mAb-DRIVEN CHIMERIC ANTIGEN RECEPTOR SYSTEMS FOR SORTING/DEPLETING ENGINEERED IMMUNE CELLS

Abstract

A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to improved chimeric antigen receptors (CAR) to be used in immunotherapy, the extracellular binding domains (scFv) of which have been modified by insertion of a mAb-specific epitope to allow both sorting and/or depletion of the immune cells endowed with said CARs. The present invention relates also to the immune cells expressing said CARs, to the methods of in vivo depleting and/or in vitro sorting said CAR-expressing immune cells, and is drawn to the their therapeutic use.

BACKGROUND

[0002] Adoptive immunotherapy, which involves the transfer of autologous antigen-specific T cells generated ex vivo, is a promising strategy to treat viral infections and cancer. The T cells used for adoptive immunotherapy can be generated either by expansion of antigen-specific T cells or redirection of T cells through genetic engineering (Park, Rosenberg et al. 2011). Transfer of viral antigen specific T cells is a well-established procedure used for the treatment of transplant associated viral infections and rare viral-related malignancies. Similarly, isolation and transfer of tumor specific T cells has been shown to be successful in treating melanoma.

[0003] Novel specificities in T cells have been successfully generated through the genetic transfer of transgenic T cell receptors or chimeric antigen receptors (CARs) (Jena, Dotti et al. 2010). CARs are synthetic receptors consisting of a targeting moiety that is associated with one or more signaling domains in a single fusion molecule. In general, the binding moiety of a CAR consists of an antigen-binding domain of a single-chain antibody (scFv), comprising the light and heavy variable fragments of a monoclonal antibody joined by a flexible linker. Binding moieties based on receptor or ligand domains have also been used successfully. The signaling domains for first generation CARs are derived from the cytoplasmic region of the CD3zeta or the Fc receptor gamma chains. First generation CARs have been shown to successfully redirect T cell cytotoxicity, however, they failed to provide prolonged expansion and anti-tumor activity in vivo. Signaling domains from co-stimulatory molecules including CD28, OX-40 (CD134), ICOS and 4-1BB (CD137) have been added alone (second generation) or in combination (third generation) to enhance survival and increase proliferation of CAR modified T cells. CARs have successfully allowed T cells to be redirected against antigens expressed at the surface of tumor cells from various malignancies including lymphomas and solid tumors (Jena, Dotti et al. 2010).

[0004] However, despite their unprecedent efficacy for tumor eradication in vivo, CAR T cells can promote acute adverse events after being transferred into patients. Among the well documented adverse events is Graft versus host disease (GvHD), on-target off-tumor activity or aberrant lymphoproliferative capacity due to vector derived insertional mutagenesis. Therefore, there is a need to develop cell specific depletion systems to prevent such deleterious events to occur in vivo.

[0005] There are many on-going researches to develop a safer CAR-based immunotherapy, such as on inhibitory signals referred to as immune checkpoints (such as CTLA-4- or PD-1) which are crucial for the maintenance of self-tolerance and also to limit immune-mediated collateral tissue damage (Dolan et al, 2014). Recently, inhibitory chimeric antigen receptors (iCARs) were designed having as objective to put the brakes on T cell function upon encountering off-target cells (Federov et al. 2013). Another system is described in Budde et al. (2013) in which a CD20 Chimeric Antigen Receptor is combined with an inducible caspase 9 (iC9) suicide switch. In the application US 2014/0286987, the latter gene is made functional in the presence of the prodrug AP1903 (tacrolimus) by binding to the mutated FK506-binding protein (FKBP1). A clinical trial is ongoing sponsored by the company Bellicum in which the above caspase technology (CaspaCIDe.TM.) is engineered into GD2 targeted third generation CAR T cells. A similar apoptosis-inducing system based on a multimerizing agent is described in the application WO 2014/152177.

[0006] Philip et al (2014) describes the RQR8 system which is being used as compact marker/suicide gene allowing selection of transduced cells. RQR8 derives from the combination of target epitopes from both CD34 and CD20 antigens. This construct allows selection with the clinically approved CliniMACS CD34 system (Miltenyi). Moreover, this RQR8 construct binds the widely used pharmaceutical antibody rituximab, resulting in selective deletion of transgene-expressing cells. Within this system, RQR8 is co-expressed with a CAR in a retroviral vector using the foot-and-mouth disease 2A peptide, resulting thereby into the expression of 2 independent transgenes (RQR8 and CAR) on the surface of the T-cells. This system presents some limitations from the industrial perspective, as first, it requires the cloning large retroviral inserts, and second, to ensure that the transformed cells express both RQR8 and CAR polypeptides, to eliminate possible "false-positive" i.e. T-cells that would not express both polypeptides, in particular the RQR8 suicide gene allowing the depletion of the engineered immune cells in the event of undesirable effects.

[0007] The concept of depleting T cells in the context of auto-immune disease and transplantation has been successfully practiced in the clinic for decades. To deplete cell-mediated immunity, including T-cells, immunosuppressive drugs such as glucocorticoids or cytostatics such as alkylating agents (cyclophosphamide, nitrosoureas, platinum compounds . . . ) or antimetabolites (methotrexate, azathioprine, fluorouracil . . . ) are widely used. However, despite their immunosuppressive efficacy, these drugs are not discriminative as they affect the proliferation of all T and B cells. Antibodies are sometimes used as a quick and potent immunosuppressive therapy to prevent the acute rejection reactions as well as a targeted treatment of lymphoproliferative or autoimmune disorders, in particular anti-CD20 monoclonals. In vivo elimination of T cell subsets was performed by Benjamin and Waldmann (1986) to determine the role of CD4+ T cells in generating antibody responses to soluble proteins, and by Cobbold et al. (1986) to determine the role of CD4+ and CD8+ T cells in rejecting bone marrow and tissue allografts. In vivo depletion has been performed extensively to study varied topics including control of antiviral cytotoxic T lymphocyte (CTL) responses (Buller et al., 1987). However, the antibodies which have been used so far on T cells direct antigens (CD3, CD4, CD52) that are all broadly present on resting or activated T cells as well as on other cell types. As such, the use of such antibodies would not allow the selective elimination of the engineered immune cells endowed with CARs.

[0008] As presented thereafter, the inventors have sought for an "all-in-one" system which allows an optimized in vitro sorting of CAR-expressing immune cells by reducing "false-positive", meanwhile allowing the in vivo depletion of the immune cells expressing said CARs in case of adverse clinical event.

SUMMARY OF THE INVENTION

[0009] The present invention is drawn to chimeric antigen receptors (CAR), which extracellular binding domain (scFv) is modified in such a way to allow both cell sorting and cell depletion (see FIG. 2 for illustrative embodiment). This structure named mAb-driven sorting/depletion system consists in inserting a selected epitope within the scFv; this epitope having a specificity to be recognized by a specific antibody (preferably mAb). Given the fact that mainly the external ligand binding domain of the CAR is modified to include the epitope, different CAR architectures can be envisioned: single-chain or multi-chain. The chimeric scFv of the invention, which is formed of the VH and VL polypeptides and the specific epitope(s) may itself have different structures depending on the position of insertion of the epitope and the use of linkers. The present invention also relates to the resulting method for sorting and/or depleting the engineered immune cells endowed with the modified CARs.

[0010] Several epitope-mAb couples can be used to generate such system; in particular those already approved for medical use, such as CD20/rituximab as a non-limiting example.

[0011] To further enhance the cytotoxicity of the engineered immune cells, the epitope-specific antibody may be conjugated with a cytotoxic drug. It is also possible to promote CDC cytotoxicity by using engineered antibodies on which are grafted component(s) of the complement system.

[0012] Finally, the invention encompasses therapeutic methods where the activation of the engineered immune cells endowed with CARs is modulated by depleting the cells by using an antibody that directs the external ligand binding domain of said CARs.

[0013] The invention can be summarized by the following items:

1. A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope. 2. The polypeptide according to item 1, wherein said mAb-specific epitope is located between the VH and VL chains. 3. The polypeptide according to item 1 or 2, wherein said VH and VL chains, and mAb specific-epitope are bound together by at least one linker and to the transmembrane domain of said CAR by a hinge. 4. The polypeptide according to item 3, wherein the mAb-epitope is joined to the VH and VL chains by two linkers. 5. The polypeptide according to any one of items 1 to 3 wherein the mAb-specific epitope is an epitope to be bound by an epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing a CAR comprising such epitope. 6. The polypeptide according to any one of items 1 to 5, wherein the polypeptide comprises one extracellular binding domain, wherein said extracellular binding domain further comprises a hinge, and said polypeptide further comprises [0014] a transmembrane domain, and, [0015] an intracellular domain. 7. The polypeptide according to any one of items 1 to 6, wherein the extracellular binding domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mAb-specific epitopes. 8. The polypeptide according to any one of items 1 to 7, wherein the extracellular binding domain comprises 1, 2, 3 or, 4 mAb-specific epitopes. 9. The polypeptide according to any one of items 1 to 8, wherein the extracellular binding domain comprises 2, 3 or, 4 mAb-specific epitopes. 10. The polypeptide according to any one of items 1 to 9, wherein the extracellular binding domain comprises the following sequence V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope1-(L).sub.x-; V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-; V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-E- pitope3-(L).sub.x-; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2; (L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-V.sub.1-L.sub.1-V.sub.2; Epitope1-(L).sub.x-Epitope2-(L).sub.x-Epitope3-(L).sub.x-V.sub.1-L.sub.1-- V.sub.2; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Ep- itope2-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope2-(- L).sub.x-Epitope3-(L).sub.x-; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope2-(- L).sub.x-Epitope3-(L).sub.x-Epitope4-(L).sub.x-; (L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(- L).sub.x-Epitope3-(L).sub.x-; (L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(- L).sub.x-Epitope3-(L).sub.x-Epitope4-(L).sub.x-; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2-(L).sub.x-Epitope2-(L).sub.x- ; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2-(L).sub.x-Epitope2-(L).sub.- x-Epitope3-(L).sub.x; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2-(L).sub.x-Epitope2-(L).sub.x- -Epitope3-(L).sub.x-Epitope4-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-(L).sub.x-Epitope2-(L).sub.x-V.sub.2- ; or, (L).sub.x-Epitope1-(L).sub.x-V.sub.1-(L).sub.x-Epitope2-(L).sub.x-V.- sub.2-(L).sub.x-Epitope3-(L).sub.x; wherein, V.sub.1 is V.sub.L and V.sub.2 is V.sub.H or V.sub.1 is V.sub.H and V.sub.2 is V.sub.L; L.sub.1 is a linker suitable to link the V.sub.H chain to the V.sub.L chain; L is a linker comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain can be identical or different to other occurrence of L in the same extracellular binding domain, and, x is 0 or 1 and each occurrence of x is selected independently from the others; and, Epitope 1, Epitope 2 and Epitope 3 are mAb-specific epitopes and can be identical or different. 11. The polypeptide according to item 10, wherein the extracellular binding domain comprises the following sequence V.sub.1-L.sub.1-V.sub.2-L-Epitope1; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2-L; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2-L-Epitope3; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2-L-Epitope3-L; V.sub.1-L.sub.1-V.sub.2-Epitope1; V.sub.1-L.sub.1-V.sub.2-Epitope1-L; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2-L; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2-L-Epitope3; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2-L-Epitope3-L; Epitope1-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-L-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-L-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-L-Epitope3-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-L-Epitope3-L-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-L-Epitope3-V-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-L-Epitope3-L-V.sub.1-L.sub.1-V.sub.2; V.sub.1-L-Epitope1-L-V.sub.2; L-Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2; V.sub.1-L-Epitope1-L-V.sub.2-L-Epitope2-L; V.sub.1-L-Epitope1-L-V.sub.2-L-Epitope2-L-Epitope3; V-L-Epitope1-L-V.sub.2-L-Epitope2-Epitope3; V.sub.1-L-Epitope1-L-V.sub.2-L-Epitope2-L-Epitope3-Epitope4; L-Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2-L-Epitope3-L; Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2-L-Epitope3-L; L-Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2-L-Epitope3; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-L; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-L-Epitope3; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-Epitope3, or Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-L-Epitope3-Epitope4 wherein V.sub.1 is V.sub.L and V.sub.2 is V.sub.H or V.sub.1 is V.sub.H and V.sub.2 is V.sub.L; L.sub.1 is any linker suitable to link the V.sub.H chain to the V.sub.L chain; L is a linker comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain can be identical or different to other occurrences of L in the same extracellular binding domain, and, Epitope 1, Epitope 2 and Epitope 3 are mAb-specific epitopes and can be identical or different. 12. The polypeptide according to item 10, wherein L.sub.1 is a linker comprising Glycine and/or Serine. 13. The polypeptide according to item 12, wherein L.sub.1 is a linker comprising the amino acid sequence (Gly-Gly-Gly-Ser).sub.n or (Gly-Gly-Gly-Gly-Ser).sub.n, where n is 1, 2, 3, 4 or 5 or a linker comprising the amino acid sequence (Gly.sub.4Ser).sub.4 or (Gly.sub.4Ser).sub.3. 14. The polypeptide according to any one of items 10 to 13 wherein L is a linker comprising Glycine and/or Serine. 15. The polypeptide according to item 14 wherein L is a linker having an amino acid sequence selected from SGG, GGS, SGGS, SSGGS, GGGG, SGGGG, GGGGS, SGGGGS, GGGGGS, SGGGGGS, SGGGGG, GSGGGGS, GGGGGGGS, SGGGGGGG, SGGGGGGGS, or SGGGGSGGGGS. 16. The polypeptide according to item 14 wherein L is a SGGGG, GGGGS or SGGGGS. 17. The polypeptide according to any one of items 10 to 16 wherein Epitope 1, Epitope 2, Epitope 3 and Epitope 4 are independently selected from mAb-specific epitopes specifically recognized by ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and ustekinumab. 18. The polypeptide according to any one of items 10 to 16 wherein Epitope 1, Epitope 2, Epitope 3 and Epitope 4 are independently selected from mAb-specific epitopes having an amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174. 19. The polypeptide according to any one of items 10 to 18 wherein Epitope 1 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35. 20. The polypeptide according to any one of items 10 to 19 wherein Epitope 2 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35. 21. The polypeptide according to any one of items 10 to 20 wherein Epitope 3 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 or SEQ ID NO 144. 22. The polypeptide according to any one of items 10 to 21 wherein Epitope 4 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35. 23. The polypeptide according to item 22 wherein Epitope 1, Epitope 2 and Epitope 4 are a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 and Epitope 3 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 144. 24. The polypeptide according to any one of items 1 to 9, wherein the mAb-specific epitope is from one polypeptide selected from those listed in Table 1. 25. The polypeptide according to any one of items 1 to 9 wherein the mAb-specific epitope is selected from mAb-specific epitopes specifically recognized by ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and ustekinumab. 26. The polypeptide according to any one of items 1 to 9 wherein the mAb-specific epitope is selected from mAb-specific epitope having an amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174. 27. The polypeptide according to any one of items 1 to 9 wherein the mAb-specific epitope is has an amino acid sequence of SEQ ID NO 35. 28. The polypeptide according to anyone of items 1 to 27, wherein said VH and VL chains have an antigenic target sequence of over 80% identity, preferably over 90%, and more preferably over 95% with SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-3v antigen) and SEQ ID NO 52 (WT1 antigen). 29. The polypeptide according to any one of items 1 to 27 wherein said antigen is a cell surface marker antigen. 30. The polypeptide according to any one of items 1 to 27 wherein said antigen is a tumor-associated surface antigen. 31. The polypeptide according to any one of items 1 to 27 wherein said antigen is selected from ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), CD19, CD20, CD30, CD40, disialoganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal-epithelial mucine, gp36, TAG-72, glycosphingolipids, glioma-associated antigen, .beta.-human chorionic gonadotropin, alphafetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxyl esterase, mut hsp70-2, M-CSF, prostase, prostase specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostein, PSMA, survivin and telomerase, prostate-carcinoma tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, ephrin B2, CD22, insulin growth factor (IGF1)-I, IGF-II, IGFI receptor, mesothelin, a major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, 5T4, ROR1, Nkp30, NKG2D, tumor stromal antigens, the extra domain A (EDA) and extra domain B (EDB) of fibronectin and the A1 domain of tenascin-C (TnC A1) and fibroblast associated protein (fap), LRP6, melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), CD38/CS1, MART1, WT1, MUC1, LMP2, Idiotype, NY-ESO-1, Ras mutant, gp100, proteinase 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, Androgen receptor; a lineage-specific or tissue specific antigen such as CD3, CD4, CD8, CD24, CD25, CD33, CD34, CD70, CD79, CD116, CD117, CD135, CD123, CD133, CD138, CTLA-4, B7-1 (CD80), B7-2 (CD86), endoglin, a major histocompatibility complex (MHC) molecule, BCMA (CD269, TNFRSF 17) or FLT-3. 32. The polypeptide according to any one of items 1 to 27 wherein VH and VL are selected from a VH of SEQ ID NO 65 and a VL of SEQ ID NO 66; a VH of SEQ ID NO 67 and a VL of SEQ ID NO 68; a VH of SEQ ID NO 69 and a VL of SEQ ID NO 70; a VH of SEQ ID NO 71 and a VL of SEQ ID NO 72; a VH of SEQ ID NO 77 and a VL of SEQ ID NO 78; a VH of SEQ ID NO 79 and a VL of SEQ ID NO 80; a VH of SEQ ID NO 81 and a VL of SEQ ID NO 82; a VH of SEQ ID NO 83 and a VL of SEQ ID NO 84; a VH of SEQ ID NO 85 and a VL of SEQ ID NO 86; a VH of SEQ ID NO 87 and a VL of SEQ ID NO 88; a VH of SEQ ID NO 89 and a VL of SEQ ID NO 90; a VH of SEQ ID NO 91 and a VL of SEQ ID NO 92; a VH of SEQ ID NO 93 and a VL of SEQ ID NO 94; a VH of SEQ ID NO 95 and a VL of SEQ ID NO 96; a VH of SEQ ID NO 97 and a VL of SEQ ID NO 98; a VH of SEQ ID NO 99 and a VL of SEQ ID NO 100; a VH of SEQ ID NO 101 and a VL of SEQ ID NO 102; a VH of SEQ ID NO 103 and a VL of SEQ ID NO 104; a VH of SEQ ID NO 105 and a VL of SEQ ID NO 106; a VH of SEQ ID NO 107 and a VL of SEQ ID NO 108; a VH of SEQ ID NO 109 and a VL of SEQ ID NO 110; a VH of SEQ ID NO 111 and a VL of SEQ ID NO 112; a VH of SEQ ID NO 113 and a VL of SEQ ID NO 114; a VH of SEQ ID NO 115 and a VL of SEQ ID NO 116; a VH of SEQ ID NO 117 and a VL of SEQ ID NO 118; a VH of SEQ ID NO 119 and a VL of SEQ ID NO 120; a VH of SEQ ID NO 121 and a VL of SEQ ID NO 122; or, a VH of SE ID NO 123 and a VL of SE ID NO 124, a VH of SE ID NO 170 and a VL of SE ID NO 171; a VH of SEQ ID NO 172 and a VL of SEQ ID NO 173; or, a VH of SEQ ID NO 174 and a VL of SEQ ID NO 175. 33. The polypeptide according to any one of items 2 to 32 wherein the hinge comprises a PD-1 hinge, an IgG4 hinge, a CD8alpha hinge or a Fc.gamma.RIII alpha hinge. 34. The polypeptide according to any one of items 2 to 33 wherein the transmembrane domain comprises the transmembrane region(s) of the alpha, beta or zeta chain of the T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154. 35. The polypeptide according to any one of items 2 to 33 wherein the transmembrane domain comprises the transmembrane region(s) of PD-1 or CD8 alpha. 36. The polypeptide according to any one of items 2 to 33 wherein the transmembrane domain comprises the transmembrane region(s) of CD8 alpha.

37. The polypeptide according to any one of items 2 to 37 wherein the intracellular domain comprises a CD3zeta signalling domain. 38. The polypeptide according to any one of items 2 to 37 wherein the intracellular domain comprises a 4-1BB domain. 39. A polypeptide according to any one of items 1-38, wherein the CAR is a single-chain CAR. 40. A polypeptide according to item 1, wherein the said polypeptide shares over 80% identity, over 90%, over 95% with or is identical to SEQ ID NO 1 to 10, SEQ ID NO 125 to 141 or SEQ ID no 145 to 150 or SEQ ID NO 152 to 169. 41. A polypeptide according to any one of items 1-38 wherein the CAR is a multi-chain CAR. 42. A polynucleotide encoding a polypeptide according to any one of items 1 to 41. 43. A polynucleotide encoding a chimeric antigen receptor according to any one of items 1 to 41, wherein said CAR comprises a CD3 zeta signaling domain and co-stimulatory domain from 4-1BB. 44. An expression vector comprising a nucleic acid of item 42 or 43. 45. An engineered immune cell expressing at its cell surface a polypeptide according to any one of items 1 to 41. 46. The engineered immune cell according to item 45, wherein said cell is derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 47. The engineered immune cell according to item 45 or 46 for use as a medicament. 48. A method for engineering an immune cell of any one of items 45-47, comprising: (a) Providing an immune cell; (b) Introducing into said cell at least one polynucleotide encoding the chimeric antigen receptor according to any one of items 1-41. (c) Expressing said polynucleotide into said cell. 49. The method for engineering an immune cell of item 48, wherein immune cell is a T-cell. 50. A method for in vitro sorting engineered immune cell expressing at its cell surface a polypeptide comprising at least one mAb-specific epitope according to any one of items 1 to 41 comprising [0016] contacting a population of immune cells comprising said engineered immune cells with a monoclonal antibody specific for the mAb-specific epitope; [0017] selecting the cells that bind to the monoclonal antibody to obtain a population of cells enriched in engineered immune cell. 51. The method according to item 50 wherein the monoclonal antibody specific for the mAb-specific epitope is conjugated to a fluorophore and the step of selecting the cells that bind to the monoclonal antibody is done by Fluorescence Activated Cell Sorting (FACS). 52. The method according to item 50 wherein the monoclonal antibody specific for the mAb-specific epitope is conjugated to a magnetic particle and the step of selecting the cells that bind to the monoclonal antibody is done by Magnetic Activated Cell Sorting (MACS). 53. The method according to any one of items 50 to 52 wherein the polypeptide comprises an mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 and the monoclonal antibody is rituximab. 54. The method according to any one of items 50 to 52 wherein the polypeptide comprises an mAb-specific epitope having an amino acid sequence of SEQ ID NO 144 and the antibody used to contact the population of immune cells is QBEND-10. 55. The method according to any one of items 50 to 54 wherein the population of cells enriched in engineered immune cell comprises at least 70%, 75%, 80%, 85%, 90%, 95% of CAR-expressing immune cells. 56. A method for in vivo depleting an engineered immune cell expressing at its cell surface a polypeptide comprising at least one mAb-specific epitope according to any one of items 1 to 41 in a patient, comprising contacting said engineered immune cell with at least one epitope-specific mAb. 57. The method according to item 56 wherein the mAb-specific epitope is a CD20 epitope or mimotope and the epitope-specific mAb is rituximab. 58. The method according to item 57 wherein the mAb-specific epitope has an amino acid sequence of SEQ ID NO 35. 59. The method according to any one of items 56 to 58 wherein the epitope-specific mAb is conjugated by a molecule able to activate the complement system. 60. The method according to any one of items 56 to 59 wherein, wherein a cytotoxic drug is coupled to the epitope-specific mAb. 61. A method for in vivo depleting an engineered immune cell expressing at its cell surface a polypeptide comprising at least one mAb-specific epitope according to any one of items 1 to 41 in a patient, comprising contacting said engineered immune cell with bi-specific mAb (BsAb) able to bind both the mAb-specific epitope borne on said cells and to an surface antigen borne on an effector (and cytotoxic) cell. 62. A method according to any one of 48 to 61, wherein said immune cell is a T-cell.

BRIEF DESCRIPTION OF THE FIGURES AND TABLE

[0018] FIG. 1: Schematic structure of the mAb-driven sorting/depletion system of the invention using here a single-chain CAR scaffold; several configurations are presented for the chimeric scFv with different positions of the VH, VL chains and the mAb-specific epitope.

[0019] FIG. 2: Schematic representation of cell sorting and cell depletion functioning by using the mAb-driven system of the invention. The addition of specific mAb (+/-complement) allows purification of CAR+ T cells by recognizing its epitope within the chimeric scFv. During the cell depletion step, the same specific mAb (+/-complement) by binding to its specific epitope within the chimeric scFv provokes a specific lysis of CAR+ T cells.

[0020] FIG. 3: Schematic representation of cell depletion using bi-specific antibody. By binding to both CAR-expressing immune cell and to an effector cell, this system allows recruitment of effector cells at the surface of CAR-expressing immune cell and triggers their specific depletion in vivo.

[0021] FIG. 4: CAR architecture for 10 CARs expressing anti-CD123 scFv with CD20 mimotope(s) used in Examples 1-2. A series of 10 chimeric scFv are designed in which one or two copies of the CD20 mimotopes (black box named "mimotope") are inserted between the anti-CD123 scFv and the hinge. As depicted in the FIG. 4, all the 10 CARs have the same hinge (CD8 hinge), transmembrane domain (CD8 TM), co-stimulatory domain (4-1BB) and stimulatory domain (ITAM CD3 zeta). SEQ ID NO 1-10 comprise the leader sequence MALPVTALLLPLALLLHAARP, which is present when the CAR is initially expressed but which is not part of the CAR expressed at the surface of the cell.

[0022] Depending on the position of the mimotope(s) in view of the scFv, 3 series of CARs are designed (Anti-CD123 No 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 corresponding to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, respectively): [0023] first series: SEQ ID NO 1-2 and SEQ ID NO 3-4 correspond to the conformations wherein respectively one and two CD20 mimotope(s) is(are) inserted between the anti-CD123 scFv and the hinge; in SEQ ID NO 2 a GS linker joins the CD20 mimotope to the hinge. In SEQ ID NO 3-4, a GS linker interspaces the two mimotopes and in SEQ ID NO 4 has an extra GS linker between the mimotopes and the hinge. [0024] second series: SEQ ID NO 5-6 correspond to the conformations wherein one copy of CD20 mimotope is inserted within the anti-CD123 scFv; the differences of sequence coming from the presence of respectively a short GS linker (SEQ ID NO 5) and a long GS linker (SEQ ID NO 6) lying on both sides. [0025] third series: SEQ ID NO 7 to 10 correspond to the conformations wherein the anti-CD123 scFv is located between the CD mimotope(s) and the hinge. In SEQ ID NO. 7-8 and SEQ ID NO. 9-10 respectively, one copy and two copies of CD20 mimotope is (are) inserted. A GS linker is inserted between the 2 CD20 mimotopes, and for SEQ ID NO. 10, a supplementary GS linker joins the mimotopes to the anti-CD123 scFv.

