61 <211> 349 <212> PRT <213> Artificial Sequence <220> <223> Full sequence of IdeE <400> 61 Met Lys Thr Ile Ala Tyr Pro Asn Lys Pro His Ser Leu Ser Ala Gly 1 5 10 15 Leu Leu Thr Ala Ile Ala Ile Phe Ser Leu Ala Ser Ser Asn Ile Thr 20 25 30 Tyr Ala Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu 35 40 45 Val Pro His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu 50 55 60 Thr Pro Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro 65 70 75 80 Tyr Leu Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly 85 90 95 Lys Asp Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His 100 105 110 Trp Trp Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys 115 120 125 His Pro Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp 130 135 140 Leu Lys Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu 145 150 155 160 Phe Asn Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln 165 170 175 Leu Gly Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr 180 185 190 Tyr Leu Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr 195 200 205 Gln Asp Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg 210 215 220 Gly Asp Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys 225 230 235 240 Gly Leu Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly 245 250 255 Arg Ala Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His 260 265 270 Val Ile Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu 275 280 285 Ala Ile Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys 290 295 300 Lys Tyr Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala 305 310 315 320 Lys Lys Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe 325 330 335 Thr Leu Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 340 345 <210> 62 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> IdeE sequence <400> 62 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 63 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> T8D <400> 63 Asp Asp Tyr Gln Arg Asn Ala Asp Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 64 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> T8E <400> 64 Asp Asp Tyr Gln Arg Asn Ala Glu Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 65 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> T8W <400> 65 Asp Asp Tyr Gln Arg Asn Ala Trp Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 66 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> T8Y <400> 66 Asp Asp Tyr Gln Arg Asn Ala Tyr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 67 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> A10K <400> 67 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Lys Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 68 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> A10R <400> 68 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Arg Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 69 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> T24A <400> 69 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Ala Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 70 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> T24G <400> 70 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Gly Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 71 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> T24S <400> 71 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Ser Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 72 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> A59I <400> 72 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ile Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 73 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> A59L <400> 73 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Leu Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 74 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> A59V <400> 74 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Val Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 75 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> E97D <400> 75 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Asp Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 76 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> R280H <400> 76 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His His His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 77 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> R280K <400> 77 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Lys His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315 <210> 78 <211> 300 <212> PRT <213> Artificial Sequence <220> <223> WT_del15 <400> 78 Pro His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr 1 5 10 15 Pro Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr 20 25 30 Leu Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys 35 40 45 Asp Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp 50 55 60 Trp Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His 65 70 75 80 Pro Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu 85 90 95 Lys Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe 100 105 110 Asn Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu 115 120 125 Gly Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr 130 135 140 Leu Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln 145 150 155 160 Asp Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly 165 170 175 Asp Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly 180 185 190 Leu Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg 195 200 205 Ala Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val 210 215 220 Ile Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala 225 230 235 240 Ile Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys 245 250 255 Tyr Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys 260 265 270 Lys Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr 275 280 285 Leu Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 300 <210> 79 <211> 299 <212> PRT <213> Artificial Sequence <220> <223> WT_del16 <400> 79 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 1 5 10 15 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 20 25 30 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 35 40 45 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 50 55 60 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 65 70 75 80 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 85 90 95 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 100 105 110 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 115 120 125 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 130 135 140 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 145 150 155 160 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 165 170 175 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 180 185 190 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 195 200 205 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 210 215 220 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 225 230 235 240 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 245 250 255 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 260 265 270 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 275 280 285 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 80 <211> 298 <212> PRT <213> Artificial Sequence <220> <223> WT_del17 <400> 80 Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu 1 5 10 15 Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala 20 25 30 His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn 35 40 45 Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe 50 55 60 Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu 65 70 75 80 Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala 85 