[0026] FIG. 5 shows the cytolytic activity of T cells expressing anti-CD123 CAR of SEQ ID NO 1-4 or 142 or control T Cell not expressing any anti CD123 CAR (mock T-cell-transfection step without any mRNA). The cytolytic activity is expressed as the frequency of specific cell lysis as detailed in Example 1.

[0027] FIG. 6 shows the result of a CDC assay where T cells expressing anti-CD123 CAR of SEQ ID NO 1-4 or control T Cell not expressing any anti CD123 CAR (mock T-cell (transfection step without any mRNA)) are incubated with Rituximab (RTX) and Baby Rabbit Complement BRC). The results are expressed as relative frequency of viable cells among anti-CD123 CAR positive T cells (with respect to control experiment) as detailed in Example 3.

[0028] FIGS. 7A, 7B and 7C discloses the general structure of CARs of SEQ ID NO 125 to 141 that have been designed and tested in Examples 4 to 6. An anti BCMA ScFV was used in all these CARs. One, two, three or four epitopes selected from a CD20 mimotope (black box named "mimotope") and or a CD34 epitope (gray box named "CD34") were included at different positions, i.e upstream to the ScFv, downstream to the ScFv or between the variable chains of the ScFv (noted as V1 and V2). As depicted in the FIG. 7, all the CARs have the same hinge (CD8 hinge), transmembrane domain (CD8 TM), co-stimulatory domain (4-1BB) and stimulatory domain (ITAM CD3 zeta).

[0029] FIGS. 8A and 8B shows the result of a CDC assay where T cells expressing anti-BCMA CAR of SEQ ID NO 125 or 130 to 141 are incubated with RTX and BRC. The results are expressed as relative frequency of viable cells among anti-BCMA CAR positive T cells (with respect to control experiment) as detailed in Example 4.

[0030] FIG. 9 shows the cytolytic activity of T cells expressing anti-BCMA CAR of SEQ ID NO 125 or 130 to 139 or control T Cell not expressing any anti BCMA CAR (T-cell). The cytolytic activity is expressed as the frequency of viable H929 cells as detailed in Example 4.

[0031] FIG. 10A shows the frequency of T-cells expressing CAR of SEQ ID NO 128 comprising a CD34 epitope and two CD20 mimotopes before or after purification with CD34 MicroBead Kit or in the flow through fraction.

[0032] FIG. 10B shows the number of T-cells expressing CAR of SEQ ID NO 128 comprising a CD34 epitope before or after purification with CD34 MicroBead Kit or in the flow through fraction.

[0033] FIG. 11 shows concentration of INF gamma produced by T cell expressing anti-BCMA CAR of SEQ ID NO 125 or 130 to 139 in the presence of RTX, phytohemagglutinin (PHA) or in the absence of both RTX anf PHA.

[0034] FIG. 12 shows the frequency of CAR positive T-Cell resulting from the detection of T Cell expressing CARs of SEQ ID NO 125 or 130 to 139 using a BCMA-Fc fusion protein and a labeled anti Fc antibody or RTX and a labeled anti Fc antibody.

[0035] FIG. 13 shows the frequency of CAR positive T-cells resulting from the detection of T Cell expressing CARs of SEQ ID NO 128 using RTX and a labeled anti Fc antibody or labeled QBEND-10.

[0036] FIGS. 14A and 14B shows the detection of T Cells expressing BCMA CARs of SEQ ID NO 145 (BC30, Wild type), 146 (LM), 147 (LML), 148 (LMLM and-149 (LMLML) containing CD20 mimotopes by flow cytometry. The CAR T cells are detected by flow cytometry using either soluble biotinylated-BCMA protein followed by PE-conjugated streptavidin (sBCMA biotin (PE) or the anti-CD20 antibody rituximab followed by FITC-conjugated anti-human IgG (Rituximab (FITC)).

[0037] FIG. 15 shows the detection of T cells not transduced, transduced with a lentivirus for the coexpression of an anti BCMA CAR of SEQ ID NO 145 and RQR8 (SEQ ID NO 150) (BC30-RQR8), or BCMA CARs of SEQ ID NO 149 containing CD20 mimotopes by flow cytometry. The CAR-T cells are detected by flow cytometry using either soluble biotinylated-BCMA protein followed by PE-conjugated streptavidin (sBCMA biotin (PE)) or the anti-CD20 antibody rituximab followed by FITC-conjugated anti-human IgG (Rituximab (FITC)).

[0038] FIG. 16 shows the result of a CDC assay where T cells expressing anti-BCMA CAR of SEQ ID NO 149 (BC30-R2), anti BCMA CAR of SEQ ID NO 145 or coexpressing an anti BCMA CAR of SEQ ID NO 145 and RQR8 (SEQ ID NO 150) (BC30-RQR8) are incubated with RTX and BRC. The percentage of cytotoxicity is determined by flow cytometry analysis using biotinylated BCMA protein. The results are expressed as the frequency of cell lysis among anti-BCMA CAR positive T cells with respect to control (cells incubated with BRC only).

[0039] FIG. 17 shows the cytolytic activity of T cells expressing anti-BCMA CAR of SEQ ID NO 149 (BC30-R2) or coexpressing an anti BCMA CAR of SEQ ID NO 145 (BC30) and RQR8 (SEQ ID NO 150) (BC30-RQR8) in the presence/absence of RTX. The cytolytic activity is expressed as the percentage of cell lysis calculated as disclosed in example 7.5 and is determined at different ratio of effector (CAR T cell):target (MM1S cells expressing BCMA).

[0040] FIG. 18 shows the percentage of activated T cells expressing anti-BCMA CAR of SEQ ID NO 149 in the presence of PBS (control), anti-CD3 OKT3 antibody (.alpha.CD3), or Rituximab (RTX). T cell activation is assessed by measuring the expression of the activation markers CD25 and CD69 using flow cytometry.

[0041] Table 1: Listing of the pharmaceutically-approved mAb with their antigenic targets. The sequences of the latter are provided, as well as epitope(s) for some of them.

[0042] Table 2: Listing of several mimotopes and epitopes corresponding to their mAb which are presented in Example 2.

[0043] Table 3: Listing of the VH & VL chains of scFv targeting the CD19, CD33, 5T4, ROR1, EGFRvIII, BCMA, CS1 and CD123 antigens.

[0044] Table 4: Exemplary sequence of CAR components

DETAILED DESCRIPTION OF THE INVENTION

[0045] The invention relates to a polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, preferably a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope. In one embodiment, the mAb-specific epitope is an epitope to be bound by an epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing a CAR comprising such epitope.

[0046] The invention relates to a polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope to be bound by a epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing said CAR.

[0047] In some embodiments, the invention relates to a CAR comprising [0048] an extracellular domain comprising [0049] at least one, preferably one, extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, preferably a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope, and, [0050] a hinge, [0051] a transmembrane domain, and, [0052] an intracellular domain.

[0053] In some embodiments, the invention relates to a CAR comprising [0054] an extracellular domain comprising [0055] at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope to be bound by a epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing said CAR, and, [0056] a hinge, [0057] a transmembrane domain, and, [0058] an intracellular domain.

[0059] In embodiments, the CAR of the invention comprises one extracellular binding domain.

[0060] By "chimeric scFv" is meant a polypeptide corresponding to a single-chain variable fragment composed of heavy and light chains (V.sub.H and V.sub.L, respectively) and of an epitope, which was not originally included in said V.sub.H and V.sub.L chains. The latter epitope is referred to as "mAb-specific epitope" when it has the capacity to be bound specifically by an antibody, in particular a monoclonal antibody. In some embodiments, the mAbs specific epitope is not an epitope recognized by the ScFv. In some embodiments, the mAbs specific epitope is not derived from the extracellular domain of the CAR. The components of this chimeric scFv (i.e. the light and heavy variable fragments of the ligand binding domain and the mAb specific epitope) may be joined together by at least one linker, usually a flexible linker. These components are generally joined to the transmembrane domain of the CAR by a hinge.

Chimeric scFv Conformations

[0061] The structure of the chimeric scFv of the invention can be various as presented in the FIG. 1 depending of the position of its main components (V.sub.H and V.sub.L and m-Ab specific epitope).

[0062] The chimeric scFv of the invention may have several conformations, at least 9 when considering the number of possible permutations of one V.sub.H, one V.sub.L and one epitope.

[0063] Preferably, each component (VH, VL and epitope) is interconnected with its neighbor(s) by at least one flexible linker such as presented previously. The suitable combinations according to the invention are the ones which provide a good affinity/specificity in both bindings: between the mAb-specific epitope and the infused mAb, and between the VH &VL chains of the chimeric scFv and the antigen of the cell target ligand.

[0064] According to one embodiment, the extracellular-binding domain of the CAR comprises at least two linkers, both of them joining the epitope to the VH and VL chains; and a hinge joining the scFv-epitope to the transmembrane domain of the CAR.

[0065] For instance, if the projected CAR conformation is such that the mAb-specific epitope is located beside the VH and VL chains, a screening is performed when the CAR is expressed and is tested for cytoxicity and/or mAb depletion.

[0066] When the mAb-specific epitope is sought for being located between the VH and VL chains, a screening may be performed by phage display before testing and/or transient expression of the CAR construct. This may be obtained by transfection of mRNA, which is sufficient for a primary cytoxicity and/or mAb depletion test.

[0067] In some embodiments, the extracellular binding domain comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mAb-specific epitopes.

[0068] In some embodiments, the extracellular binding domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mAb-specific epitopes.

[0069] In some embodiments, the extracellular binding domain comprises 1, 2 or 3 mAb-specific epitopes.

[0070] In some embodiments, when the extracellular binding domain comprises several mAb-specific epitopes, all the mAb-specific epitopes are identical.

[0071] In some embodiments, when the extracellular binding domain comprises several mAb-specific epitopes, the mAb-specific epitopes are not identical. For example, the extracellular binding domain can comprises three mAb-specific epitopes, two of them being identical and the third one being different.

[0072] In some embodiments, the extracellular binding domain comprises a VH, a VL, and one or more mAb-specific epitopes, preferably 1, 2 or 3, more preferably 2 or 3 mAb-specific epitopes.

[0073] In some embodiments, the extracellular binding domain comprises the following sequence (Nterm is located on the left hand side):

V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope-(L).sub.x; V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x; V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-E- pitope3-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2; (L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-V.sub.1-L.sub.1-V.sub.2; Epitope1-(L).sub.x-Epitope2-(L).sub.x-Epitope3-(L).sub.x-V.sub.1-L.sub.1-- V.sub.2; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Ep- itope2-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope2-(- L).sub.x-Epitope3-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(L).sub.x-Epitope2-(- L).sub.x-Epitope3-(L).sub.x-Epitope4-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-V.sub.- 1-L.sub.1-V.sub.2-(L).sub.x-Epitope3-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-Epitope2-(L).sub.x-V.sub.1-L.sub.1-V.sub.2-(- L).sub.x-Epitope3-(L).sub.x-Epitope4-(L).sub.x; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2-(L).sub.x-Epitope2-(L).sub.x- ; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2-(L).sub.x-Epitope2-(L).sub.- x-Epitope3-(L).sub.x; V.sub.1-(L).sub.x-Epitope1-(L).sub.x-V.sub.2-(L).sub.x-Epitope2-(L).sub.x- -Epitope3-(L).sub.x-Epitope4-(L).sub.x; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-(L).sub.x-Epitope2-(L).sub.x-V.sub.2- ; (L).sub.x-Epitope1-(L).sub.x-V.sub.1-(L).sub.x-Epitope2-(L).sub.x-V.sub.- 2-(L).sub.x-Epitope3-(L).sub.x; V.sub.1-L.sub.1-V.sub.2-L-Epitope1; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2-L; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2-L-Epitope3; V.sub.1-L.sub.1-V.sub.2-L-Epitope1-L-Epitope2-L-Epitope3-L; V.sub.1-L.sub.1-V.sub.2-Epitope1; V.sub.1-L.sub.1-V.sub.2-Epitope1-L; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2-L; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2-L-Epitope3; V.sub.1-L.sub.1-V.sub.2-Epitope1-L-Epitope2-L-L-Epitope3-L; Epitope1-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-L-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-L-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-L-Epitope3-V.sub.1-L.sub.1-V.sub.2; Epitope1-L-Epitope2-L-Epitope3-L-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-L-Epitope3-V.sub.1-L.sub.1-V.sub.2; L-Epitope1-L-Epitope2-L-Epitope3-L-V.sub.1-L.sub.1-V.sub.2; V.sub.1-L-Epitope1-L-V.sub.2; L-Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2; V.sub.1-L-Epitope1-L-V.sub.2-L-Epitope2-L; V.sub.1-L-Epitope1-L-V.sub.2-L-Epitope2-L-Epitope3; V.sub.1-L-Epitope1-L-V.sub.2-L-Epitope2-Epitope3; V.sub.1-L-Epitope1-L-V.sub.2-L-Epitope2-L-Epitope3-Epitope4; L-Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2-L-Epitope3-L; Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2-L-Epitope3-L; L-Epitope1-L-V.sub.1-L-Epitope2-L-V.sub.2-L-Epitope3; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-L; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-L-Epitope3; L-Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-Epitope3, or Epitope1-L-V.sub.1-L.sub.1-V.sub.2-L-Epitope2-L-Epitope3-Epitope4. wherein, V.sub.1 and V.sub.2 are V.sub.H and V.sub.L of an ScFv (i.e, V.sub.1 is V.sub.L and V.sub.2 is V.sub.H or V.sub.1 is V.sub.H and V.sub.2 is V.sub.L); L.sub.1 is any linker suitable to link the V.sub.H chain to the V.sub.L chain in an ScFv; L is a linker, preferably comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain can be identical or different to other occurrence of L in the same extracellular binding domain, and, x is 0 or 1 and each occurrence of x is independently from the others; and, Epitope 1, Epitope 2 and Epitope 3 are mAb-specific epitopes and can be identical or different.

[0074] In some embodiments, the extracellular binding domains comprises the following sequence (Nterm is located on the left hand side):

V.sub.H-L.sub.1-V.sub.L-L-Epitope1-L-Epitope2-L; L-Epitope1-L-V.sub.H-L-Epitope2-L-V.sub.L-L-Epitope3-L; V.sub.L-L.sup.1-V.sub.H-L-Epitope1-L-Epitope2-L; or, L-Epitope1-L-V.sub.L-L-Epitope2-L-V.sub.H-L-Epitope3-L, wherein L, L.sub.1, Epitope1, Epitope2 and Epitope3 are as defined above.

[0075] In some embodiments, L.sub.1 is a linker comprising Glycine and/or Serine. In some embodiments, L.sub.1 is a linker comprising the amino acid sequence (Gly-Gly-Gly-Ser).sub.n or (Gly-Gly-Gly-Gly-Ser).sub.n, where n is 1, 2, 3, 4 or 5. In some embodiments L.sub.1 is (Gly.sub.4Ser).sub.4 or (Gly.sub.4Ser).sub.3.

[0076] In some embodiments, L is a flexible linker, preferably comprising Glycine and/or Serine. In some embodiments, L has an amino acid sequence selected from SGG, GGS, SGGS, SSGGS, GGGG, SGGGG, GGGGS, SGGGGS, GGGGGS, SGGGGGS, SGGGGG, GSGGGGS, GGGGGGGS, SGGGGGGG, SGGGGGGGS, or SGGGGSGGGGS preferably SGG, SGGS, SSGGS, GGGG, SGGGGS, SGGGGGS, SGGGGG, GSGGGGS or SGGGGSGGGGS. In some embodiments, when the extracellular binding domain comprises several occurrences of L, all the Ls are identical. In some embodiments, when the extracellular binding domain comprises several occurrences of L, the Ls are not all identical. In some embodiments, L is SGGGGS. In some embodiments, the extracellular binding domain comprises several occurrences of L and all the Ls are SGGGGS.

[0077] In some embodiments, Epitope 1, Epitope 2 and Epitope 3 are identical or different and are selected from mAb-specific epitopes having an amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41 or SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174.

[0078] In some embodiments, Epitope 1, Epitope 2 and Epitope 3 are identical or different and are selected from mAb-specific epitopes specifically recognized by ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and ustekinumab.

[0079] In some embodiments, Epitope 1 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35.

[0080] In some embodiments, Epitope 2 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35.

[0081] In some embodiments, Epitope 3 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35.

[0082] In some embodiments, Epitope 4 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35.

[0083] In some embodiments, Epitope 2 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 and Epitope 3 is an mAb-specific epitope having an amino acid sequence of SEQ ID NO 144.

[0084] In some embodiments, one of Epitope 1, Epitope 2, Epitope 3 and Epitope 4 is a CD34 epitope, preferably an epitope of SEQ ID 144. In some embodiments, one of Epitope1, Epitope 2, Epitope 3 and Epitope 4 is a CD34 epitope, preferably an epitope of SEQ ID 144 and the other mAb specific epitopes are CD20 mimotopes, preferably mimotope of SEQ ID NO 35.

Inserted mAb-Specific Epitope

[0085] According to the invention, the epitope to be inserted within the chimeric scFv is specific to the monoclonal antibody (mAb) which is used for cell sorting and/or cell depletion processes.

[0086] In a preferred embodiment, the introduced epitope within chimeric scFv is chosen as part of a mAb-specific epitope/epitope-specific mAb couple, in the basis of their approval by National Health Agencies in terms of regulatory/safety. Such couples are presented in the following table 1.

TABLE-US-00001 TABLE 1 Listing of pharmaceutically-approved monoclonal antibodies with their antigenic targets. Drug bank accession n.sup.o (or other n.sup.o if Target/ SEQ ID Antibody Indication stated) Antigen NO Murine Ibritumomab Non-Hodgkin lymphoma DB00078 CD20 SEQ ID tiuxetan (with yttrium-90 or NO 11 indium-111) Muromonab-CD3 Transplant rejection DB00075 T cell CD3 SEQ ID Receptor NO 12 Tositumomab Non-Hodgkin lymphoma DB00081 CD20 SEQ ID NO 11 Chimeric Abciximab Cardiovascular disease DB00054 inhibition of SEQ ID glycoprotein NO 13 IIb/IIIa Basiliximab Transplant rejection DB00074 IL-2R.alpha. receptor SEQ ID (CD25) NO 14 Brentuximab Anaplastic large cell DB08870 CD30 SEQ ID vedotin lymphoma NO 15 Cetuximab Colorectal cancer, Head DB00002 epidermal growth SEQ ID and neck cancer factor receptor NO 16 Infliximab Several autoimmune DB00065 inhibition of TNF- SEQ ID disorders .alpha. signaling NO 17 Rituximab Non-Hodgkin lymphoma DB00073 CD20 SEQ ID NO 11 Humanized Alemtuzumab Chronic lymphocytic DB00087 CD52 SEQ ID leukemia NO 18 Bevacizumab Colorectal cancer, Age DB00112 Vascular SEQ ID related macular endothelial NO 19 degeneration (off-label) growth factor (VEGF) Certolizumab Crohn's disease DB08904 inhibition of TNF- SEQ ID pegol .alpha. signaling NO 17 Daclizumab Transplant rejection DB00111 IL-2R.alpha. receptor SEQ ID (CD25) NO 14 Eculizumab Paroxysmal nocturnal DB01257 Complement SEQ ID hemoglobinuria system protein NO 20 Efalizumab Psoriasis DB00095 CD11a SEQ ID NO 21 Gemtuzumab Acute myelogenous DB00056 CD33 SEQ ID leukemia (with NO 22 calicheamicin) Natalizumab Multiple sclerosis and DB00108 alpha-4 (.alpha.4) SEQ ID Crohn's disease integrin NO 23 Omalizumab mainly allergy-related DB00043 immunoglobulin E SEQ ID asthma (IgE) NO 24 Palivizumab Respiratory Syncytial DB00110 an epitope of the SEQ ID Virus RSV F protein NO 25 Ranibizumab Macular degeneration DB01270 Vascular SEQ ID endothelial NO 19 growth factor A (VEGF-A) Tocilizumab (or Rheumatoid arthritis DB06273 Anti-IL-6R SEQ ID Atlizumab) NO 26 Trastuzumab Breast cancer DB00072 ErbB2 SEQ ID NO 27 Vedolizumab Crohn's disease, CAS n.sup.o943609-66-3 integrin .alpha..sub.4.beta..sub.7 SEQ ID ulcerative colitis NO 28 Human Adalimumab Several auto-immune DB00051 inhibition of TNF- SEQ ID disorders .alpha. signaling NO 17 Belimumab Systemic lupus DB08879 inihibition of B- SEQ ID erythematosus cell activating NO 29 factor Canakinumab Cryopyrin-associated DB06168 IL-1.beta. SEQ ID periodic syndrome NO 30 (CAPS) Denosumab Postmenopausal DB06643 RANK Ligand SEQ ID osteoporosis, Solid inhibitor NO 31 tumor's bony metastases Golimumab Rheumatoid arthritis, DB06674 TNF-alpha SEQ ID Psoriatic arthritis, and inihibitor NO 17 Ankylosing spondylitis Ipilimumab Melanoma DB06186 blocks CTLA-4 SEQ ID (MDX-101) NO 32 Ofatumumab Chronic lymphocytic CAS n.sup.o 679818-59-8 CD20 SEQ ID leukemia NO 11 Panitumumab Colorectal cancer DB01269 epidermal growth SEQ ID factor receptor NO 16 Ustekinumab Psoriatic Arthritis, DB05679 IL-12, IL-23 SEQ ID Plaque Psoriasis NO 33 Nivolumab renal cell carcinoma, CAS n.sup.o 946414-94-4 PD-1 SEQ ID lung cancer, melanoma, NO 34 and advanced or metastatic solid tumors

TABLE-US-00002 TABLE 2 Examples of mAb-specific epitopes (and their corresponding mAbs) that can be used in the extracellular binding domain of the CAR of the invention such as for example mimotopes and epitope with their corresponding mAb as used in the Examples 1-2 Rituximab Mimotope SEQ ID NO 35 CPYSNPSLC Palivizumab Epitope SEQ ID NO 36 NSELLSLINDMPITNDQKKLMSNN Cetuximab Mimotope 1 SEQ ID NO 37 CQFDLSTRRLKC Mimotope 2 SEQ ID NO 38 CQYNLSSRALKC Mimotope 3 SEQ ID NO 39 CVWQRWQKSYVC Mimotope 4 SEQ ID NO 40 CMWDRFSRWYKC Nivolumab Epitope 1 SEQ ID NO 41 SFVLNWYRMSPSNQTDKLAAFPEDR Epitope 2 SEQ ID NO 42 SGTYLCGAISLAPKAQIKE QBEND-10 Epitope SEQ ID NO 144 ELPTQGTFSNVSTNVSPAKPTTTA Alemtuzumab Epitope SEQ ID NO 174 GQNDTSQTSSPS

[0087] In a preferred embodiment, the epitope introduced within the chimeric scFv is the CD20 antigen, preferably SEQ ID NO 35 and the infused mAb which is being used to target it--for sorting and/or depletion purpose(s) is rituximab.

[0088] In some embodiments, the mAb-specific epitope has an amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174.

[0089] In some embodiments, the extracellular binding domain of the CAR of the invention comprises one mAb-specific epitope of SEQ ID NO 35, two mAb-specific epitopes of SEQ ID NO 35, three mAb-specific epitopes of SEQ ID NO 35, one mAb-specific epitope of SEQ ID NO 35 and one mAb-specific epitope of SEQ ID NO 144, two mAb-specific epitopes of SEQ ID NO 35 and one mAb-specific epitope of SEQ ID NO 144, three mAb-specific epitopes of SEQ ID NO 35 and one mAb-specific epitope of SEQ ID NO 144.

[0090] According to another embodiment, the epitope is a mimotope. As a macromolecule, often a peptide, which mimics the structure of an epitope, the mimotope has the advantage to be smaller than conventional epitope, and therefore may be beneficial for a non-conformational sequence and easier to reproduce in a long polypeptide such a CAR. Mimotopes are known for several pharmaceutically-approved mAb such as two 10 amino acid peptides for cetuximab (Riemer et al., 2005), or a 24 aa for palivizumab (Arbiza et al, 1992). As these mimotopes can be identified by phage display, it is possible to try several of them in order to obtain a sequence which does not perturb the scFv for the same mAb. Furthermore, their use can enhance a complement-dependent cytotoxicity (CDC).

scFv

[0091] The term "extracellular ligand-binding domain" as used herein is defined as an oligo- or polypeptide that is capable of binding a ligand. Preferably, said domain is sought for being capable of interacting with a cell surface molecule. For example, the extracellular ligand-binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state. Thus examples of cell surface markers that may act as ligands include those associated with viral, bacterial and parasitic infections, autoimmune disease and cancer cells. In particular, the extracellular ligand-binding domain can comprise an antigen binding domain derived from an antibody against an antigen of the target. As non-limiting examples, the antigen of the target can be a tumor-associated surface antigen as described above. In some embodiments, the extracellular binding domain is an extracellular ligand-binding domain as defined above. According to the present invention, said extracellular ligand-binding domain is a single chain antibody fragment (scFv) comprising the light (V.sub.L) and the heavy (V.sub.H) variable fragment of a target antigen specific monoclonal antibody, and an mAb epitope specific antigen. In some embodiments, the extracellular binding domain comprises a single chain antibody fragment (scFv) comprising the light (V.sub.L) and the heavy (V.sub.H) variable fragment of a cell surface target antigen specific monoclonal antibody.

[0092] Other binding domain than scFv can also be used for predefined targeting of lymphocytes, such as camelid single-domain antibody fragments, receptor ligands like a vascular endothelial growth factor polypeptide, an integrin-binding peptide, heregulin or an IL-13 mutein, antibody binding domains, antibody hypervariable loops or CDRs as non-limiting examples.

[0093] In another embodiment, said extracellular binding domain can be a DARPin (designed ankyrin repeat protein). DARPins are genetically engineered antibody mimetic proteins typically exhibiting highly specific and high-affinity target protein binding. They are derived from natural ankyrin proteins and comprise at least three, usually four or five repeat motifs of these proteins. DARPins are small, single domain proteins which can be selected to bind any given target protein with high affinity and specificity (Epa, Dolezal et al. 2013; Friedrich, Hanauer et al. 2013; Jost, Schilling et al. 2013). According to the present invention, DARPins can be engineered to comprise multiple antigen recognition sites. Thus, said DARPins can be used to recognize a series of consecutive different antigens as well as a unique antigen. Thus, the present invention relates to a method comprising providing an immune cell, and expressing at the surface of said immune cell chimeric antigen receptor which comprises a designed ankyrin repeat protein capable of recognizing at least one specific ligand, preferably at two specific ligands.

[0094] As non-limiting example, the ligand of the target or the antigen recognized by the extracellular binding domain, preferably by the ScFv, can be a tumor-associated surface antigen, such as ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), CD19, CD20, CD30, CD40, disialoganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal-epithelial mucine, gp36, TAG-72, glycosphingolipids, glioma-associated antigen, .beta.-human chorionic gonadotropin, alphafetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxyl esterase, mut hsp70-2, M-CSF, prostase, prostase specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostein, PSMA, surviving and telomerase, prostate-carcinoma tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, ephrin B2, CD22, insulin growth factor (IGF1)-I, IGF-II, IGFI receptor, mesothelin, a major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, 5T4, ROR1, Nkp30, NKG2D, tumor stromal antigens, the extra domain A (EDA) and extra domain B (EDB) of fibronectin and the A1 domain of tenascin-C (TnC A1) and fibroblast associated protein (fap), LRP6, melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), CD38/CS1, MART1, WT1, MUC1, LMP2, Idiotype, NY-ESO-1, Ras mutant, gp100, proteinase 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, Androgen receptor; a lineage-specific or tissue specific antigen such as CD3, CD4, CD8, CD24, CD25, CD33, CD34, CD70, CD79, CD116, CD117, CD135, CD123, CD133, CD138, CTLA-4, B7-1 (CD80), B7-2 (CD86), endoglin, a major histocompatibility complex (MHC) molecule, BCMA (CD269, TNFRSF 17), FLT-3, or a virus-specific surface antigen such as an HIV-specific antigen (such as HIV gp120); an EBV-specific antigen, a CMV-specific antigen, a HPV-specific antigen, a Lasse Virus-specific antigen, an Influenza Virus-specific antigen as well as any derivate or variant of these surface markers. In specific cases, the ligand that the chimeric antigen receptor recognizes is present on the surface of a target cell, particularly cancer cell or viral cell. In some embodiments, the ligand that the chimeric antigen receptor recognizes is present in a tumor microenvironment. In some aspects of the invention, the ligand that the chimeric antigen receptor recognizes is a growth factor.

[0095] In one preferred embodiment, said VH and VL chains have as antigenic target sequence of over 80% identity, preferably over 90%, and more preferably over 95% with SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-3v antigen), SEQ ID NO 52 (WT1 antigen).

[0096] In one more preferred embodiment, said VH and VL chains have as antigenic target sequence of over 80% identity, preferably over 90%, and more preferably over 95% with or identical to SEQ ID NO 53-64 (CD19 antigen), SEQ ID NO 65-76 (CD33 antigen), SEQ ID NO 77-84 (5T4 antigen), SEQ ID NO 85-90 (ROR1 antigen), SEQ ID NO 91-94 (EGFRvIII antigen), SEQ ID NO 95-102 (BCMA antigen), SEQ ID NO 103-112 (CS1 antigen) and SEQ ID NO 113-124 (CD123 antigen) as follows in Table 3.

[0097] In some embodiments, the antigen recognized by the extracellular binding domain, preferably by the ScFv is selected from SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-vIII antigen) or SEQ ID NO 52 (WT1 antigen).

[0098] In some embodiments, the extracellular binding domain comprises: [0099] a VH of SEQ ID NO 65 and a VL of SEQ ID NO 66; a VH of SEQ ID NO 67 and a VL of SEQ ID NO 68; a VH of SEQ ID NO 69 and a VL of SEQ ID NO 70; a VH of SEQ ID NO 71 and a VL of SEQ ID NO 72; a VH of SEQ ID NO 77 and a VL of SEQ ID NO 78; a VH of SEQ ID NO 79 and a VL of SEQ ID NO 80; [0100] a VH of SEQ ID NO 81 and a VL of SEQ ID NO 82; a VH of SEQ ID NO 83 and a VL of SEQ ID NO 84; a VH of SEQ ID NO 85 and a VL of SEQ ID NO 86; a VH of SEQ ID NO 87 and a VL of SEQ ID NO 88; a VH of SEQ ID NO 89 and a VL of SEQ ID NO 90; a VH of SEQ ID NO 91 and a VL of SEQ ID NO 92; a VH of SEQ ID NO 93 and a VL of SEQ ID NO 94; a VH of SEQ ID NO 95 and a VL of SEQ ID NO 96; a VH of SEQ ID NO 97 and a VL of SEQ ID NO 98; a VH of SEQ ID NO 99 and a VL of SEQ ID NO 100; a VH of SEQ ID NO 101 and a VL of SEQ ID NO 102; a VH of SEQ ID NO 103 and a VL of SEQ ID NO 104; a VH of SEQ ID NO 105 and a VL of SEQ ID NO 106; a VH of SEQ ID NO 107 and a VL of SEQ ID NO 108; a VH of SEQ ID NO 109 and a VL of SEQ ID NO 110; a VH of SEQ ID NO 111 and a VL of SEQ ID NO 112; a VH of SEQ ID NO 113 and a VL of SEQ ID NO 114; a VH of SEQ ID NO 115 and a VL of SEQ ID NO 116; a VH of SEQ ID NO 117 and a VL of SEQ ID NO 118; a VH of SEQ ID NO 119 and a VL of SEQ ID NO 120; a VH of SEQ ID NO 121 and a VL of SEQ ID NO 122; a VH of SEQ ID NO 123 and a VL of SEQ ID NO 124; a VH of SEQ ID NO 170 and a VL of SEQ ID NO 171; a VH ofSEQ ID NO 172 and a VL of SEQ ID NO 173; or, a VH of SEQ ID NO 174 and a VL of SEQ ID NO 175.

TABLE-US-00003 [0100] TABLE 3 Listing of the VH & VL chains of scFv targeting the CD19, CD33, 5T4, ROR1, EGFRvIII, BCMA, CS1 and CD123 antigens Name of Cell scFV & SEQ surface VH or VL ID antigen chain NO Polypeptide sequence CD19 CD19-1 53 EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWG VH chain SETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAM DYWGQGTSVTV CD19-1 54 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRL VL chain HSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT CD19-2 55 EVQLQQSGPELIKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYI VH chain NPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARGTYYYGS RVFDYWGQGTTLTV CD19-2 56 DIVMTQAAPSIPVTPGESVSISCRSSKSLLNSNGNTYLYWFLQRPGQSP VL chain QLLIYRMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHL EYPFTFGAGTKLELK 26292 VH 57 QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWMNWVKQRPDQGLEWIGRI chain DPYDSETHYNQKFKDKAILIVDKSSSTAYMQLSSLTSEDSAVYYCARGNWDDY WGQGTTLTVSS 26292 VL 58 DVQITQSPSYLAASPGETITINCRASKSISKDLAWYQEKPGKTNKWYSGSTLQS chain GIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNKYPYTFGGGTKLEIK QIQLVQSGPELKKPGETVKISCKASGYIFTNYGMNWVKQAPGKSFKWMGWI 32716 VH 59 NTYTGESTYSADFKGRFAFSLETSASTAYLHINDLKNEDTATYFCARSGGYDPM chain DYWGQGTSVTVSS 32716 VL 60 DIVLTQSPASLAVSLGQRATISCRASESVDNYGNTFMHWYQQKPGQPPKLLIY chain RASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPPTFGAGTK LELK Klon43 61 MADYKDIVMTQSHKFMSTSVGDRVNITCKASQNVDSAVAWYQQKPGQSPK VH chain ALIYSASYRYSGVPDRFTGRGSGTDFTLTISSVQAEDLAVYYCQQYYSTPWTFG GGTKLEIKR Klon43 VL 62 EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLALIRS chain KADGYTTEYSASVKGRFTLSRDDSQSILYLQMNALRPEDSATYYCARDAAYYSY YSPEGAMDYWGQGTSVTVSS 12F1 VH 63 VQLQESGPGLVKPSQSLSLTCSVTDYSITSGYYWNWIRQFPGNKLEWMGYISY chain DGSNNYNPSLKNRISITRDTSKNQFFLKLSSVTTEDTATYYCSRGEGFYFDSWG QGTTLTVSSARS 12F1 VL 64 DIMMSQSPSSLAVSVGEKFTMTCKSSQSLFFGSTQKNYLAWYQQKPGQSPKL chain LIYWASTRESGVPDRFTGSGSGTDFTLAISSVMPEDLAVYYCQQYYNYPWTFG GGTKLEIK CD33 M195 VH 65 EVQLQQSGPELVKPGASVKISCKASGYTFTDYNMHWVKQSHGKSLEWIGYIY chain PYNGGTGYNQKFKSKATLTVDNSSSTAYMDVRSLTSEDSAVYYCARGRPAMD YWGQGTSVTVS M195 VL 66 DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGQPPKLLIYA chain ASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDTAMYFCQQSKEVPWTFGGG TKLEIK m2H12 67 QVQLQQSGPELVRPGTFVKISCKASGYTFTNYDINWVNQRPGQGLEWIGWIY VH chain PGDGSTKYNEKFKAKATLTADKSSSTAYLQLNNLTSENSAVYFCASGYEDAMD YWGQGTSVTVSS m2H12 VL 68 DIKMTQSPSSMYASLGERVIINCKASQDINSYLSWFQQKPGKSPKTLIYRANRL chain VDGVPSRFSGSGSGQDYSLTISSLEYEDMGIYYCLQYDEFPLTFGAGTKLELKR DRB2 VH 69 EVKLQESGPELVKPGASVKMSCKASGYKFTDYVVHWLKQKPGQGLEWIGYIN chain PYNDGTKYNEKFKGKATLTSDKSSSTAYMEVSSLTSEDSAVYYCARDYRYEVYG MDYWGQGTSVTVSS DRB2 VL 70 DIVLTQSPTIMSASPGERVTMTCTASSSVNYIHWYQQKSGDSPLRWIFDTSKV chain ASGVPARFSGSGSGTSYSLTISTMEAEDAATYYCQQWRSYPLTFGDGTRLELK RADAAPTVS My9-6 VH 71 QVQLQQPGAEVVKPGASVKMSCKASGYTFTSYYIHWIKQTPGQGLEWVGVIY chain PGNDDISYNQKFKGKATLTADKSSTTAYMQLSSLTSEDSAVYYCAREVRLRYFD VWGAGTTVTVSS My9-6 VL 72 NIMLTQSPSSLAVSAGEKVTMSCKSSQSVFFSSSQKNYLAWYQQIPGQSPKLLI chain YWASTRESGVPDRFTGSGSGTDFTLTISSVQSEDLAIYYCHQYLSSRTFGGGTKL EIKR M195 VH 73 EVQLQQSGPELVKPGASVKISCKASGYTFTDYNMHWVKQSHGKSLEWIGYIY chain PYNGGTGYNQKFKSKATLTVDNSSSTAYMDVRSLTSEDSAVYYCARGRPAMD YWGQGTSVTVS M195 VL 74 DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGQPPKLLIYA chain ASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDTAMYFCQQSKEVPWTFGGG TKLEIK m2H12 75 QVQLQQSGPELVRPGTFVKISCKASGYTFTNYDINWVNQRPGQGLEWIGWIY VH chain PGDGSTKYNEKFKAKATLTADKSSSTAYLQLNNLTSENSAVYFCASGYEDAMD YWGQGTSVTVSS m2H12 VL 76 DIKMTQSPSSMYASLGERVIINCKASQDINSYLSWFQQKPGKSPKTLIYRANRL chain VDGVPSRFSGSGSGQDYSLTISSLEYEDMGIYYCLQYDEFPLTFGAGTKLELKR H8 heavy 77 EVQLQQSGPDLVKPGASVKISCKASGYSFTGYYMHWVKQSHGKSLEWIGRIN chain PNNGVTLYNQKFKDKAILTVDKSSTTAYMELRSLTSEDSAVYYCARSTMITNYV MDYWGQVTSVTVSS H8 VL 78 SIVMTQTPTFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPTLLISYTSSR chain YAGVPDRFIGSGYGTDFTFTISTLQAEDLAVYFCQQDYNSPPTFGGGTKLEIKR A3 heavy 79 QIQLVQSGPELKKPGETVKISCKASGYTFTNFGMNWVKQGPGEGLKWMGWI chain NTNTGEPRYAEEFKGRFAFSLETTASTAYLQINNLKNEDTATYFCARDWDGAY FFDYWGQGTTLTVSS A3 light 80 SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLINFATN chain RYTGVPNRFTGSGYGTDFTFTISTVQAEDLALYFCQQDYSSPWTFGGGTKLEIK A2 heavy 81 QVQLQQSRPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGEIY chain PGSNSIYYNEKFKGRATLTADKSSSTAYMQLSSLTSEDSAVYFCAMGGNYGFD YWGQGTTLTVSS A2 light 82 QIVLTQSPAIMSASLGERVTLTCTASSSVNSNYLHWYQQKPGSSPKLWIYSTSN chain LASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCHQYHRSPLTFGAGTKLELK A3 heavy 83 EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARI chain RSKSNNYATYYADSVKDRFTISRDDSQSMLYLQMNNLKTEDTAMYYCVRQW DYDVRAMNYWGQGTSVTVSS A3 light 84 DIVMTQSHIFMSTSVGDRVSITCKASQDVDTAVAWYQQKPGQSPKLLIYWAS chain TRLTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSSYPYTFGGGTKLEIK ROR1 2A2 85 QVQLQQSGAELVRPGASVTLSCKASGYTFSDYEMHWVIQTPVHGLEWIGAID heavy PETGGTAYNQKFKGKAILTADKSSSTAYMELRSLTSEDSAVYYCTGYYDYDSFT chain YWGQGTLVTVSA 2A2 VL 86 DIVMTQSQKIMSTIVGDRVSITCKASQNVDAAVAWYQQKPGQSPKWYSAS chain NRYTGVPDRFTGSGSGTDFTLTISNMQSEDLADYFCQQYDIYPYTFGGGTKLEI K 4A5 87 EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQIPEKRLEWVASISR heavy GGTTYYPDSVKGRFTISRDNVRNILYLQMSSLRSEDTAMYYCGRYDYDGYYAM chain DYWGQGTSVTVSS 4A5 light 88 DIKMTQSPSSMYASLGERVTITCKASPDINSYLSWFQQKPGKSPKTLIYRANRL hain VDGVPSRFSGGGSGQDYSLTINSLEYEDMGIYYCLQYDEFPYTFGGGTKLEMK D10 89 QVQLKESGPGLVAPSQTLSITCTVSGFSLTSYGVHWVRQPPGKGLEWLGVIW heavy AGGFTNYNSALKSRLSISKDNSKSQVLLKMTSLQTDDTAMYYCARRGSSYSMD chain YWGQGTSVTVSS D10 light 90 EIVLSQSPAITAASLGQKVTITCSASSNVSYIHWYQQRSGTSPRPWIYEISKLASG chain VPVRFSGSGSGTSYSLTISSMEAEDAAIYYCQQWNYPLITFGSGTKLEIQ EGFRvIII 139- 91 EVQVLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAIS heavy GSGGSTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGSSGWSE chain YWGQGTLVIVSS 139- 92 DIQMTQSPSSLSASVGDRVTITCRASQGIRNNLAWYQQKPGKAPKRLIYAASN VL chain LQSGVPSRFTGSGSGTEFTLIVSSLQPEDFATYYCLQHHSYPLTSGGGTKVEIK MR1- 93 QVQLQQSGGGLVKPGASLKLSCVTSGFTFRKFGMSWVRQTSDKRLEWVASIS heavy TGGYNTYYSDNVKGRFTISRENAKNTLYLQMSSLKSEDTALYYCTRGYSSTSYA chain MDYWGQGTTVTV MR1- 94 DIELTQSPASLSVATGEKVTIRCMTSTDIDDDMNWYQQKPGEPPKFLISEGNTL light RPGVPSRFSSSGTGTDFVFTIENTLSEDVGDYYCLQSFNVPLTFGDGTKLEKAL chain BCMA BCMA-50 95 QVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMGW VH chain IYFASGNSEYNQKFTGRVTMTRDTSINTAYMELSSLTSEDTAVYFCASLYDYDW YFDVWGQGTMVTVSS BCMA-50 96 DIVMTQTPLSLSVTPGQPASISCKSSQSLVHSNGNTYLHWYLQKPGQSPQLLIY VL chain KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGIYYCSQSSIYPWTFGQGTK LEIK BCMA-30 97 QVQLVQSGAEVKKPGASVKVSCKASGYSFPDYYINWVRQAPGQGLEWMGW VH chain IYFASGNSEYNQKFTGRVTMTRDTSSSTAYMELSSLRSEDTAVYFCASLYDYD WYFDVWGQGTMVIVSS BCMA-30 98 DIVMTQTPLSLSVTPGEPASISCKSSQSLVHSNGNTYLHWYLQKPGQSPQLLIY VL chain KVSNRFSGVPDRFSGSGSGADFTLKISRVEAEDVGVYYCAETSHVPWTFGQGT KLEIK C11D5.3 99 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWIN VH chain TETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDY WGQGTSVTVSS C11D5.3 100 DIVLTGSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLA VL chain SNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEI K C13F12.1 101 QIQLVQSGPELKKPGETVKISCKASGYTFTHYSMNWVKQAPGKGLKWMGRI VH chain NTETGEPLYADDFKGRFAFSLETSASTAYLVINNLKNEDTATFFCSNDYLYSCDY WGRGTTLTVSS C13F12.1 102 DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQKPGQPPTLLIQLAS VL chain NVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK CS1 Luc63 VH 103 EVKLLESGGGLVQPGGSLKLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEIN chain PDSSTINYTPSLKDKFIISRDNAKNTLYLQMSKVRSEDTALYYCARPDGNYWYF DVWGAGTTVTVSS Luc63 VL 104 DIVMTQSHKFMSTSVGDRVSITCKASQDVGIAVAWYQQKPGQSPKWYWAS chain TRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSSYPYTFGGGTKLEI K Luc90 VH 105 QVQLQQPGAELVRPGASVKLSCKASGYSFTTYWMNWVKQRPGQGLEWIG chain MIHPSDSETRLNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCARSTMIA TRAMDYWGQGTSVTVSS Luc90 VL 106 DIVMTQSQKSMSTSVGDRVSITCKASQDVITGVAWYQQKPGQSPKLLIYSASY chain RYTGVPDRFTGSGSGTDFTFTISNVQAEDLAVYYCQQHYSTPLTFGAGTKLELK Luc34 VH 107 QVQLQQSGAELARPGASVKLSCKASGYTFTSYWMQWVKQRPGQGLEWIGA chain IYPGDGDTRYTQKFKGKATLTADKSSSTAYMQLSSLASEDSAVYYCARGKVYYG SNPFAYWGQGTLVTVSA Luc34 VL 108 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAWYQQKPGNAPRLLISGATS chain LETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLEIK LucX1 VH 109 QVQLQQSGPELVKPGASVKISCKASGYAFSSSWMNWVKQRPGQGLEWIGRI chain YPGDGDTKYNGKFKGKATLTADKSSSTAYMQLSSLTSVDSAVYFCARSTMIAT GAMDYWGQGTSVTVSS LucX1 VL 110 ETTVTQSPASLSMAIGEKVTIRCITSTDIDDDMNWYQQKPGEPPKLLISEGNTL chain RPGVPSRFSSSGYGTDFVFTIENMLSEDVADYYCLQSDNLPLTFGGGTKLEIK LucX2 VH 111 QVQLQQSGPELVKPGASVKISCKASGYAFSSSWMNWVKQRPGQGLEWIGRI chain YPGDGDTKYNGKFKGKATLTADKSSSTAYMQLSSLTSVDSAVYFCARSTMIAT GAMDYWGQGTSVTVSS LucX2 VL 112 DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPKWYSASY chain RYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTPPYTFGGGTKLEI K CD123 7G3 VH113 MGWSWIFLFLVSGTGGVLSEVQLQQSGPELVKPGASVKMSCKASGYTFTDYY chain MKWVKQSHGKSLEWIGDIIPSNGATFYNQKFKGKATLTVDRSSSTAYMHLNS LTSEDSAVYYCTRSHLLRASWFAYWGQGTLVTVSAAS 7G3 VL 114 MESQTQVLMSLLFWVSGTCGDFVMTQSPSSLTVTAGEKVTMSCKSSQSLLNS chain GNQKNYLTWYLQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQ AEDLAVYYCQNDYSYPYTFGGGTKLEIKR Old4 VH 115 WTWRFLFVVAAATGVQSQVQLLQSGAEVKKPGSSVKVSCKASGGTFSTYAIS chain WVRQAPGQGLEWMGGIIPIFGIVNYAQKFQGRVTITADESTSTAYMELSSLRS EDTAVYYCARGGGSGPDVLDIWGQGTMVTVSSAST Old4 VL 116 MDMRVPAQLLGLLLLWLPGARCVIWMTQSPSLLSASTGDRVTISCRMSQGIR chain SYLAWYQQKPGKAPELLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQSEDFAT YYCQQYYSFPYTFGQGTKLEIKRTV 26292 VH 117 QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWMNWVKQRPDQGLEWIGRI chain DPYDSETHYNQKFKDKAILWDKSSSTAYMQLSSLTSEDSAVYYCARGNWDDY WGQGTTLTVSS 26292 VL 118 DVQITQSPSYLAASPGETITINCRASKSISKDLAWYQEKPGKTNKWYSGSTLQS chain GIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNKYPYTFGGGTKLEIK 32716 VH 119 QIQLVQSGPELKKPGETVKISCKASGYIFTNYGMNWVKQAPGKSFKWMGWI chain NTYTGESTYSADFKGRFAFSLETSASTAYLHINDLKNEDTATYFCARSGGYDPM DYWGQGTSVTVSS 32716 VL 120 DIVLTQSPASLAVSLGQRATISCRASESVDNYGNTFMHWYQQKPGQPPKLLIY chain RASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPPTFGAGTK LELK Klon43 121 EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLALIRS VH chain KADGYTTEYSASVKGRFTLSRDDSQSILYLQMNALRPEDSATYYCARDAAYYSY YSPEGAMDYWGQGTSVTVSS Klon43 VL 122 MADYKDIVMTQSHKFMSTSVGDRVNITCKASQNVDSAVAWYQQKPGQSPK chain ALIYSASYRYSGVPDRFTGRGSGTDFTLTISSVQAEDLAVYYCQQYYSTPWTFG GGTKLEIKR 12F1 VH 123 VQLQESGPGLVKPSQSLSLTCSVTDYSITSGYYWNWIRQFPGNKLEWMGYISY chain DGSNNYNPSLKNRISITRDTSKNQFFLKLSSVTTEDTATYYCSRGEGFYFDSWG QGTTLTVSSARS 12F1 VL 124 DIMMSQSPSSLAVSVGEKFTMTCKSSQSLFFGSTQKNYLAWYQQKPGQSPKL chain LIYWASTRESGVPDRFTGSGSGTDFTLAISSVMPEDLAVYYCQQYYNYPWTFG GGTKLEIK FAP Humanized 170 QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGIN F19 VH PNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYD chain EGHAMDYWGQGTLVTVSS Humanized 171 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLI F19 VL FWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGT chain KVEIK FAP5 VH 172 QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIY chain PRSTNTLYNEKFKGKATLTADRSSNTAYMETELRSLTSEDSAVYFCARTLTAPFA FWGQGTLVTVSA FAP5 VL 173 QIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSK chain LASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIK R BCMA VH 174 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLE WVSAILSSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY CARYWPMDIWGQGTLVTV VL 175 EIVLTQSPGTLSLSPGERATLSCRGGQSVSSSYLAWYQQKPGQAPRLL MYDASIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYQSWPL TFGQGTKVEIK

[0101] In another preferred embodiment, said VH and VL chains have as epitope target sequence of over 80% identity, preferably over 90%, and more preferably over 95% with SEQ ID NO 11 (CD20 antigen).

[0102] The extracellular ligand-binding domain can also comprise a peptide binding an antigen of the target, a peptide or a protein binding an antibody that binds an antigen of the target, a peptide or a protein ligand such as a growth factor, a cytokine or a hormone as non-limiting examples binding a receptor on the target, or a domain derived from a receptor such as a growth factor receptor, a cytokine receptor or a hormone receptor as non-limiting examples, binding a peptide or a protein ligand on the target. Preferably the target is a cell or a virus.

[0103] The antigen binding domain of the CAR can be any domain that binds to the cell target antigen including but not limited to a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, and a functional fragment thereof.

[0104] A humanized antibody can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated herein in its entirety by reference), veneering or resurfacing (see, e.g., European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering, 7(6):805-814; and Roguska et al., 1994, PNAS, 91:969-973, each of which is incorporated herein by its entirety by reference), chain shuffling (see, e.g., U.S. Pat. No. 5,565,332, which is incorporated herein in its entirety by reference), and techniques disclosed in, e.g., U.S. Patent Application Publication No. US2005/0042664, U.S. Patent Application Publication No. US2005/0048617, U.S. Pat. No. 6,407,213, U.S. Pat. No. 5,766,886, International Publication No. WO 9317105, Tan et al., J. Immunol., 169: 1119-25 (2002), Caldas et al., Protein Eng., 13(5):353-60 (2000), Morea et al., Methods, 20(3):267-79 (2000), Baca et al., J. Biol. Chem., 272(16): 10678-84 (1997), Roguska et al., Protein Eng., 9(10):895-904 (1996), Couto et al., Cancer Res., 55 (23 Supp):5973s-5977s (1995), Couto et al., Cancer Res., 55(8): 1717-22 (1995), Sandhu J S, Gene, 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol., 235(3):959-73 (1994), each of which is incorporated herein in its entirety by reference. Often, framework residues in the framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, for example improve, antigen binding. These framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, which are incorporated herein by reference in their entireties.).

[0105] According to the invention, the scFv may be nanobodies (natural single domain antibodies) which can be obtained by immunization of dromedaries, camels, llamas, alpacas or sharks.

Linkers within the Chimeric scFv

[0106] The flexibility of scFv linker engineering can be combined with the inherent quick and adaptable characters of surface coupling chemistry (e.g., electrostatic, hydrogen bonding, or covalent attachment). Peptide linkers can vary from 10 to 25 amino acids in length and are typically, but not always, composed of hydrophilic amino acids such as glycine (G) and serine (S). Peptide linkers of shorter lengths (0-4 amino acids) have also been used. However, scFv bearing shorter linkers can form multimers. Generally, the (GGGGS).sub.3 peptide is used as an scFv peptide linker. This 15-amino acid linker sequence [designated as the (GGGGS).sub.3 linker] is used in the Recombinant Phage Antibody System (RPAS kit) commercially available from Amersham. Previous study demonstrated that scFvs (MW .sup..about.27 000) containing metal-binding amino acids (i.e., cysteine or histidine) in the scFv peptide linker can be directly immobilized onto a gold surface in a favorable antigen-binding orientation at high density that significantly increased assay sensitivity by 3-5-fold over whole IgG or Fab antibody fragments, respectively (Shen Z, Mernaugh R L, Yan H, Yu L, Zhang Y, Zeng X. Anal. Chem. 2005; 77:6834-6842; Shen Z, Stryker G A, Mernaugh R L, Yu L, Yan H, Zeng X. Anal. Chem. 2005; 77:797-805).

[0107] Amongst other linkers suitable within the present invention are the 15-mer peptide linker (RGRGRGRGRSRGGGS) (Zhihong Shen, Heping Yan, Ying Zhang, Raymond L. Mernaugh, and Xiangqun Zeng (2008), Anal Chem. 80(6): 1910-1917).