90 95 Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr 100 105 110 Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val 115 120 125 Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn 130 135 140 Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys 145 150 155 160 Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln 165 170 175 Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn 180 185 190 Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu 195 200 205 Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn 210 215 220 Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr 225 230 235 240 Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe 245 250 255 Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile 260 265 270 Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser 275 280 285 Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 81 <211> 297 <212> PRT <213> Artificial Sequence <220> <223> WT_del18 <400> 81 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 82 <211> 296 <212> PRT <213> Artificial Sequence <220> <223> WT_del19 <400> 82 Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln Phe 1 5 10 15 Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His Gln 20 25 30 Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu Leu 35 40 45 Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp Gln 50 55 60 Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys Gln 65 70 75 80 Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala Ile 85 90 95 Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe Arg 100 105 110 Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met Pro 115 120 125 Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val Phe 130 135 140 Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp Lys 145 150 155 160 Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr Thr 165 170 175 Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp Ile 180 185 190 Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala Leu 195 200 205 Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu Trp 210 215 220 Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val Thr 225 230 235 240 Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val Gly 245 250 255 Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu Gly 260 265 270 Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser Gly 275 280 285 Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 83 <211> 310 <212> PRT <213> Artificial Sequence <220> <223> WT_delC5 <400> 83 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile 305 310 <210> 84 <211> 305 <212> PRT <213> Artificial Sequence <220> <223> WT_delC10 <400> 84 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Glu Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser 305 <210> 85 <211> 297 <212> PRT <213> Artificial Sequence <220> <223> T24A_del18 <400> 85 Ile Thr Ser Val Trp Ala Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 86 <211> 297 <212> PRT <213> Artificial Sequence <220> <223> A59L_del18 <400> 86 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Leu Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 87 <211> 297 <212> PRT <213> Artificial Sequence <220> <223> A59V_del18 <400> 87 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Val Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 88 <211> 297 <212> PRT <213> Artificial Sequence <220> <223> E97D_del18 <400> 88 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Asp Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 89 <211> 297 <212> PRT <213> Artificial Sequence <220> <223> R280H_del18 <400> 89 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His His His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile Trp Gln Lys Leu Ser 290 295 <210> 90 <211> 292 <212> PRT <213> Artificial Sequence <220> <223> E97D_del18_delC5 <400> 90 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Asp Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile 290 <210> 91 <211> 287 <212> PRT <213> Artificial Sequence <220> <223> E97D_del18_delC10 <400> 91 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Asp Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser 275 280 285 <210> 92 <211> 292 <212> PRT <213> Artificial Sequence <220> <223> A59V_del18_delC5 <400> 92 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Val Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile 290 <210> 93 <211> 292 <212> PRT <213> Artificial Sequence <220> <223> A59L_del18_delC5 <400> 93 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Leu Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His Arg His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile 290 <210> 94 <211> 292 <212> PRT <213> Artificial Sequence <220> <223> R280H_del18_delC5 <400> 94 Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro Glu Gln 1 5 10 15 Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu Ala His 20 25 30 Gln Gly Trp Tyr Asp Ile Thr Lys Ala Phe Asp Gly Lys Asp Asn Leu 35 40 45 Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp Phe Asp 50 55 60 Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro Glu Lys 65 70 75 80 Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys Ala Ala 85 90 95 Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn Tyr Phe 100 105 110 Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly Val Met 115 120 125 Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu Asn Val 130 135 140 Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp Lys Asp 145 150 155 160 Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp Gln Thr 165 170 175 Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu Asn Asp 180 185 190 Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala Leu Ala 195 200 205 Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile Asn Leu 210 215 220 Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile Tyr Val 225 230 235 240 Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr Phe Val 245 250 255 Gly Ile Asn Ala His His His Val Ala Ile Ser Ala Lys Lys Ile Glu 260 265 270 Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu Ser Ser 275 280 285 Gly Lys Asp Ile 290 <210> 95 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> A59V / E97D / R280H <400> 95 Asp Asp Tyr Gln Arg Asn Ala Thr Glu Ala Tyr Ala Lys Glu Val Pro 1 5 10 15 His Gln Ile Thr Ser Val Trp Thr Lys Gly Val Thr Pro Leu Thr Pro 20 25 30 Glu Gln Phe Arg Tyr Asn Asn Glu Asp Val Ile His Ala Pro Tyr Leu 35 40 45 Ala His Gln Gly Trp Tyr Asp Ile Thr Lys Val Phe Asp Gly Lys Asp 50 55 60 Asn Leu Leu Cys Gly Ala Ala Thr Ala Gly Asn Met Leu His Trp Trp 65 70 75 80 Phe Asp Gln Asn Lys Thr Glu Ile Glu Ala Tyr Leu Ser Lys His Pro 85 90 95 Asp Lys Gln Lys Ile Ile Phe Asn Asn Gln Glu Leu Phe Asp Leu Lys 100 105 110 Ala Ala Ile Asp Thr Lys Asp Ser Gln Thr Asn Ser Gln Leu Phe Asn 115 120 125 Tyr Phe Arg Asp Lys Ala Phe Pro Asn Leu Ser Ala Arg Gln Leu Gly 130 135 140 Val Met Pro Asp Leu Val Leu Asp Met Phe Ile Asn Gly Tyr Tyr Leu 145 150 155 160 Asn Val Phe Lys Thr Gln Ser Thr Asp Val Asn Arg Pro Tyr Gln Asp 165 170 175 Lys Asp Lys Arg Gly Gly Ile Phe Asp Ala Val Phe Thr Arg Gly Asp 180 185 190 Gln Thr Thr Leu Leu Thr Ala Arg His Asp Leu Lys Asn Lys Gly Leu 195 200 205 Asn Asp Ile Ser Thr Ile Ile Lys Gln Glu Leu Thr Glu Gly Arg Ala 210 215 220 Leu Ala Leu Ser His Thr Tyr Ala Asn Val Ser Ile Ser His Val Ile 225 230 235 240 Asn Leu Trp Gly Ala Asp Phe Asn Ala Glu Gly Asn Leu Glu Ala Ile 245 250 255 Tyr Val Thr Asp Ser Asp Ala Asn Ala Ser Ile Gly Met Lys Lys Tyr 260 265 270 Phe Val Gly Ile Asn Ala His His His Val Ala Ile Ser Ala Lys Lys 275 280 285 Ile Glu Gly Glu Asn Ile Gly Ala Gln Val Leu Gly Leu Phe Thr Leu 290 295 300 Ser Ser Gly Lys Asp Ile Trp Gln Lys Leu Ser 305 310 315