[0108] In some embodiments, the "linker" as used in the context of a scFv refers to a peptide linker that consists of amino acids such as glycine and/or serine residues used alone or in combination, to link variable heavy and variable light chain regions together. In one embodiment, the flexible polypeptide linker is a Glycine/Serine linker and comprises the amino acid sequence (Gly-Gly-Gly-Ser).sub.n or (Gly-Gly-Gly-Gly-Ser).sub.n, where n is a positive integer equal to or greater than 1. For example, n=1, n=2, n=3, n=4, n=5, n=6, n=7, n=8, n=9 and n=10. In one embodiment, the flexible polypeptide linkers include, but are not limited to, (Gly.sub.4Ser).sub.4 or (Gly.sub.4Ser).sub.3. In another embodiment, the linkers include multiple repeats of (Gly.sub.xSer).sub.n, where x=1, 2, 3, 4 or 5 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, such as multiple repeat of (GlySer), (Gly.sub.2Ser) or (Gly.sub.5Ser). Also included within the scope of the invention are linkers described in WO2012/138475, incorporated herein by reference.

Chimeric Antigen Receptor (CAR)

[0109] The CAR according to the invention are sought for enabling engineered immune cells to trigger the destruction of pathological cells, in particular malignant cells. They may be designed according to single-chain or multi-chain architectures. In some embodiments, the extracellular ligand-binding domain, transmembrane domain, and intracellular signaling domain are in one polypeptide, i.e., in a single chain. Multi-chain architectures are more particularly disclosed in WO2014039523.

[0110] A multi-chain CAR is typically formed of different polypeptides such as: [0111] one transmembrane polypeptide comprising at least one extracellular ligand-binding domain and; [0112] one transmembrane polypeptide comprising at least one signal-transducing domain.

[0113] The signaling polypeptide is responsible for the activation of at least one of the normal functions of the engineered immune cell. For example, the function of a T cell can be a cytolytic activity or helper activity including the secretion of cytokines. Thus, the term "signaling protein" refers to a protein which transduces the transmitter domain function signal and directs the cell to perform a specialized function. In a particular embodiment, said transmitter domain can be a signaling protein. Transmission of the signals can result from: protein/protein interactions, protein/DNA interaction, protein/RNA interaction, protein/small molecule interaction, post translational protein modification, conformational change, subcellular relocalization.

[0114] The signaling protein can activate a gene in the nucleus. Examples of signaling protein can be members of NFAT transcription factor family which are inducible factor that could bind the interleukin-2 promoter in activated T cells. The regulation of NFAT proteins involves metabolites and proteins such as calcium, calcineurin and Homer scaffolding proteins. Said signaling protein can be an activated engineered form of NFAT avoiding regulation by calcineurin and Homer proteins. Said signaling protein can be a NF-.kappa.B engineered to avoid sequestration in the cytoplasm by I.kappa.b allowing activation of T cells. Said signaling protein can also be the expression of the three IKK subunits (IKK.alpha., IKK.beta., IKK.gamma.). Reconstituted IKK complex activated NF-.kappa.B pathway, by triggering the ubiquitination of the I.kappa.B. Also the activation of the JNK signaling could be triggered through the direct expression of signaling protein AP-1 (transcription factor). Said signaling protein can be an engineered transcription activator like effector (TALE) binding domain that will specifically target and activate transcription of the same gene as for the N FAT and NF-kb.

[0115] According to the invention, said signaling protein can inhibit a signaling pathway through protein-protein interaction or can activate a gene in the nucleus to inhibit a signaling pathway. Said signaling protein can be vaccinia H1 related proteins (VHR) a member of the mitogen-activated protein kinase phosphatases (MKPs) family which dephosphorylates and inactivates an extracellular signal regulated kinases (ERK) signaling proteins.

[0116] According to the invention, signal transducing domain for use in a CAR can be the cytoplasmic sequences of the T cell receptor and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivate or variant of these sequences and any synthetic sequence that has the same functional capability. Signal transduction domain may comprise two distinct classes of cytoplasmic signaling sequence, those that initiate antigen-dependent primary activation, and those that act in an antigen-independent manner to provide a secondary or co-stimulatory signal.

[0117] In particular embodiment the signal transduction domain of the CAR of the present invention comprises a co-stimulatory signal molecule. A co-stimulatory molecule is a cell surface molecule other than an antigen receptor or their ligands that is required for an efficient immune response.

[0118] "Co-stimulatory ligand" refers to a molecule on an antigen presenting cell that specifically binds a cognate co-stimulatory molecule on a T cell, thereby providing a signal which, in addition to the primary signal provided by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, mediates a T cell response, including, but not limited to, proliferation activation, differentiation and the like. A "co-stimulatory molecule" refers to the cognate binding partner on a T cell that specifically binds with a co-stimulatory ligand, thereby mediating a co-stimulatory response by the cell, such as, but not limited to proliferation. Co-stimulatory molecules include, but are not limited to an MHC class I molecule, BTLA and Toll ligand receptor.

[0119] For instance, a multi-chain CAR can be derived from the structure of a Fc receptor, preferably Fc.epsilon.RI, and comprise at least two of the following components: [0120] a) one polypeptide comprising the transmembrembrane domain of FcRI alpha chain fused to an extracellular ligand-binding domain, [0121] b) one polypeptide comprising a part of N- and C-terminal cytoplasmic tail fused to the transmembrane domain of a FcRI beta chain, and/or [0122] c) two additional polypeptides comprising each one part of an intracytoplasmic tail and/or the transmembrane domain of FcRI gamma chain,

[0123] In general, these different polypeptides multimerize together spontaneously to form dimeric, trimeric or tetrameric structures that arise at the cell surface in a juxtamembrane position.

[0124] In some embodiments, the invention relates to an immune cell comprising a single-chain CAR as well defined in the prior art, as well as in any of U.S. Pat. No. 7,446,190, WO2008/121420, U.S. Pat. No. 8,252,592, US20140024809, WO2012/079000, WO2014153270, WO2012/099973, WO2014/011988, WO2014/011987, WO2013/067492, WO2013/070468, WO2013/040557, WO2013/126712, WO2013/126729, WO 2013/126726, WO2013/126733, U.S. Pat. No. 8,399,645, US20130266551, US20140023674, WO2014039523, U.S. Pat. No. 7,514,537, U.S. Pat. No. 8,324,353, WO2010/025177, U.S. Pat. No. 7,446,179, WO2010/025177, WO2012/031744, WO2012/136231A1, WO2012/050374A2, WO2013074916, WO/2009/091826A3, WO2013/176915 or WO/2013/059593.

[0125] In some embodiments, the invention relates to a CAR comprising [0126] an extracellular domain comprising [0127] at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, preferably a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope, and, [0128] a hinge, [0129] a transmembrane domain, and, [0130] an intracellular domain.

[0131] In one embodiment, the transmembrane domain comprises the transmembrane region(s) of the alpha, beta or zeta chain of the T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154.

[0132] In another embodiment, the hinge is an IgG4 hinge or a CD8 alpha hinge, preferably a CD8 alpha hinge.

[0133] The distinguishing features of appropriate transmembrane domains comprise the ability to be expressed at the surface of a cell, preferably in the present invention an immune cell, in particular lymphocyte cells or Natural killer (NK) cells, and to interact together for directing cellular response of immune cell against a predefined target cell. The transmembrane domain can be derived either from a natural or from a synthetic source. The transmembrane domain can be derived from any membrane-bound or transmembrane protein. As non-limiting examples, the transmembrane polypeptide can be a subunit of the T cell receptor such as .alpha., .beta., .gamma. or .delta., polypeptide constituting CD3 complex, IL2 receptor p55 (.alpha. chain), p75 (.beta. chain) or .gamma. chain, subunit chain of Fc receptors, in particular Fc.gamma. receptor III or CD proteins. Alternatively the transmembrane domain can be synthetic and can comprise predominantly hydrophobic residues such as leucine and valine. In a preferred embodiment said transmembrane domain is derived from the human CD8 alpha chain (e.g. NP_001139345.1). Said transmembrane domain can also be a CD8 transmembrane domain (alpha and beta chains). Said Transmembrane domain can be engineered to create obligated hetero or homodimers. In particular embodiment said CARs can comprise transmembrane domains or intracellular domains which can only dimerize after ligand recognition. Another example of transmembrane domain can be NKG2-D receptor. NKG2D (natural killer cell group 2D) is a C-type lectin-like receptor expressed on NK cells, .gamma..delta.-TcR.sup.+ T cells, and CD8.sup.+.alpha..beta.-TcR.sup.+ T cells (Bauer, Groh et al., 1999, Science 285(5428):727-9. NKG2D is associated with the transmembrane adapter protein DAP10 (Wu, Song et al. 1999, Science 285(5428):730-2), whose cytoplasmic domain binds to the p 85 subunit of the PI-3 kinase.

[0134] Said transmembrane domain can also be an integrin. Integrins are heterodimeric integral membrane proteins composed of a .alpha. and .beta. chains which combined together form the LFA-1 (integrin lymphocyte function-associated antigen-1) which is expressed on all leukocytes. LFA-1 plays a central role in leukocyte intercellular adhesion through interactions with its ligand, ICAMs 1-3 (intercellular adhesion molecules 1 through 3), and also it has an important role in lymphocyte co-stimulatory signaling (Chen and Flies 2013, Nat Rev Immunol 13(4):227-42). The molecular details of the binding of LAF-1 to its immunoglobulin ICAM-1 are quite known allowing a careful engineering of LAF-1 binding site. The affinity of .alpha..sub.L domain for ICAM-1 is regulated by the displacement of its C-terminal helix which is conformational linked to alterations of specific loops in LAF-1. The active and low conformations differ of 500 and 10,000 folds. It is also interesting to note that two types of antagonists are known for LFA-1 and their mechanism of action is known. Integrin cell surface adhesion receptors can transmit a signal from the outside to inside but also vice-versa. There are cytoskeletal proteins as Talin which binds to the integrin tail LFA-1 to transfer a message from inside to outside.

[0135] According to one embodiment, the transmembrane domain comprises the transmembrane region of PD-1 or the transmembrane region(s) of CD8 alpha.

[0136] In one aspect of the invention, the transmembrane domain is attached to the extracellular domain of the CAR via a hinge e.g., a hinge from a human protein. For example, in one embodiment, the hinge can be a human Ig (immunoglobulin) hinge, e.g., a PD-1 hinge, an IgG4 hinge, or a CD8alpha hinge.

[0137] In a preferred embodiment, the hinge of the CAR is a human immunoglobulin hinge.

[0138] In a more preferred embodiment, the hinge of the CAR is an IgG4 hinge or a CD8 alpha hinge.

[0139] In some embodiments, the hinge is an Fc.gamma.RIII alpha hinge.

[0140] In some embodiments, the hinge is a CD8 alpha hinge.

[0141] In some embodiments, the hinge is a CD8 alpha hinge has amino acid sequence with at least about 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% sequence identity with an amino acid sequence shown in SEQ. ID NO: 179, 180 or 181.

[0142] The term "hinge region" (also named stalk region in the literature) used herein generally means any oligo- or polypeptide that functions to link the transmembrane domain to the extracellular ligand-binding domain. In particular, stalk region are used to provide more flexibility and accessibility for the extracellular ligand-binding domain. A stalk region may comprise up to 300 amino acids, preferably 10 to 100 amino acids and most preferably 25 to 50 amino acids. Stalk region may be derived from all or part of naturally occurring molecules, such as from all or part of the extracellular region of CD8, CD4, CD28 or RTK, or from all or part of an antibody constant region. Alternatively the stalk region may be a synthetic sequence that corresponds to a naturally occurring stalk sequence, or may be an entirely synthetic stalk sequence.

[0143] The intracellular domain (also referred to herein as a "cytoplasmic signaling domain" or "an intracellular signaling domain") comprises a functional signaling domain derived from a stimulatory molecule as defined below. In some embodiments, the stimulatory molecule is the zeta chain associated with the T-cell receptor complex. In some embodiments, the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below. In some embodiments, the costimulatory molecule is chosen from 4-1BB (i.e., CD137), CD27 and/or CD28.

[0144] The term "stimulatory molecule," refers to a molecule expressed by a T-cell that provides the positive cytoplasmic signaling sequence(s) that regulate positive activation of the TCR complex in a stimulatory way for at least some aspect of the T-cell signaling pathway. In some embodiments, the positive signal is initiated by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, and which leads to mediation of a T-cell response, including, but not limited to, proliferation, activation, differentiation, and the like. A positive cytoplasmic signaling sequence (also referred to as a "positive signaling domain" or positive intracellular signaling domain) that acts in a stimulatory manner may contain a signaling motif which is known as immunoreceptor tyrosine-based activation motif or ITAM. Examples of an ITAM containing positive cytoplasmic signaling sequence includes, but is not limited to, those derived from TCR zeta (or CD3zeta), FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (also known as "ICOS") and CD66d. In some embodiments, the intracellular signaling domain of the CAR can comprise the CD3.zeta. (zeta) signaling domain which has amino acid sequence with at least about 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% sequence identity with an amino acid sequence shown in SEQ. ID NO: 175.

[0145] In some aspect, the intracellular signaling domain of the CAR generates a signal that promotes an immune effector function of the CAR containing cell. Examples of immune effector function, e.g., in a CAR T-cell, include cytolytic activity and helper activity, including the secretion of cytokines.

[0146] The term "costimulatory molecule" refers to the cognate binding partner on a T-cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T-cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an efficient immune response. Costimulatory molecules include, but are not limited to an MHC class I molecule, BTLA and a Toll ligand receptor, as well as OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18) and 4-IBB (CD137).

[0147] A costimulatory intracellular signaling domain can be the intracellular portion of a costimulatory molecule. A costimulatory molecule can be represented in the following protein families: TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), and activating NK cell receptors. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and a ligand that specifically binds with CD83, and the like. In some embodiments, the intracellular signaling domain of the CAR of the invention comprises amino acid sequence which comprises at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% sequence identity with an amino acid sequence shown in SEQ. ID NO: 176 and SEQ. ID NO: 177.

TABLE-US-00004 TABLE 4 provide exemplary sequence of CAR components SEQ ID Domain Amino Acid Sequence NO: CD8.alpha. signal peptide MALPVTALLLPLALLLHAARP 178 Fc.gamma.RIII.alpha. hinge GLAVSTISSFFPPGYQ 179 CD8.alpha. hinge TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD 180 IgG1 hinge EPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVD 181 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK CD8.alpha. IYIWAPLAGTCGVLLLSLVITLYC 182 transmembrane (TM) domain 41BB intracellular KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 176 signaling domain (ISD) CD3.zeta. intracellular RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGG 175 signaling domain KPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS (ISD) TATKDTYDALHMQALPPR Fc.epsilon.R1 .alpha.-TM-IC FFIPLLVVILFAVDTGLFISTQQQVTFLLKIKRTRKGFRLLNPHPKPNPKNN 183 (Fc.epsilon.R1 .alpha. chain transmembrane and intracellular domain) Fc.epsilon.RI.beta.-.DELTA.ITAM MDTESNRRANLALPQEPSSVPAFEVLEISPQEVSSGRLLKSASSPPLHTW 184 (Fc.epsilon.RI.beta. chain LTVLKKEQEFLGVTQILTAMICLCFGTVVCSVLDISHIEGDIFSSFKAGYPF without ITAM) WGAIFFSISGMLSIISERRNATYLVRGSLGANTASSIAGGTGITILIINLKKS LAYIHIHSCQKFFETKCFMASFSTEIVVMMLFLTILGLGSAVSLTICGAGE ELKGNKVPE 41BB-IC (41BB co- KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 177 stimulatory domain) CD28-IC (CD28 co- RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 185 stimulatory domain)

[0148] CARs and immune cells comprising them have been extensively disclosed and can be prepared by the skilled person according to known methods. For example, methodologies to prepare CARs and cells comprising such CARs are disclosed in U.S. Pat. No. 7,446,190, WO2008/121420, U.S. Pat. No. 8,252,592, US20140024809, WO2012/079000, WO2014153270, WO2012/099973, WO2014/011988, WO2014/011987, WO2013/067492, WO2013/070468, WO2013/040557, WO2013/126712, WO2013/126729, WO 2013/126726, WO2013/126733, U.S. Pat. No. 8,399,645, US20130266551, US20140023674, WO2014039523, U.S. Pat. No. 7,514,537, U.S. Pat. No. 8,324,353, WO2010/025177, U.S. Pat. No. 7,446,179, WO2010/025177, WO2012/031744, WO2012/136231A1, WO2012/050374A2, WO2013074916, WO2009/091826A3, WO2013/176915 or WO/2013/059593 which are all incorporated herein in their entirety by reference.

[0149] The present invention encompasses a recombinant DNA construct comprising sequences encoding an CAR as defined above, wherein the CAR comprises an extracellular domain such as an antibody fragment that binds specifically to cell target antigen, and wherein the sequence of the extracellular domain is contiguous with and in the same reading frame as a nucleic acid sequence encoding a transmembrane domain and an intracellular domain. An exemplary CAR construct may comprise an optional leader sequence, an extracellular cell target antigen binding domain, a hinge, a transmembrane domain, and an intracellular inhibitory signaling domain

[0150] In some embodiments, the invention relates to a recombinant DNA construct comprising sequences encoding a CAR as defined above. In some embodiments, the CAR comprises an extracellular domain comprising [0151] at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope to be bound by a epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing said CAR and wherein comprising comprising an extracellular binding domain, and, [0152] a hinge, [0153] a transmembrane domain, and, [0154] an intracellular domain.

Method for Sorting CAR-Positive Immune Cells

[0155] According to one aspect, the invention relates to a method for in vitro sorting CAR-expressing immune cell, comprising contacting a population of said engineered immune with antigen-specific antibody (preferably monoclonal Abs) to collect only cells expressing CAR.

[0156] In some embodiments, the invention relates to a method for in vitro sorting CAR-expressing immune cell, wherein said CAR comprises at least one extracellular binding domain comprising at least one mAb-specific epitope as described above, comprising [0157] contacting a population of said immune cells with a monoclonal antibody specific for said mAb-specific epitope to collect only said CAR-expressing immune cell.

[0158] In some embodiments, the invention relates to a method for in vitro sorting CAR-expressing immune cells, wherein said CAR comprises at least one extracellular binding domain comprising at least one mAb-specific epitope, comprising [0159] contacting a population of said immune cells with a monoclonal antibody (epitope-specific mAb) specific for said mAb-specific epitope, [0160] selecting the cells that bind to the monoclonal antibody, to obtain a population of cells enriched in CAR-expressing immune cell.

[0161] In some embodiments, said monoclonal antibody specific for said mAb-specific epitope is conjugated to a fluorophore and the step of selecting the cells that bind to the monoclonal antibody is done by Fluorescence Activated Cell Sorting (FACS).

[0162] In some embodiments, said monoclonal antibody specific for said mAb-specific epitope is conjugated to a magnetic particle and the step of selecting the cells that bind to the monoclonal antibody is done by Magnetic Activated Cell Sorting (MACS).

[0163] In some embodiments, the extracellular binding domain of the CAR comprises a mAb-specific epitope of SEQ ID NO 144.

[0164] In some embodiments, the extracellular binding domain of the CAR comprises a mAb-specific epitope of SEQ ID NO 144 and the antibody used to contact the population of immune cells is QBEND-10.

[0165] In some embodiments, the extracellular binding domain of the CAR comprises a mAb-specific epitope of SEQ ID NO 35.

[0166] In some embodiments, the extracellular binding domain of the CAR comprises a mAb-specific epitope of SEQ ID NO 35 and the antibody used to contact the population of immune cells is Rituximab.

[0167] In some embodiments, the population CAR-expressing immune cells obtained when using the method for in vitro sorting CAR-expressing immune cells described above, comprises at least 70%, 75%, 80%, 85%, 90%, 95% of CAR-expressing immune cells. In some embodiments, the population CAR-expressing immune cells obtained when using the method for in vitro sorting CAR-expressing immune cells described above, comprises at least 85% CAR-expressing immune cells.

[0168] In some embodiments, the population of CAR-expressing immune cells obtained when using the method for in vitro sorting CAR-expressing immune cells described above shows increased cytotoxic activity in vitro compared with the initial (non-sorted) cell population using the protocol described in Example 7.5. In a preferred embodiment, said cytotoxic activity in vitro is increased by 10%, 20%, 30% or 50%.

[0169] Preferably, the mAbs are previously bound onto a support such as a column or on beads such as routinely realized by the skilled in the art.

[0170] According to a favored embodiment, immune cells are T-cells.

[0171] According to the invention, cells to be administered to the recipient may be enriched in vitro from the source population.

[0172] Methods of expanding source populations are well known in the art, and may include selecting cells that express an antigen such as CD34 antigen, using combinations of density centrifugation, immuno-magnetic bead purification, affinity chromatography, and fluorescent activated cell sorting, known to those skilled in the art.

Flow Cytometry

[0173] Flow cytometry is widely used in the art and is a method well known to one of ordinary skill to sort and quantify specific cell types within a population of cells. In general, flow cytometry is a method for quantitating components or structural features of cells primarily by optical means. Since different cell types can be distinguished by quantitating structural features, flow cytometry and cell sorting can be used to count and sort cells of different phenotypes in a mixture.

[0174] A flow cytometric analysis involves two basic steps: 1) labeling selected cell types with one or more labeled markers, and T) determining the number of labeled cells relative to the total number of cells in the population.

[0175] The primary method of labeling cell types is by binding labeled antibodies to markers expressed by the specific cell type. The antibodies are either directly labeled with a fluorescent compound or indirectly labeled using, for example, a fluorescent-labeled second antibody which recognizes the first antibody.

[0176] In a preferred embodiment, the method used for sorting T cells expressing CAR is the Magnetic-Activated Cell Sorting (MACS).

[0177] Magnetic-activated cell sorting (MACS) is a method for separation of various cell populations depending on their surface antigens (CD molecules) by using superparamagnetic nanoparticles and columns. It takes only a few simple steps to get pure cell populations Cells in a single-cell suspension are magnetically labeled with microbeads. The sample is applied to a column composed of ferromagnetic spheres, which are covered with a cell-friendly coating allowing fast and gentle separation of cells. The unlabeled cells pass through while the magnetically labeled cells are retained within the column. The flow-through can be collected as the unlabeled cell fraction. After a short washing step, the column is removed from the separator, and the magnetically labeled cells are eluted from the column.

[0178] Amongst other technique, FACS is a technique of choice to purify cell populations of known phenotype as very high purity of the desired population can be achieved, or when the target cell population expresses a very low level of the identifying marker, or when cell populations require separation based on differential marker density. In addition, FACS is the only available purification technique to isolate cells based on internal staining or intracellular protein expression, such as a genetically modified fluorescent protein marker. FACS allows the purification of individual cells based on size, granularity and fluorescence. In order to purify cells of interest, they are first stained with fluorescently-tagged monoclonal antibodies (mAb), which recognize specific surface markers on the desired cell population.

[0179] Detailed protocol for the purification of specific cell population such as T-cell can be found in Basu S et al. (2010). (Basu S, Campbell H M, Dittel B N, Ray A. Purification of specific cell population by fluorescence activated cell sorting (FACS). J Vis Exp. (41): 1546).

[0180] In a preferred embodiment of the invention, the mAb used in the method for sorting T cells expressing the CAR is chosen amongst ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and ustekinumab.

[0181] In a more preferred embodiment, said mAb is rituximab.

[0182] In a more preferred embodiment, said mAb is QBEND-10.

Method for Depleting CAR-Expressing Immune Cells

[0183] By "in vivo depletion" is meant in the present invention the administration of a treatment to a mammalian organism aiming to stop the proliferation of CAR-expressing immune cells by inhibition or elimination.

[0184] One aspect of the invention is related to a method for in vivo depleting an engineered immune cell expressing a CAR comprising an m-Ab specific epitope as previously described, comprising contacting said engineered immune cell or said CAR-expressing immune cell with at least one epitope-specific mAbs. Another aspect of the invention relates to a method for in vivo depleting immune CAR-expressing immune cell which comprises the above chimeric scFv (formed by insertion of a mAb-specific epitope) by contacting said engineered immune cell with epitope-specific antibodies.

[0185] Preferably, said immune cells are T-cells and/or the antibodies are monoclonal.

[0186] According to one embodiment, the in vivo depletion of immune engineered cell is performed on engineered immune cell which has been previously sorted using the in vitro method of the present invention. In this case, this will be the same infused mAb used.

[0187] According to a preferred embodiment, the mAb-specific antigen is CD20 antigen and the epitope-specific mAb is rituximab.

[0188] In some embodiments, the invention relates to a method for in vivo depleting an engineered immune cell expressing a CAR comprising an mAb-specific epitope (CAR-expressing immune cell) as previously described, in a patient comprising contacting said CAR-expressing immune cell with at least one epitope-specific mAb.

[0189] In a preferred embodiment of the invention, the mAb used in the method for depleting an engineered immune cell expressing a CAR is chosen amongst ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and ustekinumab.

[0190] In some embodiments, said mAb-specific epitope is a CD20 epitope or mimotope, preferably SEQ ID NO 35 and the epitope-specific mAbs is rituximab.

[0191] In some embodiments, the step of contacting said engineered immune cell or said CAR-expressing immune cell with at least one epitope-specific mAb comprises infusing the patient with epitope-specific mAb, preferably rituximab. In some embodiments, the amount of epitope-specific mAb administered to the patient is sufficient to eliminate at least 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the CAR-expressing immune cell in the patient.

[0192] In some embodiments, the step of contacting said engineered immune cell or said CAR-expressing immune cell with at least one epitope-specific mAb comprises infusing the patient with 375 mg/m.sup.2 of rituximab, once or several times, preferably once weekly.

[0193] In some embodiments, when immune cells expressing a CAR comprising an mAb-specific epitope (CAR-expressing immune cells) are depleted in a CDC assay using epitope-specific mAb, the amount of viable CAR-expressing immune cells decreases, preferably by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. Preferably the CDC assay is the assay disclosed in Example 3, Example 4 or Example 7.4. In some embodiments, said mAb-specific epitope is a CD20 epitope or mimotope, preferably SEQ ID NO 35 and the epitope-specific mAbs is rituximab.

[0194] To one particular embodiment, the in vivo depletion of CAR-engineered immune cells is performed by infusing bi-specific antibodies. By definition, a bispecific monoclonal antibody (BsAb) is an artificial protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen. These BsAbs and their use in immunotherapy have been extensively reviewed in Muller D and Kontermann R. E. (2010) Bispecific Antibodies for Cancer Immunotherapy, BioDrugs 24 (2): 89-98.

[0195] By "effector cell", this term includes immune cells such as lymphocytes, macrophages, dendritic cells, natural killer cells (NK Cell), cytotoxic T lymphocytes (CTL).

[0196] According to another particular embodiment, the infused bi-specific mAb is able to bind both the mAb-specific epitope borne on engineered immune cells expressing the chimeric scFv and to a surface antigen on an effector and cytotoxic cell. This aspect is presented in FIG. 3. By doing so, the depletion of engineered immune cells triggered by the BsAb can occur through antibody-dependent cellular cytotoxicity (ADCC). Such conformation can be found by instance in Deo Y M, Sundarapandiyan K, Keler T, Wallace P K, and Graziano R F, (2000), Journal of Immunology, 165 (10):5954-5961].

[0197] According to a particular embodiment, a cytotoxic drug is coupled to the epitope-specific mAbs which are used in to deplete CAR-expressing immune cells. By combining targeting capabilities of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs, antibody-drug conjugate (ADC) allows a sensitive discrimination between healthy and diseased tissue when compared to the use of the drug alone. Market approvals were received for several ADCs; the technology for making them--particularly on linkers--is abundantly presented in the following prior art (Payne, G. (2003) Cancer Cell 3:207-212; Trail et al (2003) Cancer Immunol. Immunother. 52:328-337; Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Del. Rev. 26:151-172; U.S. Pat. No. 4,975,278).

[0198] According to another particular embodiment, the epitope-specific mAb to be infused is conjugated beforehand with a molecule able to promote complement dependent cytotoxicity (CDC). Therefore, the complement system helps or complements the ability of antibodies to clear pathogens from the organism. When stimulated by one of several, is triggered an activation cascade as a massive amplification of the response and activation of the cell-killing membrane attack complex.

[0199] Different molecule may be used to conjugate the mAb, such as glycans [Courtois, A, Gac-Breton, S., Berthou, C., Guezennec, J., Bordron, A. and Boisset, C. (2012), Complement dependent cytotoxicity activity of therapeutic antibody fragments is acquired by immunogenic glycan coupling, Electronic Journal of Biotechnology ISSN: 0717-3458; http://www.ejbiotechnology.info DOI: 10.2225/vol15-issue5).

[0200] In some embodiments of the invention, the epitope-specific mAb used in the method for sorting and depleting an engineered immune cell expressing a CAR is the same and is chosen amongst ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and ustekinumab.

[0201] In some embodiments of the invention, different antibodies are used for sorting and depleting the cells. In some embodiments, the extracellular binding domain comprises at least one epitope specifically bound by rituximab such as an mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 and at least one epitope specifically bound by QBEND10 such as SEQ ID NO 144 and the mAb used for sorting the cells is QBEND10 and the mAb used to deplete the cell is rituximab.

Methods of Engineering Immune Cells

[0202] The inventors developed methods of engineering immune cells expressing a chimeric antigen receptor (CAR), preferably a CAR as described above, with all components necessary to trigger a cell surface target antigen and to expand/amplify. Further, this CAR has the particularity of to carry a chimeric scFv wherein the scFv is modified to include an epitope able to be specifically recognized by an antibody for cell sorting and/or cell depletion purposes.

[0203] In one embodiment, the method for engineering an immune cell chimeric antigen receptor (CAR), comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to a cell surface marker antigen and one mAb-specific epitope to be bound by a epitope-specific mAb, comprising: [0204] (a) Providing an immune cell; [0205] (b) Introducing into said cell at least one polynucleotide encoding the said chimeric antigen receptor. [0206] (c) Expressing said polynucleotide into said cell.

[0207] In one embodiment, the method for engineering an immune cell expressing a chimeric antigen receptor (CAR) as described above, preferably comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to a cell surface marker antigen and one mAb-specific epitope to be bound by a epitope-specific mAb, comprises:

(a) Providing an immune cell; (b) Introducing into said cell at least one polynucleotide encoding the said chimeric antigen receptor; and, (c) Expressing said polynucleotide into said cell.

[0208] CARs and immune cells comprising them have been extensively disclosed and can be prepared by the skilled person according to known methods. For example, methodologies to prepare CAR and cells comprising such CARs are disclosed earlier. Immune cells comprising a CAR can be prepared by the skilled person according to the methodologies disclosed in the above mentioned references. In a preferred embodiment, immune cells comprising a CAR can be prepared by the skilled person according to the methodologies disclosed in WO2013/176915.

[0209] In some embodiments, the immune cell can be derived from an inflammatory T-lymphocyte, a cytotoxic T-lymphocyte, a regulatory T-lymphocyte, or a helper T-lymphocyte.

[0210] In some embodiments, immune cell is obtained from a healthy donor. In some embodiments, the immune cell is obtained from a patient.

[0211] In some embodiments, the method to engineer cell of the invention further comprises one or more additional genomic modification step. By additional genomic modification step, can be intended the introduction into cells to engineer of one or more protein of interest. Said protein of interest can be a CAR.

[0212] In some embodiments, the method of engineering T-cells of invention can comprise: [0213] (a) modifying T-cells by inactivating at least: [0214] a first gene expressing a target for an immunosuppressive agent, and [0215] a second gene encoding a component of the T-cell receptor (TCR) [0216] (b) expanding said cells, optionally in presence of said immunosuppressive agent.

[0217] An immunosuppressive agent is an agent that suppresses immune function by one of several mechanisms of action. In other words, an immunosuppressive agent is a role played by a compound which is exhibited by a capability to diminish the extent and/or voracity of an immune response. As non-limiting example, an immunosuppressive agent can be a calcineurin inhibitor, a target of rapamycin, an interleukin-2 u-chain blocker, an inhibitor of inosine monophosphate dehydrogenase, an inhibitor of dihydrofolic acid reductase, a corticosteroid or an immunosuppressive antimetabolite.

[0218] In a particular embodiment, the genetic modification step of the method relies on the inactivation of one gene selected from the group consisting of CD52, GR, TCR alpha and TCR beta. In another embodiment, the genetic modification step of the method relies on the inactivation of two genes selected from the group consisting of CD52 and GR, CD52 and TCR alpha, CDR52 and TCR beta, GR and TCR alpha, GR and TCR beta, TCR alpha and TCR beta. In another embodiment, the genetic modification step of the method relies on the inactivation of more than two genes. The genetic modification is preferably operated ex-vivo.

[0219] The rare-cutting endonucleases used for inactivating the genes in T-cells are preferably Transcription Activator like Effector (TALE), but may be also a Cas9 coupled to a RNA guide as respectively described in WO 2013/176915 and WO 2014/191128.

Delivery Methods

[0220] The different methods described above involve expressing CAR at the surface of a cell. As non-limiting example, said CAR can be expressed by introducing the latter into a cell. CARs can be introduced as transgene encoded by one plasmid vector. Said plasmid vector can also contain a selection marker which provides for identification and/or selection of cells which received said vector.

[0221] Polypeptides may be synthesized in situ in the cell as a result of the introduction of polynucleotides encoding said polypeptides into the cell. Alternatively, said polypeptides could be produced outside the cell and then introduced thereto. Methods for introducing a polynucleotide construct into cells are known in the art and including as non-limiting examples stable transformation methods wherein the polynucleotide construct is integrated into the genome of the cell, transient transformation methods wherein the polynucleotide construct is not integrated into the genome of the cell and virus mediated methods. Said polynucleotides may be introduced into a cell by for example, recombinant viral vectors (e.g. retroviruses, adenoviruses), liposome and the like. For example, transient transformation methods include for example microinjection, electroporation or particle bombardment. Said polynucleotides may be included in vectors, more particularly plasmids or virus, in view of being expressed in cells.

Polynucleotides and Vectors

[0222] In one embodiment, said isolated cell according to the present invention comprises a polynucleotide encoding the chimeric antigen receptor carrying the chimeric scFv.

[0223] The present invention also relates to polynucleotides, vectors encoding the above described CAR according to the invention.

[0224] The polynucleotide may consist in an expression cassette or expression vector (e.g. a plasmid for introduction into a bacterial host cell, or a viral vector such as a baculovirus vector for transfection of an insect host cell, or a plasmid or viral vector such as a lentivirus for transfection of a mammalian host cell).

[0225] Those skilled in the art will recognize that, in view of the degeneracy of the genetic code, considerable sequence variation is possible among these polynucleotide molecules. Preferably, the nucleic acid sequences of the present invention are codon-optimized for expression in mammalian cells, preferably for expression in human cells. Codon-optimization refers to the exchange in a sequence of interest of codons that are generally rare in highly expressed genes of a given species by codons that are generally frequent in highly expressed genes of such species, such codons encoding the amino acids as the codons that are being exchanged.

Therapeutic Applications

[0226] In another embodiment, isolated cell or immune cell expressing a CAR as described herein obtained by the different methods or cell line derived from said isolated cell as previously described can be used as a medicament.

[0227] In another embodiment, said medicament can be used for treating pathologies such as cancer in a patient in need thereof.

[0228] In another embodiment, said isolated cell or immune cell expressing a CAR as described herein I according to the invention or cell line derived from said isolated cell can be used in the manufacture of a medicament for treatment of a pathology such as a cancer in a patient in need thereof.

[0229] In another aspect, the present invention relies on methods for treating patients in need thereof, said method comprising at least one of the following steps: [0230] (a) providing an immune-cell obtainable by any one of the methods previously described; [0231] (b) Administrating said transformed immune cells to said patient,

[0232] In one embodiment, said immune cell, preferably T cells, of the invention can undergo robust in vivo T cell expansion and can persist for an extended amount of time.

[0233] Said treatment can be ameliorating, curative or prophylactic. It may be either part of an autologous immunotherapy or part of an allogenic immunotherapy treatment. By autologous, it is meant that cells, cell line or population of cells used for treating patients are originating from said patient or from a Human Leucocyte Antigen (HLA) compatible donor. By allogeneic is meant that the cells or population of cells used for treating patients are not originating from said patient but from a donor.

[0234] Said treatment can be used to treat patients diagnosed with cancer, viral infection, autoimmune disorders or Graft versus Host Disease (GvHD). Cancers that may be treated include tumors that are not vascularized, or not yet substantially vascularized, as well as vascularized tumors. The cancers may comprise non solid tumors (such as hematological tumors, for example, leukemias and lymphomas) or may comprise solid tumors. Types of cancers to be treated with the CAR of the invention include, but are not limited to, carcinoma, blastoma, and sarcoma, and certain leukemia or lymphoid malignancies, benign and malignant tumors, and malignancies e.g., sarcomas, carcinomas, and melanomas. Adult tumors/cancers and pediatric tumors/cancers are also included.

[0235] It can be a treatment in combination with one or more therapies against cancer selected from the group of antibodies therapy, chemotherapy, cytokines therapy, dendritic cell therapy, gene therapy, hormone therapy, laser light therapy and radiation therapy.

[0236] The administration of the cells or population of cells according to the present invention may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The compositions described herein may be administered to a patient subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous or intralymphatic injection, or intraperitoneally. In one embodiment, the cell compositions of the present invention are preferably administered by intravenous injection.

[0237] The administration of the cells or population of cells can consist of the administration of 10.sup.4-10.sup.9 cells per kg body weight, preferably 10.sup.5 to 10.sup.6 cells/kg body weight including all integer values of cell numbers within those ranges. The cells or population of cells can be administrated in one or more doses. In another embodiment, said effective amount of cells are administrated as a single dose. In another embodiment, said effective amount of cells are administrated as more than one dose over a period time. Timing of administration is within the judgment of managing physician and depends on the clinical condition of the patient. The cells or population of cells may be obtained from any source, such as a blood bank or a donor. While individual needs vary, determination of optimal ranges of effective amounts of a given cell type for a particular disease or conditions within the skill of the art. An effective amount means an amount which provides a therapeutic or prophylactic benefit. The dosage administrated will be dependent upon the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.

[0238] In another embodiment, said effective amount of cells or composition comprising those cells are administrated parenterally. Said administration can be an intravenous administration. Said administration can be directly done by injection within a tumor.

[0239] In certain embodiments of the present invention, cells are administered to a patient in conjunction with (e.g., before, simultaneously or following) any number of relevant treatment modalities, including but not limited to treatment with agents such as antiviral therapy, cidofovir and interleukin-2, Cytarabine (also known as ARA-C) or nataliziimab treatment for MS patients or efaliztimab treatment for psoriasis patients or other treatments for PML patients. In further embodiments, the T cells of the invention may be used in combination with chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies or other antibody therapies, cytoxin, fludaribine, cyclosporin, FK506, rapamycin, mycoplienolic acid, steroids, FR901228, cytokines, and irradiation. These drugs inhibit either the calcium dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit the p70S6 kinase that is important for growth factor induced signaling (rapamycin) (Henderson, Naya et al. 1991, Immunology 73(3):316-21; Liu, Albers et al. 1992, 31(16):3896-901; Bierer, Hollander et al. 1993, Curr Opin Immunol 5(5):763-73). In a further embodiment, the cell compositions of the present invention are administered to a patient in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH, In another embodiment, the cell compositions of the present invention are administered following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan. For example, in one embodiment, subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, following the transplant, subjects receive an infusion of the expanded immune cells of the present invention. In an additional embodiment, expanded cells are administered before or following surgery.

Other Definitions

[0240] Amino acid residues in a polypeptide sequence are designated herein according to the one-letter code, in which, for example, Q means Gln or Glutamine residue, R means Arg or Arginine residue and D means Asp or Aspartic acid residue. [0241] Nucleotides are designated as follows: one-letter code is used for designating the base of a nucleoside: a is adenine, t is thymine, c is cytosine, and g is guanine. For the degenerated nucleotides, r represents g or a (purine nucleotides), k represents g or t, s represents g or c, w represents a or t, m represents a or c, y represents t or c (pyrimidine nucleotides), d represents g, a or t, v represents g, a or c, b represents g, t or c, h represents a, t or c, and n represents g, a, t or C. [0242] "As used herein, "nucleic acid" or "polynucleotides" refers to nucleotides and/or polynucleotides, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), oligonucleotides, fragments generated by the polymerase chain reaction (PCR), and fragments generated by any of ligation, scission, endonuclease action, and exonuclease action. Nucleic acid molecules can be composed of monomers that are naturally-occurring nucleotides (such as DNA and RNA), or analogs of naturally-occurring nucleotides (e.g., enantiomeric forms of naturally-occurring nucleotides), or a combination of both. Modified nucleotides can have alterations in sugar moieties and/or in pyrimidine or purine base moieties. Sugar modifications include, for example, replacement of one or more hydroxyl groups with halogens, alkyl groups, amines, and azido groups, or sugars can be functionalized as ethers or esters. Moreover, the entire sugar moiety can be replaced with sterically and electronically similar structures, such as aza-sugars and carbocyclic sugar analogs. Examples of modifications in a base moiety include alkylated purines and pyrimidines, acylated purines or pyrimidines, or other well-known heterocyclic substitutes. Nucleic acid monomers can be linked by phosphodiester bonds or analogs of such linkages. Nucleic acids can be either single stranded or double stranded. [0243] By chimeric antigen receptor (CAR) is intended molecules that combine a binding domain against a component present on the target cell, for example an antibody-based specificity for a desired antigen (e.g., tumor antigen) with a T cell receptor-activating intracellular domain to generate a chimeric protein that exhibits a specific anti-target cellular immune activity. Generally, CAR consists of an extracellular single chain antibody (scFv) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (scFv:.zeta.) and have the ability, when expressed in T cells, to redirect antigen recognition based on the monoclonal antibody's specificity. [0244] By "delivery vector" or "delivery vectors" is intended any delivery vector which can be used in the present invention to put into cell contact (i.e "contacting") or deliver inside cells or subcellular compartments (i.e "introducing") agents/chemicals and molecules (proteins or nucleic acids) needed in the present invention. It includes, but is not limited to liposomal delivery vectors, viral delivery vectors, drug delivery vectors, chemical carriers, polymeric carriers, lipoplexes, polyplexes, dendrimers, microbubbles (ultrasound contrast agents), nanoparticles, emulsions or other appropriate transfer vectors. These delivery vectors allow delivery of molecules, chemicals, macromolecules (genes, proteins), or other vectors such as plasmids, peptides developed by Diatos. In these cases, delivery vectors are molecule carriers. By "delivery vector" or "delivery vectors" are also intended delivery methods to perform transfection. [0245] The terms "vector" or "vectors" refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. A "vector" in the present invention includes, but is not limited to, a viral vector, a plasmid, a RNA vector or a linear or circular DNA or RNA molecule which may consists of a chromosomal, non chromosomal, semi-synthetic or synthetic nucleic acids. Preferred vectors are those capable of autonomous replication (episomal vector) and/or expression of nucleic acids to which they are linked (expression vectors). Large numbers of suitable vectors are known to those of skill in the art and commercially available.

[0246] Viral vectors include retrovirus, adenovirus, parvovirus (e. g. adenoassociated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e. g., influenza virus), rhabdovirus (e. g., rabies and vesicular stomatitis virus), paramyxovirus (e. g. measles and Sendai), positive strand RNA viruses such as picornavirus and alphavirus, and double-stranded DNA viruses including adenovirus, herpesvirus (e. g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxvirus (e. g., vaccinia, fowlpox and canarypox). Other viruses include Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus, for example. Examples of retroviruses include: avian leukosis-sarcoma, mammalian C-type, B-type viruses, D type viruses, HTLV-BLV group, lentivirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B. N. Fields, et al., Eds., Lippincott-Raven Publishers, Philadelphia, 1996). [0247] By "lentiviral vector" is meant HIV-Based lentiviral vectors that are very promising for gene delivery because of their relatively large packaging capacity, reduced immunogenicity and their ability to stably transduce with high efficiency a large range of different cell types. Lentiviral vectors are usually generated following transient transfection of three (packaging, envelope and transfer) or more plasmids into producer cells. Like HIV, lentiviral vectors enter the target cell through the interaction of viral surface glycoproteins with receptors on the cell surface. On entry, the viral RNA undergoes reverse transcription, which is mediated by the viral reverse transcriptase complex. The product of reverse transcription is a double-stranded linear viral DNA, which is the substrate for viral integration in the DNA of infected cells. By "integrative lentiviral vectors (or LV)", is meant such vectors as nonlimiting example, that are able to integrate the genome of a target cell. At the opposite by "non-integrative lentiviral vectors (or NILV)" is meant efficient gene delivery vectors that do not integrate the genome of a target cell through the action of the virus integrase. [0248] Delivery vectors and vectors can be associated or combined with any cellular permeabilization techniques such as sonoporation or electroporation or derivatives of these techniques. [0249] by "mutation" is intended the substitution, deletion, insertion of up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty, twenty five, thirty, fourty, fifty, or more nucleotides/amino acids in a polynucleotide (cDNA, gene) or a polypeptide sequence. The mutation can affect the coding sequence of a gene or its regulatory sequence. It may also affect the structure of the genomic sequence or the structure/stability of the encoded mRNA. [0250] by "functional variant" is intended a catalytically active mutant of a protein or a protein domain; such mutant may have the same activity compared to its parent protein or protein domain or additional properties, or higher or lower activity. [0251] "identity" refers to sequence identity between two nucleic acid molecules or polypeptides. Identity can be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base, then the molecules are identical at that position. A degree of similarity or identity between nucleic acid or amino acid sequences is a function of the number of identical or matching nucleotides at positions shared by the nucleic acid sequences. Various alignment algorithms and/or programs may be used to calculate the identity between two sequences, including FASTA, or BLAST which are available as a part of the GCG sequence analysis package (University of Wisconsin, Madison, Wis.), and can be used with, e.g., default setting. For example, polypeptides having at least 70%, 85%, 90%, 95%, 98% or 99% identity to specific polypeptides described herein and preferably exhibiting substantially the same functions, as well as polynucleotide encoding such polypeptides, are contemplated. [0252] The term "subject" or "patient" as used herein includes all members of the animal kingdom including non-human primates and humans. In some embodiments, the patient is human.

[0253] In addition to the preceding features, the invention comprises further features which will emerge from the following examples illustrating the method of in vitro sorting or in vivo depleting immune cells expressing CAR for immunotherapy, as well as the appended drawings.

Example 1. Generation of Rituximab-Driven Depletion Systems Embedded in an Anti-CD123 CAR

[0254] All 10 CARs having different conformations in terms of chimeric scFv (anti-CD123 scFv with CD20 mimotope(s)) are depicted in FIG. 4: their resulting polypeptide sequences are shown in SEQ ID NO 1 to 10.

[0255] The DNA construct of the 10 CARs are transcribed into their corresponding mRNA via in vitro transcription and used to transfect by electroporation primary T cells freshly isolated from buffy coat via a standard ficoll procedure. One day post transfection, T cells were recovered and used to performed a flow based cytotoxicity assay as described as follows.

Generation of Anti CD123 CAR T Cells.

[0256] To generate primary T cells expressing anti-CD123 CAR, primary T cells are first purified from buffy-coat samples and activated using Dynabeads human T activator CD3/CD28. 3 days post activation, 1 million of activated T cells are transduced with lentiviral vectors harboring an anti-CD123 CAR expression cassette under the control of the Ef1.alpha. promoter, at the multiplicity of infection (MOI) of 1. T cells are kept in culture at 37.degree. C. in the presence of 5% CO.sub.2, 20 ng/ml IL-2 (final concentration) and 5% human AB serum in X-vivo-15 media (Lonza) for further characterization. 5 days post transduction, cells are used to perform the flow-based cytotoxicity assay.

Flow-Based Cytotoxicity Assay

[0257] The cytolytic activity and specificity of anti-CD123 CAR T cell are assessed according to the flow cytometry-based cytotoxicity assay as routinely performed (see for example Valton. et Al (2015) Mol Ther; 23(9):1507-1518). This assay consists of labeling 10.sup.4 CD123 positive tumor cells and 10.sup.4 CD123-negative control cells with 0.5 mM CellTrace.TM. CFSE and 0.5 mM CellTrace.TM. violet (Life Technology) and co-incubating them with 10.sup.5 effector CAR T cells (E/T ratio of 10:1) in a final volume of 100 .mu.l X-Vivo-15 media, for 5 H at 37.degree. C. Cells are then recovered and labeled with eFluor780 viability marker before being fixed by 4% PFA as described above. Fixed cells are then analysed by flow cytometry to determine their viability. The frequency of specific cell lysis is calculated and displayed in the following:

Frequency of specific cell lysis=(Via CD123+cells with T/CD123-cells with T)/(Via CD123+cells/Via CD123-cells)

where Via CD123+ with T and Via CD123- with T correspond respectively to the % of viable CD123+ cells and CD123- cells obtained after 5 H in the presence of CAR T cells and where Via CD123+ cells and Via CD123- cells correspond respectively to the % of CD123+ cells and CD123- cells obtained after 5 H in the absence of CAR T cells.

[0258] The results show that T cells transfected with engineered anti-CD123 CAR are able to kill CD123- positive tumor cell models. As shown in FIG. 5, results from flow-based cytotoxicity assays described above showed that T cells expressing SEQ ID 1-4 displayed the same activity than T cells expressing unmodified anti-CD123 CAR SEQ ID 142 (FIG. 5). These data suggest that insertion of CD20 mimotope in the sequence of the anti-CD123 CAR (SEQ ID 142) does not significantly impair its ability to specifically recognize the CD123 antigen and to kill CD123-expressing tumor cells. In some embodiments, the CARs of the invention comprising one of two mAb-specific epitope, preferably of SEQ ID NO 35 are able to specifically recognize the antigen targeted by the CAR and to kill cells expressing said antigen.

[0259] Consistent with these findings, transfected CAR T cells are tested for their capacity to degranulate when exposed to a CD123 recombinant protein coated on a 96 well plate. Together, our experiments are designed to show that insertion of CD20 mimotope in the sequence of the anti-CD123 CAR does not significantly impair its ability to specifically recognize the CD123 antigen.

[0260] To demonstrate the ability of rituximab to inhibit T cell cytotoxicity functions through specific recognition of CD20 mimotopes, transfected T cells are incubated in the presence of CD123-positive tumor cells, in the presence or in the absence of rituximab and baby rabbit-complement. The objective is to show that the cytotoxic activity and degranulation capacity of transfected T cells are impaired in the presence of rituximab and baby rabbit complement, indicating further that efficient recognition of engineered anti-CD123 CAR by rituximab leads to T cell depletion.

Example 2. Flexibility of the mAb-Driven Depletion Systems in the Anti-CD123 Chimeric Antigen Receptor

[0261] To further demonstrate the flexibility of the mAb-driven depletion system, different epitopes or mimotopes (SEQ ID NO 35-42) specific for cetuximab, palivizumab and nivolumab mAbs are inserted within the anti-CD123 CAR constructions using the same procedure and architecture as the one used for the CD20 mimotope described in Example 1. The results aim to show that transfected T cells retain their cytolytic activity and degranulation capacity toward CD123 positive tumor cells. In addition, the experiments are designed also to indicate that transfected T cells are depleted by some of the aforementioned mAbs

Example 3. Rituximab-Dependent Depletion of Anti-CD123 CAR Containing an mAb-Driven Depletion System

[0262] To explore the ability of the mAb-driven depletion system to allow depletion of anti-CD123 CAR T cells, transduced T cell expressing a CAR of SEQ ID NO 1, 2, 3 or 4 or an unmodified anti-CD123 CAR (SEQ ID NO 142), were subjected to a complement dependant cytotoxicity assay (CDC).

[0263] CDC Assay

[0264] The CDC assay consisted in incubating 0.2 10.sup.6 transduced T cells either alone, or in the presence of Rituximab (RTX, ROCHE, 400 ng) and Babby Rabbit Complement (BRC, AbD Serotec, ref# C12CA, 100 .mu.L of the solution diluted according to the manufacturer protocol) for 3 hours at 37.degree. C. in a final volume of 400 .mu.L of Xvivo 10% FBS. At the end of incubation, anti CD123-CAR T cells were recovered and labeled with recombinant CD123 protein fused to an FC fragment (SEQ ID 143) and a PE labeled anti-FC secondary monoclonal antibody (Jackson ImmunoResearch, ref#115-115-164, diluted 1/200). Cells were then recovered in PFA 4% before being analyzed by flow cytometry. The flow cytometry gating strategy consisted of determining the viability of anti-CD123 CAR positive T cells (PE positive cells) among the singlet found in the total population of cells. This analysis was performed on cells incubated alone and in the presence of RTX and BRC. Results are expressed as the ratio named "Relative frequency of viable cells among anti-CD123 CAR positive T cells (with respect to control experiment)" described below:

(Frequency of viable cells among anti-CD123 CAR positive T cells obtained in the presence of RTX and BRC).times.100/(Frequency of viable cells among anti-CD123 CAR positive T cells obtained in the absence of RTX and BRC)

[0265] The results showed that all CAR architectures allowed the RTX-dependent depletion of CAR T cells (FIG. 6). CAR T cells expressing SEQ ID NO 3 and 4 were more efficiently depleted than the ones expressing SEQ ID NO 1 and 2 suggesting that the number of CD20 mimotope present in the CAR architecture influenced the extent and/or the kinetic of T cells depletion.

[0266] In some embodiments, CARs of the invention having architectures illustrated by FIG. 4 allow rituximab dependent depletion of CAR T cells. In some embodiments, CAR of the invention comprising at least 2 mAb-specific epitopes, preferably having CAR architecture of SEQ ID NO 3 or 4 are particularly efficiently depleted.