Claims

1. A drug combination, comprising an immunoglobulin degrading enzyme and a protein containing Fc, wherein the drug combination is used to prepare a drug for treating hyperglobulinemia, wherein the immunoglobulin degrading enzyme is a variant of IdeE, wherein the variant has an amino acid deletion relative to SEQ ID NO: 5, and the amino acid deletion includes a deletion of the first 15 amino acids at the N-terminus, a deletion of the first 16 amino acids at the N-terminus, a deletion of the first 17 amino acids at the N-terminus, a deletion of the first 18 amino acids at the N-terminus, or a deletion of the first 19 amino acids at the N-terminus; and the protein containing Fc is a CD38-specific binding antibody; The variant is capable of reducing blood immunoglobulin levels to 60% or less of the original level; The variant is a mutant obtained by replacing at least one or more of positions 24, 59, 97 and 280 of the amino acid sequence of SEQ ID NO: 5; in, The threonine at position 24 is replaced with alanine; The alanine at position 59 is replaced with leucine or valine; The glutamic acid at position 97 is replaced by aspartic acid; The arginine at position 280 is replaced with histidine; The variant is produced by genetic engineering recombination.

2. The drug combination according to claim 1, wherein the amino acid deletion is the deletion of the first 18 amino acids at the N-terminus; and the replacement is replacing at least position 97 of the amino acid sequence of SEQ ID NO: 5 with aspartic acid.

3. The pharmaceutical combination according to claim 1, characterized in that The immunoglobulin degrading enzyme comprises an amino acid sequence as shown in any one of SEQ ID NOs: 85 to 94 or consists of the amino acid sequence.

4. The pharmaceutical combination according to claim 1, characterized in that It also comprises one or more of a chemotherapeutic agent, a hormonal agent, a proteasome inhibitor, a targeted small molecule agent, a B cell depleting agent, and an immunosuppressant.

5. The pharmaceutical combination according to claim 4, characterized in that The B cell depleting agent is an antibody that specifically binds to CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD70, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85 or CD86.

6. The pharmaceutical combination of claim 1, wherein the CD38-specific binding antibody has binding specificity to human effector cells, and / or the antibody is capable of killing cells expressing CD38 by apoptosis, and / or antibody-dependent cell-mediated cytotoxicity, and / or complement-dependent cytotoxicity.

7. The pharmaceutical combination according to claim 1, characterized in that The CD38-specific binding antibody is an antibody linked to a cytotoxic agent, a radioisotope or a drug.

8. The pharmaceutical combination according to claim 1, characterized in that The CD38-specific binding antibody has binding specificity to CD3, CD4, CD138, IL-15R, membrane-bound or receptor-bound TNF-α, human Fc receptor, or membrane-bound or receptor-bound IL-15.

9. The pharmaceutical combination according to claim 1, characterized in that The CD38-specific binding antibody comprises at least one heavy chain and at least one light chain, wherein the light chain comprises three consecutive complementarity determining regions shown in the amino acid sequences of SEQ ID NO: 43, SEQ ID NO: 44 and SEQ ID NO: 45, and the heavy chain comprises three consecutive complementarity determining regions shown in the amino acid sequences of SEQ ID NO: 46, 47 and 48; or wherein the light chain comprises three consecutive complementarity determining regions shown in the amino acid sequences of SEQ ID NO: 49, SEQ ID NO: 50 and SEQ ID NO: 51, and the heavy chain comprises three consecutive complementarity determining regions shown in the amino acid sequences of SEQ ID NO: 52, SEQ ID NO: 53 and SEQ ID NO:

54.

10. The pharmaceutical combination according to claim 9, characterized in that The light chain comprises the amino acid sequence shown in SEQ ID NO. 55, and the heavy chain comprises the amino acid sequence shown in SEQ ID NO. 56; or the light chain comprises the amino acid sequence shown in SEQ ID NO. 57, and the heavy chain comprises the amino acid sequence shown in SEQ ID NO.

58.

11. The pharmaceutical combination according to claim 10, characterized in that The amino acid sequence of the light chain is shown in SEQ ID NO. 55, and the amino acid sequence of the heavy chain is shown in SEQ ID NO. 56; or the amino acid sequence of the light chain is shown in SEQ ID NO. 57, and the amino acid sequence of the heavy chain is shown in SEQ ID NO.

58.

12. A pharmaceutical composition comprising the pharmaceutical combination according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier or diluent.

13. The pharmaceutical composition according to claim 12, which is a lyophilized powder or a liquid.

14. A product comprising the pharmaceutical combination according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 or 13, wherein the immunoglobulin degrading enzyme is immobilized on a surface.

15. Use of the pharmaceutical combination according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 12 or 13 in the preparation of a medicament for treating CD38-related cancer, wherein the CD38-related cancer is multiple myeloma.

16. A kit comprising the pharmaceutical combination according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 or 13.

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