Example 4. Efficiency of the mAb-Driven Depletion System in Cells Expressing an Anti-BCMA CAR Comprising One or More mAbs Specific Epitopes in the Extracellular Domain

[0267] To explore the ability of the mAb-driven depletion system to allow depletion of anti-BCMA CAR T cells, 15 different CAR architectures (SEQ ID 125-139, FIG. 7) were constructed. These architectures were designed to contain 1, 2 or 3 CD20 mimotopes localized at different portions of the extracellular domain of the anti-BCMA CAR (SEQ ID NO 125), i.e in the N terminal domain, in the linker domain separating the V1 and V2 of the ScFv or upstream to the CD8 hinge linking the ScFv to the transmembrane domain of the CAR.

[0268] To generate primary T cells expressing anti-BCMA CAR, primary T cells were first purified from buffy-coat samples and activated using Dynabeads human T activator CD3/CD28. 3 days post activation, 5 million of activated T cells were transfected with either 15 or 30 g of poly adenylated mRNA encoding the different anti-BCMA CAR architectures (SEQ ID 125-139, FIG. 7). T cells were then kept in culture at 37.degree. C. in the presence of 5% CO.sub.2, 20 ng/ml IL-2 (final concentration) and 5% human AB serum in X-vivo-15 media (Lonza) for further characterization. One day post transfection, cells were used to perform the CDC assay, a flow based cytotoxicity assay, a detection assay and an Interferon .gamma. (IFN .gamma.) release assay.

[0269] CDC Assay

[0270] The CDC assay consisted in incubating 0.2 10.sup.6 transfected cells either alone, or in the presence of Rituximab (RTX, ROCHE, 400 ng) and Babby Rabbit Complement (BRC, AbD Serotec, ref#C12CA, 100 .mu.L of the solution diluted according to the manufacturer protocol) for 2 hours at 37.degree. C. in a final volume of 400 .mu.L of Xvivo 10% FBS. At the end of incubation, anti BCMA-CAR T cells were recovered and labeled with recombinant BCMA protein fused to an FC fragment (SEQ ID NO 151) and a PE labeled anti-FC secondary monoclonal antibody (Jackson ImmunoResearch, ref#115-115-164, diluted 1/200). Cells were then recovered in PFA 4% before being analyzed by flow cytometry. The flow cytometry gating strategy was to determine the viability of anti-BCMA CAR positive T cells (PE positive cells) among the singlet found in the total population of cells. This analysis was performed on cells incubated alone and in the presence of RTX and BRC. Results are expressed as the ratio named "Relative frequency of viable cells among BCMA CAR positive T cells (with respect to control experiment)" described below:

(Frequency of viable cells among anti-BCMA CAR positive T cells obtained in the presence of RTX and BRC).times.100/(Frequency of viable cells among anti-BCMA CAR positive T cells obtained in the absence of RTX and BRC)

[0271] Flow-Based Cytotoxicity Assay

[0272] The cytolytic activity and specificity of anti-BCMA CAR T cell were assessed according to the flow cytometry-based cytotoxicity assay reported in Valton. et Al (2015) Mol Ther; 23(9):1507-1518. This assay consisted of labeling BCMA positive tumor target cell (T, H929) with 0.5 mM CellTrace.TM. CFSE (Life Technology, incubation 10 min 37.degree. C. according to manufacturer protocol) and co-incubate them with 10.sup.5 anti BCMA CAR T effector (E) cells (E/T ratio of 10:1) in a final volume of 100 .mu.l X-Vivo-15 media, for 5 H at 37.degree. C. Cells were then recovered and labeled with eFluor780 viability marker before being fixated by 4% PFA. Fixated cells were then analysed by flow cytometry to determine their viability.

[0273] IFN .gamma. Release Assay

[0274] To investigate autoactivation of T cell expressing various anti-BCMA CAR comprising RTX specific epitopes by clinically relevant dose of RTX, primary T cells transfected with mRNA encoding SEQ ID 125, 130-139 were incubated, one day post transfection, for 72 hours in X-vivo-15 medium supplemented with 5% AB serum, 20 ng/mL IL2 in the absence or in the presence of 500 .mu.g/mL RTX at a concentration of 0.1 10.sup.6 cells/wells in a final volume of 100 .mu.l. CAR T cells were then spun down, the supernatant was recovered and analysed by ELISA (using the Human IFN-gamma Quantikine ELISA Kit, RandD systems, ref # DIF50) to determine the amount of IFN .gamma. released in the culture media. As positive control for CAR T cell activation and IFN .gamma. release, cells were incubated with 10 .mu.g/mL phytohemagglutinin (PHA).

[0275] Purification of Anti-BCMA CAR T Cells Using Miltenyi CD34 Purification Kit

[0276] To test the capacity of certain anti-BCMA CAR architectures (containing the CD34 epitope, SEQ ID NO 144 recognized by the QBEND10 antibody) to be purified, 100 10.sup.6 primary T cells steadily expressing SEQ ID 128 were purified using the CD34 MicroBead Kit (Miltenyi, ref#130-046-702) according to the manufacturer protocol.

[0277] Results

[0278] Depletability of Anti-BCMA CAR Positive T Cells

[0279] The results showed that T cells expressing SEQ ID 126-139 were all depleted to different extents by BRC and RTX in contrast to the unmodified anti-BCMA CAR (SEQ ID NO 125) that was not markedly depleted (FIG. 8A). The results show that efficiency of depletion increase along with the number of CD20 mimotopes present in the CAR architecture. In addition, the results show that separating multiple CD20 mimotopes by domain larger than GS linkers, increased the efficiency of depletion as seen when comparing the extents of depletion obtained with T cells expressing SEQ ID NO 127 and SEQ ID NO 137 containing 3 CD20 mimotopes, as well as SEQ ID NO 139 and SEQ ID NO 136 containing 2 CD20 mimotopes (FIG. 7-8A).

[0280] In some embodiments, the CAR of the invention having CAR architecture of SEQ ID NO126-139 allow rituximab dependent depletion of CAR T cell. In some embodiments the CAR of the invention having CAR architecture such as in SEQ ID, 136, 137, 138, i.e where the CAR comprises at least two identical mAb specific epitope separated by one or more other domains (such as VH, VL, VH-L1-VL . . . ) are particularly efficiently depleted.

[0281] Cytotoxic Activity of Anti-BCMA CAR+ T Cells

[0282] The flow-based cytotoxicity assay results indicated that all architectures (SEQ ID 126-139) were able to recognize and kill BCMA-expressing H929 tumor cells to a similar extent than T cells expressing the unmodified version of anti-BCMA CAR architecture (SEQ ID NO 125, FIG. 9). Consistent with the results obtained in Example 1, the presence of 1, 2 or 3 mAb specific epitopes and in particular 1, 2 or 3 CD20 mimotopes inside the CAR architecture, did not significantly influence the cytolytic activity of anti-BCMA CAR T cells.

[0283] In some embodiments, the CARs of the invention having CAR architectures of SEQ ID NO126-139 have similar cytotoxic activity as compared to a CAR without mAb-specific epitope such as a CAR of SEQ ID 125.

[0284] Anti-BCMA Positive CAR T Cells Sorting from an Heterogeneous Population of Cells

[0285] To test the capacity of T-cell expressing the anti-BCMA CAR of SEQ ID 128 (FIG. 7A) to be purified from an heterogeneous population of cells, a bulk population of 100.times.10.sup.6 primary T cells containing 31.5% of CAR positive cells was purified using the CD34 MicroBead Kit according to the manufacturer protocol. The results showed that the purified fraction harbored about 90% of anti-BCMA CAR positive T cells indicating that the purification process was efficient (FIG. 10). Out of 31.5.times.10.sup.6 anti-BCMA CAR positive T cells, about 20.times.10.sup.6 anti-BCMA CAR positive T cells were recovered after purification indicating that less than 40% of anti-BCMA CAR positive T cells were lost throughout the purification process.

[0286] IFN .gamma. Release Assay

[0287] The ELISA assay results showed that the presence of one or multiple CD20 mimotopes within the CAR architecture did not influence the propensity of CAR T cells to be activated by RTX (FIG. 11). Indeed The results showed that the level of IFN .gamma. released by all architectures in the presence of RTX were similar to the basal level of IFN .gamma. released in the absence of RTX.

Example 5. Hybrid Anti-BCMA Chimeric Antigen Receptor Architectures for Optimal Depletion and Purification of CAR T Cells

[0288] To improve the depletability of anti-BCMA CAR T cells and at the same time, allow to sort them, two new hybrid CAR architectures SEQ ID NO 140 and 141 (FIG. 7C) were designed. These two architectures contained three CD20 mimotopes separated from one another by protein domains and one CD34 epitope. Their ability to be depleted by RTX and BRC was assessed by CDC assay according to the protocol described in Example 4. The results showed that these two architectures were efficiently depleted to a similar extent than T cells expressing SEQ ID 137 (FIG. 8B). Their cytolytic properties were also assessed using the flow-based assay described earlier. The results showed that they share similar cytotoxic activity than the T cells expressing the unmodified anti-BCMA CAR T cells (SEQ ID NO 125) indicating that the presence of CD20 mimotopes and CD34 epitope (SEQ ID NO 35 and 144 respectively) did not negatively impact the cytolytic activity of CAR T cells.

[0289] In some embodiments the CAR of the invention having CAR architecture such as in SEQ ID 140, 141, i.e where the CAR comprises at three identical mAb-specific epitope recognized by an approved antibody such as rituximab which can be used for depletion of the cells and one mAb specific epitope which can be used for purification are particularly efficiently depleted and can also be efficiently purified.

[0290] Additional CARs based on the architecture of SEQ ID NO 140 and 141 but comprising VH and VL of ScFv specific for CD19 (CAR of SEQ ID NO 162-163 and 168-169), CD123 (CAR of SEQ ID NO 164-165), CD20 (CAR of SEQ ID NO 166-167) were assembled according to the protocol described in Example 4. Their ability to be depleted by RTX and BRC can be assessed by CDC assay according to the protocol described in Example 4.

Example 6. Universal Detection of CAR T Cells Bearing a mAb-Driven Depletion System

[0291] Monitoring and comparing proliferation of different CAR T cells in vivo has been tiedous and cumbersome due to the lack of universal detection system. The ability of different CAR architectures to be detected was tested by flow cytometry using RTX as primary antibody and an FITC-coupled anti-Fab'2 monoclonal antibody (Life technologies, ref# H10101C, diluted 1/200) or using an APC labeled anti-CD34 monoclonal antibody named QBEND10 (Miltenyi Biotec, ref#130-090-954, diluted 1/25). Results were compared side by side with detection performed with recombinant BCMA protein fused to an FC fragment (SEQ ID NO 151) and a PE labeled anti-FC secondary monoclonal antibody (Jackson ImmunoResearch, ref#115-115-164, diluted 1/200).

[0292] The results, showed that the frequency of positive CAR T cells expressing SEQ ID NO 128 and 130-139 detected with RTX were similar to the ones obtained when they were detected with recombinant BCMA protein (FIG. 12). Similar results were found when CAR T cells expressing SEQ ID NO 128 were detected with QBEND10 and rituximab (FIG. 13). Altogether, The results showed that the presence of CD20 mimotope or CD34 epitope allow for efficient and universal detection of different CAR architectures.

Example 7--Anti-BCMA CAR T Cells Expressing Anti BCMA CAR Comprising One, Two or Three mAB Specific Epitopes

7.1--Plasmids

[0293] The below CD20 mimotope-containing CARs are codon-optimized, synthesized and subcloned into the lentiviral vector pLVX-EF1a-IRES-Puro (Clontech) using the EcoRI (5') and MluI (3') restriction sites (thus removing the IRES-Puro cassette). Lentiviruses are produced using psPAX2, an HIV-1 gag-pol packaging plasmid, and pMD2.G, a VSV-G expression plasmid.

[0294] BC30 (SEQ ID NO 145) comprises the following domains:

leader-BCMA30 VH-linker-BCMA30 VL-CD8 Hinge-CD8 TM-4-1BB-CD3z wherein BCMA30 VH and BCMA30 VL are respectively SEQ ID NO 97 and SEQ ID NO 98.

[0295] BC30-LM (SEQ ID NO 146) comprises the following domains:

Leader-BCMA30 VH-linker-BCMA30 VL-linker(L)-Mimotope (M)-CD8 Hinge-CD8 TM-4-1BB-CD3z wherein BCMA30 VH and BCMA30 VL are respectively SEQ ID NO 97 and SEQ ID NO 98 and the mimotope is SEQ ID NO35.

[0296] BC30-LML (SEQ ID NO 147) comprises the following domains:

Leader-BCMA30 VH-linker-BCMA30 VL-linker(L)-Mimotope (M)-linker(L)-CD8 Hinge-CD8 TM-4-1BB-CD3z wherein BCMA30 VH and BCMA30 VL are respectively SEQ ID NO 97 and SEQ ID NO 98 and the mimotope is SEQ ID NO35.

[0297] BC30-LMLM (SEQ ID NO 148) comprises the following domains:

Leader-BCMA30 VH-linker-BCMA30 VL-linker(L)-Mimotope (M)-linker(L)-Mimotope (M)-CD8 Hinge-CD8 TM-4-1BB-CD3z wherein BCMA30 VH and BCMA30 VL are respectively SEQ ID NO 97 and SEQ ID NO 98 and the mimotopes are both SEQ ID NO 35.

[0298] BC30-LMLML (SEQ ID NO 149) comprises the following domains:

Leader-BCMA30 VH-linker-BCMA30 VL-linker(L)-Mimotope (M)-linker(L)-Mimotope (M)-linker(L)-CD8 Hinge-CD8 TM-4-1BB-CD3z wherein BCMA30 VH and BCMA30 VL are respectively SEQ ID NO 97 and SEQ ID NO 98 and the mimotopes are both SEQ ID NO 35.

7.2--T Cell Activation and Lentiviral Transduction

[0299] Untouched T cells are isolated from human peripheral blood mononuclear cells (PBMCs) using the Pan T Cell isolation kit (Miltenyi Biotec) and activated for three days with antibodies against human CD2, CD3, and CD28 (T Cell activation/expansion kit--Miltenyi Biotec). Lentiviral vectors (LV) are produced by transient transfection of sub-confluent HEK-293T/17 (American Type Culture Collection (ATCC)) cells in 6-well plates. Briefly, pLVX, psPAX2, and pMD2.G plasmids are transfected at a 4:3:1 ratio, respectively, using Lipofectamine 2000 (Invitrogen) following the manufacturer's instructions. The following day, the media is replaced with T cell culture medium (5% human AB serum in X-vivo-15 medium (Lonza)), and 48 h after transfection the LV supernatant is harvested and filtered through a 0.45 .mu.m syringe filter (Millipore). Activated T cells are seeded at 0.25.times.10.sup.6 cells/mL in T cell culture medium containing 40 ng/ml IL-2 and transduced by adding an equal volume of fresh LV supernatant. Cells are cultured at 37.degree. C. and 5% CO2 for three days and used for flow cytometry analysis or expanded in fresh T cell medium containing 20 ng/ml IL-2.

7.3--Detection of BCMA CARs Containing CD20 Mimotopes by Flow Cytometry

[0300] To test the utility of intra CAR CD20 mimotopes for detection and tracking of CAR-T cells, flow cytometry analysis is performed on transduced T cells using either biotinylated-BCMA protein, which binds the scFV region of the CAR followed by PE-conjugated streptavidin, or the anti-CD20 antibody rituximab followed by FITC-conjugated anti-human IgG (Rituximab (FITC)). FIGS. 14A and 14B show that T cells transduced with the different CD20-mimotope-containing CARs are detected with comparable efficiency by flow cytometry using biotinylated-BCMA followed by PE-conjugated streptavidin. Detection of intra CAR CD20 mimotope(s) with rituximab is weak in cells transduced with the LM construct (15.5%) but very high in all other formats tested. For example, the LMLML CAR is detected in 85.6% of the cells, indicating that this format allows the identification of virtually all cells expressing the CAR (FIGS. 14A and 14B). Thus, the presence of two CD20 epitopes separated by flexible linkers allows for enhanced binding to rituximab and provides an optimum system to detect CAR+ cells.

[0301] The functionality of intra CAR CD20 epitopes for CAR-T cell detection is assessed by comparison with the RQR8 marker/suicide gene system (SEQ ID NO 150), which consists of a compact protein containing two CD20 epitopes and a CD34 epitope that is normally co-expressed with the CAR (Philip, Blood 2014). For this experiment, T cells are transduced with a lentivirus that allows the co-expression of the BCMA30 CAR (SEQ ID NO 145) and the RQR8 protein (SEQ ID NO 150) (BC30-RQR8 construct). For comparison, T cells are transduced with the BCMA30 LMLML CAR construct (BC30-R2 construct--SEQ ID NO 149) and analyzed by flow cytometry three days post-transduction. In addition, non-transduced (NT) T cells serve as negative control. FIG. 15 aims to show that incorporating the CD20 epitopes in the CAR molecule significantly improves detection of CAR-T cells with the anti-CD20 antibody rituximab. In addition, increased transduction efficiency and CAR expression is observed in cells transduced with the BC30-R2 construct compared with those transduced with the vector encoding RQR8 and the CAR, as indicated by flow cytometry analysis with biotinylated BCMA (FIG. 15). Thus, insertion of CD20 epitopes into the CAR molecule enables enhanced transduction, improved detection, and absolute correlation between CAR expression and mAb specific epitope(s) expression.

7.4--Intra CAR CD20 Epitopes Sensitize CAR-T Cells to Complement-Dependent Cytotoxicity

[0302] The ability of intra CAR CD20 epitopes to enable selective elimination of CAR-T cells is evaluated in vitro using a CDC assay. The objective is to show that the presence of CD20 epitopes in the CAR molecule renders CAR-T cells highly susceptible to rituximab-mediated depletion. For this experiment, T cells transduced with either the BC30-R2 construct or the BC30-RQR8 construct are mixed with 25% baby-rabbit complement (AbD serotec) in the presence or absence of rituximab (100 .mu.g/mL) and incubated at 37.degree. C. and 5% CO2 for 4 hours. Selective deletion of CAR-T cells is determined by flow cytometry analysis using biotinylated BCMA protein. FIG. 16 shows that while both the RQR8 and intra CAR CD20 epitope suicide gene systems enable CAR-T cell depletion, cells transduced with the BC30-R2 construct are depleted more efficiently than those expressing RQR8. As expected, T cells expressing the BCMA30 CAR but no CD20 epitopes (BC30 construct) are spared. These differences may be due to the high expression of the BC30-R2 CAR and the absolute correlation between CAR expression and suicide gene expression.

7.5--Incorporation of CD20 Epitopes into CARs does not Impair the Cytolytic Activity of CAR-T Cells

[0303] The possibility that insertion of CD20 epitopes between the hinge and the scFv regions of the CAR might impair CAR activity is evaluated in a cytotoxicity assay. Briefly, T cells expressing either the BC30-R2 construct or the BC30-RQR8 construct are incubated with Luciferase-positive MM1S target cells at different ratios. For these killing assays, cells are seeded in 96-well white opaque tissue culture plates in a final volume of 100 .mu.l of 5% human AB serum in X-vivo-15 medium (Lonza). After 4 hours, cells are equilibrated to room temperature and one volume of Bright-Glo.TM. Reagent (Promega) is added to each well. Luminescence is measured in a GLOMAX 96 microplate luminometer (Promega) and percentage of cell lysis is calculated according to the following formula:

100.times.(1-(Sample lysis-max lysis)/(Spontaneous lysis-max lysis)).

Maximum lysis is determined by addition of 8% Triton X-100 (Sigma) to Luc+ MM1S cells. For spontaneous lysis, MM1S cells are incubated in the absence of effector CAR-T cells.

[0304] The results show that BC30-R2 CAR-T cells effectively eliminate BCMA-expressing MM1S cells in vitro (FIG. 17). Moreover, the cytolytic activity of BC30-R2 CAR-T cells is not influenced by rituximab (100 .mu.g/mL), which is added to the effector cell population 2 h before these cells are mixed with the target cells (FIG. 17). This experiment aims to demonstrate that insertion of CD20 epitopes into the BC30 CAR molecule does not affect its ability to mediate killing of BCMA+ target cells, even in the presence of rituximab.

7.6 Rituximab Binding to Intra CAR CD20 Epitopes does not Lead to CAR-T Cell Activation

[0305] To investigate if crosslinking of CARs by rituximab might lead to T cell activation due to CAR aggregation on the cell surface, BC30-R2 CAR-T cells are grown in the presence of rituximab. The anti-CD3 OKT3 antibody (eBioscience) causes crosslinking of the T cell receptor (TCR) resulting in cellular activation and proliferation and is used as a positive control. Briefly, BC30-R2 CAR-T cells are cultured in T cell medium in the presence/absence of rituximab for three days. T cell activation is then assessed by measuring the expression of the activation markers CD25 and CD69 using flow cytometry. This experiment shows that the percentage of activated T cells in the presence of RTX is not significantly different from the control (PBS). Therefore, soluble rituximab has no significant effect on the activation state of BC30-R2 CAR-T cells (FIG. 18).

REFERENCES

[0306] Arbiza J., Taylor G., Lopez J. A., Furze J., Wyld S., Whyte P., Stott E. J., Wertz G., Sullender W., Trudel M., et al. (1992), Characterization of two antigenic sites recognized by neutralizing monoclonal antibodies directed against the fusion glycoprotein of human respiratory syncytial virus. J Gen Virol.; 73 (9):2225-34). [0307] Benjamin, R J and Waldmann, H. (1986). Induction of tolerance by monoclonal antibody therapy. Nature 520: 449-451. [0308] Boch, J., H. Scholze, et al. (2009). Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326(5959): 1509-12. [0309] Budde, L. E., Berger C, Lin Y, Wang J, Lin X, Frayo S E, Brouns S A, Spencer D M, Till B G, Jensen M C, Riddell S R (2013). Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PLoS One. December 17; 8(12):e82742 [0310] Buller R. M., Holmes K. L., Hugin A., Fredrickson T. N., Morse H. C. (1987). Induction of cytotoxic T cell responses in vivo in the absence of CD4 helper cells. Nature; 328:77-79. [0311] Cobbold, S. P., Martin, G., Qin, S., and Waldmann, H. (1986). Monoclonal antibodies to promote marrow engraftment and tissue graft rejection. Nature 323:164-166 [0312] Dolan D E, Gupta S. 2014 PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 21(3):231-7. [0313] Epa, V. C., O. Dolezal, et al. (2013). Structural model for the interaction of a designed Ankyrin Repeat Protein with the human epidermal growth factor receptor 2. PLoS One 8(3): e59163. [0314] Fedorov V. D., Themeli M and Sadelain M. (2013). PD-1- and CTLA-4-Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses. Sci Transl Med:5 (215), 215 [0315] Friedrich, K., J. R. Hanauer, et al. (2013). DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety. Mol Ther 21(4): 849-59. [0316] Jena, B., G. Dotti, et al. (2010). Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood 116(7): 1035-44. [0317] Jost, C., J. Schilling, et al. (2013). Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via Binding to the Extracellular Domain of HER2. Structure 21(11): 1979-91. [0318] Moscou, M. J. and A. J. Bogdanove (2009). A simple cipher governs DNA recognition by TAL effectors. Science 326(5959): 1501. [0319] Park, T. S., S. A. Rosenberg, et al. (2011). Treating cancer with genetically engineered T cells. Trends Biotechnol 29(11): 550-7. [0320] Philip B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, Flutter B, Marin V, Marafioti T, Chakraverty R, Linch D, Quezada S A, Peggs K S, Pule M (2014). A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood. 124(8):1277-87 [0321] Riemer A. B., Kurz H., Klinger, M., Scheiner, O., Zielinski, C., and Jensen-Jarolim, E. (2005), Vaccination with cetuximab mimotopes and biological properties of induced anti-epidermal growth factor receptor antibodies, J Natl Cancer Inst.; 97(22):1663-70) [0322] Valton J., Guyot V., Marechal A., Filhol J M., Juillerat A., Duclert A., Duchateau P., Poirot L. (2015) A multidrug resistant engineered CAR T cell for allogeneic combination immunotherapy. Mol Ther; 23(9):1507-1518 [0323] Philip B, Kokalaki E, Mekkaoui L, Thomas S, et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 2014; 124(8):1277-87.

Embodiments of the Invention

[0324] 1. A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to a cell surface marker antigen, wherein said extracellular binding domain includes at least one mAb-specific epitope to be bound by a epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of the immune cells expressing said CAR. 2. A polypeptide according to embodiment 1, wherein said mAb-specific epitope is located between the VH and VL chains. 3. A polypeptide according to embodiment 1 or 2, wherein said VH and VL chains, and mAb specific-epitope are bound together by at least one linker and to the transmembrane domain of said CAR by a hinge. 4. A polypeptide according to embodiment 3, wherein the mAb-epitope is joined to the VH and VL chains by two linkers. 5. A polypeptide according to anyone of embodiment 1 to 4, wherein the mAb-epitope is from one polypeptide selected from those listed in Table 1. 6. A polypeptide according to anyone of embodiment 1 to 4, wherein said VH and VL chains have as antigenic target sequence of over 80% identity, preferably over 90%, and more preferably over 95% with SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-3v antigen) and SEQ ID NO 52 (WT1 antigen). 7. A polypeptide according to anyone of embodiment 1 to 5, wherein said VH and VL chains have as antigenic target sequence of over 80% identity, preferably over 90%, and more preferably over 95% with SEQ ID NO 53-64 (CD19 antigen), SEQ ID NO 65-76 (CD33 antigen), SEQ ID NO 77-84 (5T4 antigen), SEQ ID NO 85-90 (ROR1 antigen), SEQ ID NO 91-94 (EGFRvIII antigen), SEQ ID NO 95-102 (BCMA antigen), SEQ ID NO 103-112 (CS1 antigen) and SEQ ID NO 113-124 (CD123 antigen). 8. A polypeptide according to anyone of embodiment 1-7, wherein said VH and VL chains have as epitope target sequence of over 80% identity, preferably over 90%, and more preferably over 95% identity with the CD20 antigen of SEQ ID NO. 11. 9. A polypeptide according to anyone of embodiment 1-8, wherein the CAR is a single-chain CAR. 10. A polypeptide according to embodiment 9, wherein the said CAR polypeptide shares over 80% identity, preferably over 90%, and more preferably over 95% with SEQ ID NO 1 to 10. 11. A polypeptide according to anyone of embodiment 1-10 wherein the CAR is a multi-chain CAR. 12. A polynucleotide encoding a chimeric antigen receptor according to anyone of embodiments 1 to 9, wherein said CAR comprises a CD3 zeta signaling domain and co-stimulatory domain from 4-1BB. 13. An expression vector comprising a nucleic acid of embodiment 12. 14. An engineered immune cell expressing at its cell surface a chimeric antigen receptor according to anyone of embodiments 1 to 12. 15. An engineered immune cell according to embodiment 14, derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 16. An engineered immune cell according to embodiment 14 or 15 for use as a medicament. 17. A method for engineering an immune cell of anyone of embodiment 14-16, comprising: (a) Providing an immune cell; (b) Introducing into said cell at least one polynucleotide encoding the chimeric antigen receptor according to anyone of embodiment 1-12. (c) Expressing said polynucleotide into said cell. 18. A method for engineering an immune cell of embodiment 17, wherein immune cell is a T-cell. 19. A method for sorting CAR-expressing immune cells comprising contacting a population of immune cells engineered according to anyone of embodiment 14-16 with antigen-specific mAbs in order to collect CAR-expressing immune cells only. 20. A method for sorting CAR-expressing immune cells according to embodiment 19 wherein the mAb is rituximab. 21. A method for sorting CAR-expressing immune cells according to anyone of embodiment 19-20, wherein the immune cell is a T-cell. 22. A method for depleting immune cell engineered according to anyone of embodiment 14-16, or CAR-expressing immune cell sorted according to anyone of embodiment 19-21, comprising contacting said immune cell or said CAR-expressing immune cell with epitope-specific mAbs. 23. A method for depleting immune cell or CAR-expressing immune cell according to embodiment 22, wherein said epitope-specific mAb is conjugated by a molecule able to activate the complement system. 24. A method for depleting immune cell CAR-expressing immune cell according to anyone of embodiment 22-23, wherein a cytotoxic drug is coupled to the epitope-specific mAbs. 25. A method for depleting immune cell CAR-expressing immune cell according to anyone of embodiment 22-24, wherein the mAb-specific antigen is CD20 antigen and the epitope-specific mAb is rituximab. 26. A method for depleting immune cell CAR-expressing immune cell according to anyone of embodiment 22-25, comprising contacting said immune cell or CAR-expressing immune cell with bi-specific mAb (BsAb) able to bind both the mAb-specific epitope borne on said cells and to an surface antigen borne on an effector (and cytotoxic) cell. 27. A method for depleting immune cell CAR-expressing immune cell according to anyone of embodiment 22-26, wherein said immune cell is a T-cell. 28. Method for regulating the activation of an engineered immune cell comprising at least the step of: (i) Endowing said immune cell with a CAR, which extracellular binding domain comprises a scFv recognizing a cell surface marker linked to a mAb specific epitope (ii). Expanding said immune cell expressing said CAR and said mAb epitope on its surface (iii) Contacting the resulting immune cells with the mAb specific to said epitope to immobilize said immune cells.

Sequence CWU 1

1

1851511PRTartificial sequenceAnti-CD123 NO1 1Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu 20 25 30 Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys 50 55 60 Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr 65 70 75 80 Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr 100 105 110 Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln 145 150 155 160 Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser 165 170 175 Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg 195 200 205 Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly 210 215 220 Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp 225 230 235 240 Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe 245 250 255 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly 260 265 270 Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr 275 280 285 Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser 290 295 300 Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly 305 310 315 320 Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp 325 330 335 Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile 340 345 350 Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys 355 360 365 Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys 370 375 380 Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val 385 390 395 400 Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn 405 410 415 Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val 420 425 430 Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg 435 440 445 Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 450 455 460 Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 465 470 475 480 Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 485 490 495 Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 500 505 510 2517PRTartificial sequenceAnti-CD123 No2 2Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu 20 25 30 Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys 50 55 60 Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr 65 70 75 80 Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr 100 105 110 Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln 145 150 155 160 Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser 165 170 175 Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg 195 200 205 Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly 210 215 220 Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp 225 230 235 240 Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe 245 250 255 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly 260 265 270 Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly 275 280 285 Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro 290 295 300 Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys 305 310 315 320 Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala 325 330 335 Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu 340 345 350 Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys 355 360 365 Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr 370 375 380 Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly 385 390 395 400 Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 405 410 415 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 420 425 430 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 435 440 445 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 450 455 460 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 465 470 475 480 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 485 490 495 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 500 505 510 Leu Pro Pro Arg Glu 515 3526PRTartificial sequenceAnti-CD123 No3 3Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu 20 25 30 Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys 50 55 60 Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr 65 70 75 80 Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr 100 105 110 Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln 145 150 155 160 Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser 165 170 175 Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg 195 200 205 Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly 210 215 220 Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp 225 230 235 240 Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe 245 250 255 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly 260 265 270 Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly 275 280 285 Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr 290 295 300 Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln 305 310 315 320 Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala 325 330 335 Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala 340 345 350 Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr 355 360 365 Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln 370 375 380 Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser 385 390 395 400 Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys 405 410 415 Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln 420 425 430 Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu 435 440 445 Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg 450 455 460 Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met 465 470 475 480 Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly 485 490 495 Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp 500 505 510 Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 515 520 525 4532PRTartificial sequenceAnti-CD123 No4 4Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu 20 25 30 Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys 50 55 60 Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr 65 70 75 80 Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr 100 105 110 Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln 145 150 155 160 Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser 165 170 175 Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg 195 200 205 Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly 210 215 220 Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp 225 230 235 240 Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe 245 250 255 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly 260 265 270 Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly 275 280 285 Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly 290 295 300 Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 305 310 315 320 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 325 330 335 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 340 345 350 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 355 360 365 Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu 370 375 380 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 385 390 395 400 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 405 410 415 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 420 425 430 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 435 440 445 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 450 455 460 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 465 470 475 480 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 485 490 495 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 500 505 510 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 515 520 525 Pro Pro Arg Glu 530 5495PRTartificial sequenceAnti-CD123 No5 5Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu 20 25 30 Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys 50 55 60 Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr 65 70 75 80 Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr 100 105 110 Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Cys Pro 130 135 140 Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser Asp Ile Val Leu 145 150 155 160 Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr 165 170 175 Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe 180 185 190 Met His

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 195 200 205 Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly 210 215 220 Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala 225 230 235 240 Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro 245 250 255 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr 260 265 270 Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser 275 280 285 Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly 290 295 300 Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp 305 310 315 320 Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile 325 330 335 Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys 340 345 350 Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys 355 360 365 Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val 370 375 380 Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn 385 390 395 400 Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val 405 410 415 Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg 420 425 430 Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 435 440 445 Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 450 455 460 Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 465 470 475 480 Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 485 490 495 6501PRTartificial sequenceAnti-CD123 No6 6Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu 20 25 30 Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys 50 55 60 Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr 65 70 75 80 Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr 100 105 110 Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Gly 130 135 140 Gly Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Gly Gly 145 150 155 160 Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser 165 170 175 Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp 180 185 190 Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln 195 200 205 Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile 210 215 220 Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr 225 230 235 240 Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln 245 250 255 Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 260 265 270 Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro 275 280 285 Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys 290 295 300 Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala 305 310 315 320 Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu 325 330 335 Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys 340 345 350 Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr 355 360 365 Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly 370 375 380 Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 385 390 395 400 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 405 410 415 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 420 425 430 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 435 440 445 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 450 455 460 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 465 470 475 480 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 485 490 495 Leu Pro Pro Arg Glu 500 7508PRTartificial sequenceAnti-CD123 No7 7Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro 20 25 30 Ser Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys 35 40 45 Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile 50 55 60 Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser 65 70 75 80 Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr 85 90 95 Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala 100 105 110 Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala 115 120 125 Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp 130 135 140 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 145 150 155 160 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser 165 170 175 Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys 180 185 190 Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp 195 200 205 Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala 210 215 220 Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser 225 230 235 240 Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val 245 250 255 Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly 260 265 270 Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro 275 280 285 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 290 295 300 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 305 310 315 320 Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu 325 330 335 Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr 340 345 350 Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe 355 360 365 Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg 370 375 380 Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser 385 390 395 400 Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr 405 410 415 Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys 420 425 430 Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn 435 440 445 Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 450 455 460 Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly 465 470 475 480 His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr 485 490 495 Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 500 505 8514PRTartificial sequenceAnti-CD123 No8 8Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro 20 25 30 Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln 35 40 45 Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys 50 55 60 Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys 65 70 75 80 Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr 85 90 95 Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe 100 105 110 Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu 115 120 125 Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr 130 135 140 Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 145 150 155 160 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 165 170 175 Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln 180 185 190 Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly 195 200 205 Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys 210 215 220 Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg 225 230 235 240 Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro 245 250 255 Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu 260 265 270 Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser 275 280 285 Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 290 295 300 Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 305 310 315 320 Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 325 330 335 Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 340 345 350 Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr 355 360 365 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 370 375 380 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 385 390 395 400 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 405 410 415 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 420 425 430 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 435 440 445 Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 450 455 460 Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu 465 470 475 480 Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 485 490 495 Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 500 505 510 Arg Glu 9523PRTartificial sequenceAnti-CD123 No9 9Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro 20 25 30 Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser 35 40 45 Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys 50 55 60 Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe 65 70 75 80 Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe 85 90 95 Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser 100 105 110 Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser 115 120 125 Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr 130 135 140 Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly 145 150 155 160 Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 165 170 175 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro 180 185 190 Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg 195 200 205 Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr 210 215 220 Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser 225 230 235 240 Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg 245 250 255 Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala 260 265 270 Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala 275 280 285 Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala 290 295 300 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 305 310 315 320 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 325 330 335 Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 340 345 350 Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 355 360 365 Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 370 375 380 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 385 390 395 400 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 405 410 415 Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn 420 425 430 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 435 440 445 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro 450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala 465 470 475 480 Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His 485 490 495 Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp 500 505 510 Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 515 520 10529PRTartificial sequenceAnti-CD123 No10 10Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro 20 25 30 Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser 35 40 45 Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser 50 55 60 Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys 65 70 75 80 Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln 85 90 95 Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr 100 105 110 Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser 115 120 125 Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys 130 135 140 Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp 145 150 155 160 Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly 165 170 175 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 180 185 190 Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg 195 200 205 Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn 210 215 220 Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu 225 230 235 240 Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe 245 250 255 Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val 260 265 270 Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp 275 280 285 Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp 290 295 300 Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile 305 310 315 320 Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala 325 330 335 Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr 340 345 350 Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu 355 360 365 Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile 370 375 380 Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp 385 390 395 400 Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 405 410 415 Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 420 425 430 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 435 440 445 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 450 455 460 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 465 470 475 480 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 485 490 495 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 500 505 510 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 515 520 525 Glu 11297PRThomo sapiens 11Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro 1 5 10 15 Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg 20 25 30 Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu 35 40 45 Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile 50 55 60 Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile 65 70 75 80 Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile 85 90 95 Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu 100 105 110 Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile 115 120 125 Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser 130 135 140 His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro 145 150 155 160 Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn 165 170 175 Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly 180 185 190 Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile 195 200 205 Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys 210 215 220 Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile 225 230 235 240 Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro 245 250 255 Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu 260 265 270 Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser 275 280 285 Ser Pro Ile Glu Asn Asp Ser Ser Pro 290 295 12207PRThomo sapiens 12Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser 1 5 10 15 Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr 20 25 30 Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr 35 40 45 Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys 50 55 60 Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp 65 70 75 80 His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr 85 90 95 Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu 100 105 110 Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met 115 120 125 Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu 130 135 140 Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys 145 150 155 160 Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn 165 170 175 Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg 180 185 190 Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile 195 200 205 131039PRThomo sapiens 13Met Ala Arg Ala Leu Cys Pro Leu Gln Ala Leu Trp Leu Leu Glu Trp 1 5 10 15 Val Leu Leu Leu Leu Gly Pro Cys Ala Ala Pro Pro Ala Trp Ala Leu 20 25 30 Asn Leu Asp Pro Val Gln Leu Thr Phe Tyr Ala Gly Pro Asn Gly Ser 35 40 45 Gln Phe Gly Phe Ser Leu Asp Phe His Lys Asp Ser His Gly Arg Val 50 55 60 Ala Ile Val Val Gly Ala Pro Arg Thr Leu Gly Pro Ser Gln Glu Glu 65 70 75 80 Thr Gly Gly Val Phe Leu Cys Pro Trp Arg Ala Glu Gly Gly Gln Cys 85 90 95 Pro Ser Leu Leu Phe Asp Leu Arg Asp Glu Thr Arg Asn Val Gly Ser 100 105 110 Gln Thr Leu Gln Thr Phe Lys Ala Arg Gln Gly Leu Gly Ala Ser Val 115 120 125 Val Ser Trp Ser Asp Val Ile Val Ala Cys Ala Pro Trp Gln His Trp 130 135 140 Asn Val Leu Glu Lys Thr Glu Glu Ala Glu Lys Thr Pro Val Gly Ser 145 150 155 160 Cys Phe Leu Ala Gln Pro Glu Ser Gly Arg Arg Ala Glu Tyr Ser Pro 165 170 175 Cys Arg Gly Asn Thr Leu Ser Arg Ile Tyr Val Glu Asn Asp Phe Ser 180 185 190 Trp Asp Lys Arg Tyr Cys Glu Ala Gly Phe Ser Ser Val Val Thr Gln 195 200 205 Ala Gly Glu Leu Val Leu Gly Ala Pro Gly Gly Tyr Tyr Phe Leu Gly 210 215 220 Leu Leu Ala Gln Ala Pro Val Ala Asp Ile Phe Ser Ser Tyr Arg Pro 225 230 235 240 Gly Ile Leu Leu Trp His Val Ser Ser Gln Ser Leu Ser Phe Asp Ser 245 250 255 Ser Asn Pro Glu Tyr Phe Asp Gly Tyr Trp Gly Tyr Ser Val Ala Val 260 265 270 Gly Glu Phe Asp Gly Asp Leu Asn Thr Thr Glu Tyr Val Val Gly Ala 275 280 285 Pro Thr Trp Ser Trp Thr Leu Gly Ala Val Glu Ile Leu Asp Ser Tyr 290 295 300 Tyr Gln Arg Leu His Arg Leu Arg Gly Glu Gln Met Ala Ser Tyr Phe 305 310 315 320 Gly His Ser Val Ala Val Thr Asp Val Asn Gly Asp Gly Arg His Asp 325 330 335 Leu Leu Val Gly Ala Pro Leu Tyr Met Glu Ser Arg Ala Asp Arg Lys 340 345 350 Leu Ala Glu Val Gly Arg Val Tyr Leu Phe Leu Gln Pro Arg Gly Pro 355 360 365 His Ala Leu Gly Ala Pro Ser Leu Leu Leu Thr Gly Thr Gln Leu Tyr 370 375 380 Gly Arg Phe Gly Ser Ala Ile Ala Pro Leu Gly Asp Leu Asp Arg Asp 385 390 395 400 Gly Tyr Asn Asp Ile Ala Val Ala Ala Pro Tyr Gly Gly Pro Ser Gly 405 410 415 Arg Gly Gln Val Leu Val Phe Leu Gly Gln Ser Glu Gly Leu Arg Ser 420 425 430 Arg Pro Ser Gln Val Leu Asp Ser Pro Phe Pro Thr Gly Ser Ala Phe 435 440 445 Gly Phe Ser Leu Arg Gly Ala Val Asp Ile Asp Asp Asn Gly Tyr Pro 450 455 460 Asp Leu Ile Val Gly Ala Tyr Gly Ala Asn Gln Val Ala Val Tyr Arg 465 470 475 480 Ala Gln Pro Val Val Lys Ala Ser Val Gln Leu Leu Val Gln Asp Ser 485 490 495 Leu Asn Pro Ala Val Lys Ser Cys Val Leu Pro Gln Thr Lys Thr Pro 500 505 510 Val Ser Cys Phe Asn Ile Gln Met Cys Val Gly Ala Thr Gly His Asn 515 520 525 Ile Pro Gln Lys Leu Ser Leu Asn Ala Glu Leu Gln Leu Asp Arg Gln 530 535 540 Lys Pro Arg Gln Gly Arg Arg Val Leu Leu Leu Gly Ser Gln Gln Ala 545 550 555 560 Gly Thr Thr Leu Asn Leu Asp Leu Gly Gly Lys His Ser Pro Ile Cys 565 570 575 His Thr Thr Met Ala Phe Leu Arg Asp Glu Ala Asp Phe Arg Asp Lys 580 585 590 Leu Ser Pro Ile Val Leu Ser Leu Asn Val Ser Leu Pro Pro Thr Glu 595 600 605 Ala Gly Met Ala Pro Ala Val Val Leu His Gly Asp Thr His Val Gln 610 615 620 Glu Gln Thr Arg Ile Val Leu Asp Cys Gly Glu Asp Asp Val Cys Val 625 630 635 640 Pro Gln Leu Gln Leu Thr Ala Ser Val Thr Gly Ser Pro Leu Leu Val 645 650 655 Gly Ala Asp Asn Val Leu Glu Leu Gln Met Asp Ala Ala Asn Glu Gly 660 665 670 Glu Gly Ala Tyr Glu Ala Glu Leu Ala Val His Leu Pro Gln Gly Ala 675 680 685 His Tyr Met Arg Ala Leu Ser Asn Val Glu Gly Phe Glu Arg Leu Ile 690 695 700 Cys Asn Gln Lys Lys Glu Asn Glu Thr Arg Val Val Leu Cys Glu Leu 705 710 715 720 Gly Asn Pro Met Lys Lys Asn Ala Gln Ile Gly Ile Ala Met Leu Val 725 730 735 Ser Val Gly Asn Leu Glu Glu Ala Gly Glu Ser Val Ser Phe Gln Leu 740 745 750 Gln Ile Arg Ser Lys Asn Ser Gln Asn Pro Asn Ser Lys Ile Val Leu 755 760 765 Leu Asp Val Pro Val Arg Ala Glu Ala Gln Val Glu Leu Arg Gly Asn 770 775 780 Ser Phe Pro Ala Ser Leu Val Val Ala Ala Glu Glu Gly Glu Arg Glu 785 790 795 800 Gln Asn Ser Leu Asp Ser Trp Gly Pro Lys Val Glu His Thr Tyr Glu 805 810 815 Leu His Asn Asn Gly Pro Gly Thr Val Asn Gly Leu His Leu Ser Ile 820 825 830 His Leu Pro Gly Gln Ser Gln Pro Ser Asp Leu Leu Tyr Ile Leu Asp 835 840 845 Ile Gln Pro Gln Gly Gly Leu Gln Cys Phe Pro Gln Pro Pro Val Asn 850 855 860 Pro Leu Lys Val Asp Trp Gly Leu Pro Ile Pro Ser Pro Ser Pro Ile 865 870 875 880 His Pro Ala His His Lys Arg Asp Arg Arg Gln Ile Phe Leu Pro Glu 885 890 895 Pro Glu Gln Pro Ser Arg Leu Gln Asp Pro Val Leu Val Ser Cys Asp 900 905 910 Ser Ala Pro Cys Thr Val Val Gln Cys Asp Leu Gln Glu Met Ala Arg 915 920 925 Gly Gln Arg Ala Met Val Thr Val Leu Ala Phe Leu Trp Leu Pro Ser 930 935 940 Leu Tyr Gln Arg Pro Leu Asp Gln Phe Val Leu Gln Ser His Ala Trp 945 950 955 960 Phe Asn Val Ser Ser Leu Pro Tyr Ala Val Pro Pro Leu Ser Leu Pro 965 970 975 Arg Gly Glu Ala Gln Val Trp Thr Gln Leu Leu Arg Ala Leu Glu Glu 980 985 990 Arg Ala Ile Pro Ile Trp Trp Val Leu Val Gly Val Leu Gly Gly Leu 995 1000 1005 Leu Leu Leu Thr Ile Leu Val Leu Ala Met Trp Lys Val Gly Phe 1010 1015 1020 Phe Lys Arg Asn Arg Pro Pro Leu Glu Glu Asp Asp Glu Glu Gly 1025 1030 1035 Glu 14272PRThomo sapiens 14Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val 1 5 10 15 Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro 20 25 30 His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn 35 40 45 Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr 50 55 60 Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys 65 70 75 80 Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro 85 90 95 Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro 100 105 110 Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro 115 120 125 Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val 130 135 140 Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His 145

150 155 160 Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg 165 170 175 Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln 180 185 190 Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu 195 200 205 Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln Thr 210 215 220 Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr Gln 225 230 235 240 Val Ala Val Ala Gly Cys Val Phe Leu Leu Ile Ser Val Leu Leu Leu 245 250 255 Ser Gly Leu Thr Trp Gln Arg Arg Gln Arg Lys Ser Arg Arg Thr Ile 260 265 270 15595PRThomo sapiens 15Met Arg Val Leu Leu Ala Ala Leu Gly Leu Leu Phe Leu Gly Ala Leu 1 5 10 15 Arg Ala Phe Pro Gln Asp Arg Pro Phe Glu Asp Thr Cys His Gly Asn 20 25 30 Pro Ser His Tyr Tyr Asp Lys Ala Val Arg Arg Cys Cys Tyr Arg Cys 35 40 45 Pro Met Gly Leu Phe Pro Thr Gln Gln Cys Pro Gln Arg Pro Thr Asp 50 55 60 Cys Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Asp Arg 65 70 75 80 Cys Thr Ala Cys Val Thr Cys Ser Arg Asp Asp Leu Val Glu Lys Thr 85 90 95 Pro Cys Ala Trp Asn Ser Ser Arg Val Cys Glu Cys Arg Pro Gly Met 100 105 110 Phe Cys Ser Thr Ser Ala Val Asn Ser Cys Ala Arg Cys Phe Phe His 115 120 125 Ser Val Cys Pro Ala Gly Met Ile Val Lys Phe Pro Gly Thr Ala Gln 130 135 140 Lys Asn Thr Val Cys Glu Pro Ala Ser Pro Gly Val Ser Pro Ala Cys 145 150 155 160 Ala Ser Pro Glu Asn Cys Lys Glu Pro Ser Ser Gly Thr Ile Pro Gln 165 170 175 Ala Lys Pro Thr Pro Val Ser Pro Ala Thr Ser Ser Ala Ser Thr Met 180 185 190 Pro Val Arg Gly Gly Thr Arg Leu Ala Gln Glu Ala Ala Ser Lys Leu 195 200 205 Thr Arg Ala Pro Asp Ser Pro Ser Ser Val Gly Arg Pro Ser Ser Asp 210 215 220 Pro Gly Leu Ser Pro Thr Gln Pro Cys Pro Glu Gly Ser Gly Asp Cys 225 230 235 240 Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Gly Arg Cys 245 250 255 Thr Ala Cys Val Ser Cys Ser Arg Asp Asp Leu Val Glu Lys Thr Pro 260 265 270 Cys Ala Trp Asn Ser Ser Arg Thr Cys Glu Cys Arg Pro Gly Met Ile 275 280 285 Cys Ala Thr Ser Ala Thr Asn Ser Cys Ala Arg Cys Val Pro Tyr Pro 290 295 300 Ile Cys Ala Ala Glu Thr Val Thr Lys Pro Gln Asp Met Ala Glu Lys 305 310 315 320 Asp Thr Thr Phe Glu Ala Pro Pro Leu Gly Thr Gln Pro Asp Cys Asn 325 330 335 Pro Thr Pro Glu Asn Gly Glu Ala Pro Ala Ser Thr Ser Pro Thr Gln 340 345 350 Ser Leu Leu Val Asp Ser Gln Ala Ser Lys Thr Leu Pro Ile Pro Thr 355 360 365 Ser Ala Pro Val Ala Leu Ser Ser Thr Gly Lys Pro Val Leu Asp Ala 370 375 380 Gly Pro Val Leu Phe Trp Val Ile Leu Val Leu Val Val Val Val Gly 385 390 395 400 Ser Ser Ala Phe Leu Leu Cys His Arg Arg Ala Cys Arg Lys Arg Ile 405 410 415 Arg Gln Lys Leu His Leu Cys Tyr Pro Val Gln Thr Ser Gln Pro Lys 420 425 430 Leu Glu Leu Val Asp Ser Arg Pro Arg Arg Ser Ser Thr Gln Leu Arg 435 440 445 Ser Gly Ala Ser Val Thr Glu Pro Val Ala Glu Glu Arg Gly Leu Met 450 455 460 Ser Gln Pro Leu Met Glu Thr Cys His Ser Val Gly Ala Ala Tyr Leu 465 470 475 480 Glu Ser Leu Pro Leu Gln Asp Ala Ser Pro Ala Gly Gly Pro Ser Ser 485 490 495 Pro Arg Asp Leu Pro Glu Pro Arg Val Ser Thr Glu His Thr Asn Asn 500 505 510 Lys Ile Glu Lys Ile Tyr Ile Met Lys Ala Asp Thr Val Ile Val Gly 515 520 525 Thr Val Lys Ala Glu Leu Pro Glu Gly Arg Gly Leu Ala Gly Pro Ala 530 535 540 Glu Pro Glu Leu Glu Glu Glu Leu Glu Ala Asp His Thr Pro His Tyr 545 550 555 560 Pro Glu Gln Glu Thr Glu Pro Pro Leu Gly Ser Cys Ser Asp Val Met 565 570 575 Leu Ser Val Glu Glu Glu Gly Lys Glu Asp Pro Leu Pro Thr Ala Ala 580 585 590 Ser Gly Lys 595 161091PRThomo sapiens 16Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Gly Gln Lys 130 135 140 Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu 145 150 155 160 Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly 165 170 175 Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala 180 185 190 Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys 195 200 205 Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu 210 215 220 Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr 225 230 235 240 Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val 245 250 255 Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu 260 265 270 Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys 275 280 285 Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu 290 295 300 Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile 305 310 315 320 Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe 325 330 335 Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr 340 345 350 Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn 355 360 365 Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg 370 375 380 Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile 385 390 395 400 Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val 405 410 415 Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp 420 425 430 Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn 435 440 445 Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu 450 455 460 Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser 465 470 475 480 Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu 485 490 495 Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln 500 505 510 Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly 515 520 525 Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro 530 535 540 His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr 545 550 555 560 Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His 565 570 575 Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro 580 585 590 Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala 595 600 605 Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg 610 615 620 Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu 625 630 635 640 Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln 645 650 655 Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val 660 665 670 Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro 675 680 685 Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu 690 695 700 Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val 705 710 715 720 Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys 725 730 735 Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys 740 745 750 Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr 755 760 765 Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu 770 775 780 Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val 785 790 795 800 Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu 805 810 815 Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro 820 825 830 Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His 835 840 845 Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr 850 855 860 Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser 865 870 875 880 Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile 885 890 895 Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser 900 905 910 Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg 915 920 925 Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu 930 935 940 Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu 945 950 955 960 Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln 965 970 975 Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser 980 985 990 Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 995 1000 1005 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1010 1015 1020 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1025 1030 1035 Asp Thr Phe Leu Pro Val Pro Gly Glu Trp Leu Val Trp Lys Gln 1040 1045 1050 Ser Cys Ser Ser Thr Ser Ser Thr His Ser Ala Ala Ala Ser Leu 1055 1060 1065 Gln Cys Pro Ser Gln Val Leu Pro Pro Ala Ser Pro Glu Gly Glu 1070 1075 1080 Thr Val Ala Asp Leu Gln Thr Gln 1085 1090 17233PRThomo sapiens 17Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala 1 5 10 15 Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe 20 25 30 Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe 35 40 45 Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro 50 55 60 Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser 65 70 75 80 Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro 85 90 95 Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu 100 105 110 Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser 115 120 125 Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly 130 135 140 Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala 145 150 155 160 Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro 165 170 175 Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu 180 185 190 Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu 195 200 205 Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly 210 215 220 Gln Val Tyr Phe Gly Ile Ile Ala Leu 225 230 1861PRThomo sapiens 18Met Lys Arg Phe Leu Phe Leu Leu Leu Thr Ile Ser Leu Leu Val Met 1 5 10 15 Val Gln Ile Gln Thr Gly Leu Ser Gly Gln Asn Asp Thr Ser Gln Thr 20 25 30 Ser Ser Pro Ser Ala Ser Ser Asn Ile Ser Gly Gly Ile Phe Leu Phe 35 40 45 Phe Val Ala Asn Ala Ile Ile His Leu Phe Cys Phe Ser 50 55 60 19232PRThomo sapiens 19Met Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu Ala Leu Leu Leu 1 5 10 15 Tyr Leu His His Ala Lys Trp Ser Gln Ala Ala Pro Met Ala Glu Gly 20 25 30 Gly Gly Gln Asn His His Glu Val Val Lys Phe Met Asp Val Tyr Gln 35 40 45 Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val Asp Ile Phe Gln Glu 50 55 60 Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pro Ser Cys Val Pro Leu 65 70 75 80 Met Arg Cys Gly Gly Cys Cys Asn Asp Glu Gly Leu Glu Cys Val Pro 85 90 95 Thr Glu Glu Ser Asn Ile Thr Met Gln Ile Met Arg Ile Lys Pro His 100 105 110 Gln Gly Gln His Ile Gly Glu Met Ser Phe Leu Gln His Asn Lys Cys 115 120 125 Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu Lys Lys Ser Val 130 135 140 Arg Gly Lys Gly Lys Gly Gln Lys Arg Lys Arg Lys Lys Ser Arg Tyr 145 150 155 160 Lys Ser Trp Ser Val Tyr Val Gly Ala Arg Cys Cys Leu Met Pro Trp 165 170 175 Ser Leu Pro Gly Pro His Pro Cys Gly Pro Cys Ser Glu Arg Arg Lys 180

185 190 His Leu Phe Val Gln Asp Pro Gln Thr Cys Lys Cys Ser Cys Lys Asn 195 200 205 Thr Asp Ser Arg Cys Lys Ala Arg Gln Leu Glu Leu Asn Glu Arg Thr 210 215 220 Cys Arg Cys Asp Lys Pro Arg Arg 225 230 201676PRThomo sapiens 20Met Gly Leu Leu Gly Ile Leu Cys Phe Leu Ile Phe Leu Gly Lys Thr 1 5 10 15 Trp Gly Gln Glu Gln Thr Tyr Val Ile Ser Ala Pro Lys Ile Phe Arg 20 25 30 Val Gly Ala Ser Glu Asn Ile Val Ile Gln Val Tyr Gly Tyr Thr Glu 35 40 45 Ala Phe Asp Ala Thr Ile Ser Ile Lys Ser Tyr Pro Asp Lys Lys Phe 50 55 60 Ser Tyr Ser Ser Gly His Val His Leu Ser Ser Glu Asn Lys Phe Gln 65 70 75 80 Asn Ser Ala Ile Leu Thr Ile Gln Pro Lys Gln Leu Pro Gly Gly Gln 85 90 95 Asn Pro Val Ser Tyr Val Tyr Leu Glu Val Val Ser Lys His Phe Ser 100 105 110 Lys Ser Lys Arg Met Pro Ile Thr Tyr Asp Asn Gly Phe Leu Phe Ile 115 120 125 His Thr Asp Lys Pro Val Tyr Thr Pro Asp Gln Ser Val Lys Val Arg 130 135 140 Val Tyr Ser Leu Asn Asp Asp Leu Lys Pro Ala Lys Arg Glu Thr Val 145 150 155 160 Leu Thr Phe Ile Asp Pro Glu Gly Ser Glu Val Asp Met Val Glu Glu 165 170 175 Ile Asp His Ile Gly Ile Ile Ser Phe Pro Asp Phe Lys Ile Pro Ser 180 185 190 Asn Pro Arg Tyr Gly Met Trp Thr Ile Lys Ala Lys Tyr Lys Glu Asp 195 200 205 Phe Ser Thr Thr Gly Thr Ala Tyr Phe Glu Val Lys Glu Tyr Val Leu 210 215 220 Pro His Phe Ser Val Ser Ile Glu Pro Glu Tyr Asn Phe Ile Gly Tyr 225 230 235 240 Lys Asn Phe Lys Asn Phe Glu Ile Thr Ile Lys Ala Arg Tyr Phe Tyr 245 250 255 Asn Lys Val Val Thr Glu Ala Asp Val Tyr Ile Thr Phe Gly Ile Arg 260 265 270 Glu Asp Leu Lys Asp Asp Gln Lys Glu Met Met Gln Thr Ala Met Gln 275 280 285 Asn Thr Met Leu Ile Asn Gly Ile Ala Gln Val Thr Phe Asp Ser Glu 290 295 300 Thr Ala Val Lys Glu Leu Ser Tyr Tyr Ser Leu Glu Asp Leu Asn Asn 305 310 315 320 Lys Tyr Leu Tyr Ile Ala Val Thr Val Ile Glu Ser Thr Gly Gly Phe 325 330 335 Ser Glu Glu Ala Glu Ile Pro Gly Ile Lys Tyr Val Leu Ser Pro Tyr 340 345 350 Lys Leu Asn Leu Val Ala Thr Pro Leu Phe Leu Lys Pro Gly Ile Pro 355 360 365 Tyr Pro Ile Lys Val Gln Val Lys Asp Ser Leu Asp Gln Leu Val Gly 370 375 380 Gly Val Pro Val Thr Leu Asn Ala Gln Thr Ile Asp Val Asn Gln Glu 385 390 395 400 Thr Ser Asp Leu Asp Pro Ser Lys Ser Val Thr Arg Val Asp Asp Gly 405 410 415 Val Ala Ser Phe Val Leu Asn Leu Pro Ser Gly Val Thr Val Leu Glu 420 425 430 Phe Asn Val Lys Thr Asp Ala Pro Asp Leu Pro Glu Glu Asn Gln Ala 435 440 445 Arg Glu Gly Tyr Arg Ala Ile Ala Tyr Ser Ser Leu Ser Gln Ser Tyr 450 455 460 Leu Tyr Ile Asp Trp Thr Asp Asn His Lys Ala Leu Leu Val Gly Glu 465 470 475 480 His Leu Asn Ile Ile Val Thr Pro Lys Ser Pro Tyr Ile Asp Lys Ile 485 490 495 Thr His Tyr Asn Tyr Leu Ile Leu Ser Lys Gly Lys Ile Ile His Phe 500 505 510 Gly Thr Arg Glu Lys Phe Ser Asp Ala Ser Tyr Gln Ser Ile Asn Ile 515 520 525 Pro Val Thr Gln Asn Met Val Pro Ser Ser Arg Leu Leu Val Tyr Tyr 530 535 540 Ile Val Thr Gly Glu Gln Thr Ala Glu Leu Val Ser Asp Ser Val Trp 545 550 555 560 Leu Asn Ile Glu Glu Lys Cys Gly Asn Gln Leu Gln Val His Leu Ser 565 570 575 Pro Asp Ala Asp Ala Tyr Ser Pro Gly Gln Thr Val Ser Leu Asn Met 580 585 590 Ala Thr Gly Met Asp Ser Trp Val Ala Leu Ala Ala Val Asp Ser Ala 595 600 605 Val Tyr Gly Val Gln Arg Gly Ala Lys Lys Pro Leu Glu Arg Val Phe 610 615 620 Gln Phe Leu Glu Lys Ser Asp Leu Gly Cys Gly Ala Gly Gly Gly Leu 625 630 635 640 Asn Asn Ala Asn Val Phe His Leu Ala Gly Leu Thr Phe Leu Thr Asn 645 650 655 Ala Asn Ala Asp Asp Ser Gln Glu Asn Asp Glu Pro Cys Lys Glu Ile 660 665 670 Leu Arg Pro Arg Arg Thr Leu Gln Lys Lys Ile Glu Glu Ile Ala Ala 675 680 685 Lys Tyr Lys His Ser Val Val Lys Lys Cys Cys Tyr Asp Gly Ala Cys 690 695 700 Val Asn Asn Asp Glu Thr Cys Glu Gln Arg Ala Ala Arg Ile Ser Leu 705 710 715 720 Gly Pro Arg Cys Ile Lys Ala Phe Thr Glu Cys Cys Val Val Ala Ser 725 730 735 Gln Leu Arg Ala Asn Ile Ser His Lys Asp Met Gln Leu Gly Arg Leu 740 745 750 His Met Lys Thr Leu Leu Pro Val Ser Lys Pro Glu Ile Arg Ser Tyr 755 760 765 Phe Pro Glu Ser Trp Leu Trp Glu Val His Leu Val Pro Arg Arg Lys 770 775 780 Gln Leu Gln Phe Ala Leu Pro Asp Ser Leu Thr Thr Trp Glu Ile Gln 785 790 795 800 Gly Val Gly Ile Ser Asn Thr Gly Ile Cys Val Ala Asp Thr Val Lys 805 810 815 Ala Lys Val Phe Lys Asp Val Phe Leu Glu Met Asn Ile Pro Tyr Ser 820 825 830 Val Val Arg Gly Glu Gln Ile Gln Leu Lys Gly Thr Val Tyr Asn Tyr 835 840 845 Arg Thr Ser Gly Met Gln Phe Cys Val Lys Met Ser Ala Val Glu Gly 850 855 860 Ile Cys Thr Ser Glu Ser Pro Val Ile Asp His Gln Gly Thr Lys Ser 865 870 875 880 Ser Lys Cys Val Arg Gln Lys Val Glu Gly Ser Ser Ser His Leu Val 885 890 895 Thr Phe Thr Val Leu Pro Leu Glu Ile Gly Leu His Asn Ile Asn Phe 900 905 910 Ser Leu Glu Thr Trp Phe Gly Lys Glu Ile Leu Val Lys Thr Leu Arg 915 920 925 Val Val Pro Glu Gly Val Lys Arg Glu Ser Tyr Ser Gly Val Thr Leu 930 935 940 Asp Pro Arg Gly Ile Tyr Gly Thr Ile Ser Arg Arg Lys Glu Phe Pro 945 950 955 960 Tyr Arg Ile Pro Leu Asp Leu Val Pro Lys Thr Glu Ile Lys Arg Ile 965 970 975 Leu Ser Val Lys Gly Leu Leu Val Gly Glu Ile Leu Ser Ala Val Leu 980 985 990 Ser Gln Glu Gly Ile Asn Ile Leu Thr His Leu Pro Lys Gly Ser Ala 995 1000 1005 Glu Ala Glu Leu Met Ser Val Val Pro Val Phe Tyr Val Phe His 1010 1015 1020 Tyr Leu Glu Thr Gly Asn His Trp Asn Ile Phe His Ser Asp Pro 1025 1030 1035 Leu Ile Glu Lys Gln Lys Leu Lys Lys Lys Leu Lys Glu Gly Met 1040 1045 1050 Leu Ser Ile Met Ser Tyr Arg Asn Ala Asp Tyr Ser Tyr Ser Val 1055 1060 1065 Trp Lys Gly Gly Ser Ala Ser Thr Trp Leu Thr Ala Phe Ala Leu 1070 1075 1080 Arg Val Leu Gly Gln Val Asn Lys Tyr Val Glu Gln Asn Gln Asn 1085 1090 1095 Ser Ile Cys Asn Ser Leu Leu Trp Leu Val Glu Asn Tyr Gln Leu 1100 1105 1110 Asp Asn Gly Ser Phe Lys Glu Asn Ser Gln Tyr Gln Pro Ile Lys 1115 1120 1125 Leu Gln Gly Thr Leu Pro Val Glu Ala Arg Glu Asn Ser Leu Tyr 1130 1135 1140 Leu Thr Ala Phe Thr Val Ile Gly Ile Arg Lys Ala Phe Asp Ile 1145 1150 1155 Cys Pro Leu Val Lys Ile Asp Thr Ala Leu Ile Lys Ala Asp Asn 1160 1165 1170 Phe Leu Leu Glu Asn Thr Leu Pro Ala Gln Ser Thr Phe Thr Leu 1175 1180 1185 Ala Ile Ser Ala Tyr Ala Leu Ser Leu Gly Asp Lys Thr His Pro 1190 1195 1200 Gln Phe Arg Ser Ile Val Ser Ala Leu Lys Arg Glu Ala Leu Val 1205 1210 1215 Lys Gly Asn Pro Pro Ile Tyr Arg Phe Trp Lys Asp Asn Leu Gln 1220 1225 1230 His Lys Asp Ser Ser Val Pro Asn Thr Gly Thr Ala Arg Met Val 1235 1240 1245 Glu Thr Thr Ala Tyr Ala Leu Leu Thr Ser Leu Asn Leu Lys Asp 1250 1255 1260 Ile Asn Tyr Val Asn Pro Val Ile Lys Trp Leu Ser Glu Glu Gln 1265 1270 1275 Arg Tyr Gly Gly Gly Phe Tyr Ser Thr Gln Asp Thr Ile Asn Ala 1280 1285 1290 Ile Glu Gly Leu Thr Glu Tyr Ser Leu Leu Val Lys Gln Leu Arg 1295 1300 1305 Leu Ser Met Asp Ile Asp Val Ser Tyr Lys His Lys Gly Ala Leu 1310 1315 1320 His Asn Tyr Lys Met Thr Asp Lys Asn Phe Leu Gly Arg Pro Val 1325 1330 1335 Glu Val Leu Leu Asn Asp Asp Leu Ile Val Ser Thr Gly Phe Gly 1340 1345 1350 Ser Gly Leu Ala Thr Val His Val Thr Thr Val Val His Lys Thr 1355 1360 1365 Ser Thr Ser Glu Glu Val Cys Ser Phe Tyr Leu Lys Ile Asp Thr 1370 1375 1380 Gln Asp Ile Glu Ala Ser His Tyr Arg Gly Tyr Gly Asn Ser Asp 1385 1390 1395 Tyr Lys Arg Ile Val Ala Cys Ala Ser Tyr Lys Pro Ser Arg Glu 1400 1405 1410 Glu Ser Ser Ser Gly Ser Ser His Ala Val Met Asp Ile Ser Leu 1415 1420 1425 Pro Thr Gly Ile Ser Ala Asn Glu Glu Asp Leu Lys Ala Leu Val 1430 1435 1440 Glu Gly Val Asp Gln Leu Phe Thr Asp Tyr Gln Ile Lys Asp Gly 1445 1450 1455 His Val Ile Leu Gln Leu Asn Ser Ile Pro Ser Ser Asp Phe Leu 1460 1465 1470 Cys Val Arg Phe Arg Ile Phe Glu Leu Phe Glu Val Gly Phe Leu 1475 1480 1485 Ser Pro Ala Thr Phe Thr Val Tyr Glu Tyr His Arg Pro Asp Lys 1490 1495 1500 Gln Cys Thr Met Phe Tyr Ser Thr Ser Asn Ile Lys Ile Gln Lys 1505 1510 1515 Val Cys Glu Gly Ala Ala Cys Lys Cys Val Glu Ala Asp Cys Gly 1520 1525 1530 Gln Met Gln Glu Glu Leu Asp Leu Thr Ile Ser Ala Glu Thr Arg 1535 1540 1545 Lys Gln Thr Ala Cys Lys Pro Glu Ile Ala Tyr Ala Tyr Lys Val 1550 1555 1560 Ser Ile Thr Ser Ile Thr Val Glu Asn Val Phe Val Lys Tyr Lys 1565 1570 1575 Ala Thr Leu Leu Asp Ile Tyr Lys Thr Gly Glu Ala Val Ala Glu 1580 1585 1590 Lys Asp Ser Glu Ile Thr Phe Ile Lys Lys Val Thr Cys Thr Asn 1595 1600 1605 Ala Glu Leu Val Lys Gly Arg Gln Tyr Leu Ile Met Gly Lys Glu 1610 1615 1620 Ala Leu Gln Ile Lys Tyr Asn Phe Ser Phe Arg Tyr Ile Tyr Pro 1625 1630 1635 Leu Asp Ser Leu Thr Trp Ile Glu Tyr Trp Pro Arg Asp Thr Thr 1640 1645 1650 Cys Ser Ser Cys Gln Ala Phe Leu Ala Asn Leu Asp Glu Phe Ala 1655 1660 1665 Glu Asp Ile Phe Leu Asn Gly Cys 1670 1675 211170PRThomo sapiens 21Met Lys Asp Ser Cys Ile Thr Val Met Ala Met Ala Leu Leu Ser Gly 1 5 10 15 Phe Phe Phe Phe Ala Pro Ala Ser Ser Tyr Asn Leu Asp Val Arg Gly 20 25 30 Ala Arg Ser Phe Ser Pro Pro Arg Ala Gly Arg His Phe Gly Tyr Arg 35 40 45 Val Leu Gln Val Gly Asn Gly Val Ile Val Gly Ala Pro Gly Glu Gly 50 55 60 Asn Ser Thr Gly Ser Leu Tyr Gln Cys Gln Ser Gly Thr Gly His Cys 65 70 75 80 Leu Pro Val Thr Leu Arg Gly Ser Asn Tyr Thr Ser Lys Tyr Leu Gly 85 90 95 Met Thr Leu Ala Thr Asp Pro Thr Asp Gly Ser Ile Leu Ala Cys Asp 100 105 110 Pro Gly Leu Ser Arg Thr Cys Asp Gln Asn Thr Tyr Leu Ser Gly Leu 115 120 125 Cys Tyr Leu Phe Arg Gln Asn Leu Gln Gly Pro Met Leu Gln Gly Arg 130 135 140 Pro Gly Phe Gln Glu Cys Ile Lys Gly Asn Val Asp Leu Val Phe Leu 145 150 155 160 Phe Asp Gly Ser Met Ser Leu Gln Pro Asp Glu Phe Gln Lys Ile Leu 165 170 175 Asp Phe Met Lys Asp Val Met Lys Lys Leu Ser Asn Thr Ser Tyr Gln 180 185 190 Phe Ala Ala Val Gln Phe Ser Thr Ser Tyr Lys Thr Glu Phe Asp Phe 195 200 205 Ser Asp Tyr Val Lys Arg Lys Asp Pro Asp Ala Leu Leu Lys His Val 210 215 220 Lys His Met Leu Leu Leu Thr Asn Thr Phe Gly Ala Ile Asn Tyr Val 225 230 235 240 Ala Thr Glu Val Phe Arg Glu Glu Leu Gly Ala Arg Pro Asp Ala Thr 245 250 255 Lys Val Leu Ile Ile Ile Thr Asp Gly Glu Ala Thr Asp Ser Gly Asn 260 265 270 Ile Asp Ala Ala Lys Asp Ile Ile Arg Tyr Ile Ile Gly Ile Gly Lys 275 280 285 His Phe Gln Thr Lys Glu Ser Gln Glu Thr Leu His Lys Phe Ala Ser 290 295 300 Lys Pro Ala Ser Glu Phe Val Lys Ile Leu Asp Thr Phe Glu Lys Leu 305 310 315 320 Lys Asp Leu Phe Thr Glu Leu Gln Lys Lys Ile Tyr Val Ile Glu Gly 325 330 335 Thr Ser Lys Gln Asp Leu Thr Ser Phe Asn Met Glu Leu Ser Ser Ser 340 345 350 Gly Ile Ser Ala Asp Leu Ser Arg Gly His Ala Val Val Gly Ala Val 355 360 365 Gly Ala Lys Asp Trp Ala Gly Gly Phe Leu Asp Leu Lys Ala Asp Leu 370 375 380 Gln Asp Asp Thr Phe Ile Gly Asn Glu Pro Leu Thr Pro Glu Val Arg 385 390 395 400 Ala Gly Tyr Leu Gly Tyr Thr Val Thr Trp Leu Pro Ser Arg Gln Lys 405 410 415 Thr Ser Leu Leu Ala Ser Gly Ala Pro Arg Tyr Gln His Met Gly Arg 420 425 430 Val Leu Leu Phe Gln Glu Pro Gln Gly Gly Gly His Trp Ser Gln Val 435 440 445 Gln Thr Ile His Gly Thr Gln Ile Gly Ser Tyr Phe Gly Gly Glu Leu 450 455 460 Cys Gly Val Asp Val Asp Gln Asp Gly Glu Thr Glu Leu Leu Leu Ile 465 470 475 480 Gly Ala Pro Leu Phe Tyr Gly Glu Gln Arg Gly Gly Arg Val Phe Ile 485 490 495 Tyr Gln Arg Arg Gln Leu Gly Phe Glu Glu Val Ser Glu Leu Gln Gly 500 505 510 Asp Pro Gly Tyr Pro Leu Gly Arg Phe Gly Glu Ala Ile Thr Ala Leu 515 520 525 Thr Asp Ile Asn Gly Asp Gly Leu Val Asp Val Ala Val Gly Ala Pro 530 535 540 Leu Glu Glu Gln

Gly Ala Val Tyr Ile Phe Asn Gly Arg His Gly Gly 545 550 555 560 Leu Ser Pro Gln Pro Ser Gln Arg Ile Glu Gly Thr Gln Val Leu Ser 565 570 575 Gly Ile Gln Trp Phe Gly Arg Ser Ile His Gly Val Lys Asp Leu Glu 580 585 590 Gly Asp Gly Leu Ala Asp Val Ala Val Gly Ala Glu Ser Gln Met Ile 595 600 605 Val Leu Ser Ser Arg Pro Val Val Asp Met Val Thr Leu Met Ser Phe 610 615 620 Ser Pro Ala Glu Ile Pro Val His Glu Val Glu Cys Ser Tyr Ser Thr 625 630 635 640 Ser Asn Lys Met Lys Glu Gly Val Asn Ile Thr Ile Cys Phe Gln Ile 645 650 655 Lys Ser Leu Ile Pro Gln Phe Gln Gly Arg Leu Val Ala Asn Leu Thr 660 665 670 Tyr Thr Leu Gln Leu Asp Gly His Arg Thr Arg Arg Arg Gly Leu Phe 675 680 685 Pro Gly Gly Arg His Glu Leu Arg Arg Asn Ile Ala Val Thr Thr Ser 690 695 700 Met Ser Cys Thr Asp Phe Ser Phe His Phe Pro Val Cys Val Gln Asp 705 710 715 720 Leu Ile Ser Pro Ile Asn Val Ser Leu Asn Phe Ser Leu Trp Glu Glu 725 730 735 Glu Gly Thr Pro Arg Asp Gln Arg Ala Gln Gly Lys Asp Ile Pro Pro 740 745 750 Ile Leu Arg Pro Ser Leu His Ser Glu Thr Trp Glu Ile Pro Phe Glu 755 760 765 Lys Asn Cys Gly Glu Asp Lys Lys Cys Glu Ala Asn Leu Arg Val Ser 770 775 780 Phe Ser Pro Ala Arg Ser Arg Ala Leu Arg Leu Thr Ala Phe Ala Ser 785 790 795 800 Leu Ser Val Glu Leu Ser Leu Ser Asn Leu Glu Glu Asp Ala Tyr Trp 805 810 815 Val Gln Leu Asp Leu His Phe Pro Pro Gly Leu Ser Phe Arg Lys Val 820 825 830 Glu Met Leu Lys Pro His Ser Gln Ile Pro Val Ser Cys Glu Glu Leu 835 840 845 Pro Glu Glu Ser Arg Leu Leu Ser Arg Ala Leu Ser Cys Asn Val Ser 850 855 860 Ser Pro Ile Phe Lys Ala Gly His Ser Val Ala Leu Gln Met Met Phe 865 870 875 880 Asn Thr Leu Val Asn Ser Ser Trp Gly Asp Ser Val Glu Leu His Ala 885 890 895 Asn Val Thr Cys Asn Asn Glu Asp Ser Asp Leu Leu Glu Asp Asn Ser 900 905 910 Ala Thr Thr Ile Ile Pro Ile Leu Tyr Pro Ile Asn Ile Leu Ile Gln 915 920 925 Asp Gln Glu Asp Ser Thr Leu Tyr Val Ser Phe Thr Pro Lys Gly Pro 930 935 940 Lys Ile His Gln Val Lys His Met Tyr Gln Val Arg Ile Gln Pro Ser 945 950 955 960 Ile His Asp His Asn Ile Pro Thr Leu Glu Ala Val Val Gly Val Pro 965 970 975 Gln Pro Pro Ser Glu Gly Pro Ile Thr His Gln Trp Ser Val Gln Met 980 985 990 Glu Pro Pro Val Pro Cys His Tyr Glu Asp Leu Glu Arg Leu Pro Asp 995 1000 1005 Ala Ala Glu Pro Cys Leu Pro Gly Ala Leu Phe Arg Cys Pro Val 1010 1015 1020 Val Phe Arg Gln Glu Ile Leu Val Gln Val Ile Gly Thr Leu Glu 1025 1030 1035 Leu Val Gly Glu Ile Glu Ala Ser Ser Met Phe Ser Leu Cys Ser 1040 1045 1050 Ser Leu Ser Ile Ser Phe Asn Ser Ser Lys His Phe His Leu Tyr 1055 1060 1065 Gly Ser Asn Ala Ser Leu Ala Gln Val Val Met Lys Val Asp Val 1070 1075 1080 Val Tyr Glu Lys Gln Met Leu Tyr Leu Tyr Val Leu Ser Gly Ile 1085 1090 1095 Gly Gly Leu Leu Leu Leu Leu Leu Ile Phe Ile Val Leu Tyr Lys 1100 1105 1110 Val Gly Phe Phe Lys Arg Asn Leu Lys Glu Lys Met Glu Ala Gly 1115 1120 1125 Arg Gly Val Pro Asn Gly Ile Pro Ala Glu Asp Ser Glu Gln Leu 1130 1135 1140 Ala Ser Gly Gln Glu Ala Gly Asp Pro Gly Cys Leu Lys Pro Leu 1145 1150 1155 His Glu Lys Asp Ser Glu Ser Gly Gly Gly Lys Asp 1160 1165 1170 22364PRThomo sapiens 22Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala 1 5 10 15 Met Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln 20 25 30 Glu Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro 35 40 45 Tyr Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly 50 55 60 Ala Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln 65 70 75 80 Glu Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro 85 90 95 Ser Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp 100 105 110 Asn Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser 115 120 125 Tyr Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg 130 135 140 Pro Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn 145 150 155 160 Leu Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile 165 170 175 Phe Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr 180 185 190 His Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr 195 200 205 Asn Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu 210 215 220 Arg Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr 225 230 235 240 Gly Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly 245 250 255 Val Val His Gly Ala Ile Gly Gly Ala Gly Val Thr Ala Leu Leu Ala 260 265 270 Leu Cys Leu Cys Leu Ile Phe Phe Ile Val Lys Thr His Arg Arg Lys 275 280 285 Ala Ala Arg Thr Ala Val Gly Arg Asn Asp Thr His Pro Thr Thr Gly 290 295 300 Ser Ala Ser Pro Lys His Gln Lys Lys Ser Lys Leu His Gly Pro Thr 305 310 315 320 Glu Thr Ser Ser Cys Ser Gly Ala Ala Pro Thr Val Glu Met Asp Glu 325 330 335 Glu Leu His Tyr Ala Ser Leu Asn Phe His Gly Met Asn Pro Ser Lys 340 345 350 Asp Thr Ser Thr Glu Tyr Ser Glu Val Arg Thr Gln 355 360 231032PRThomo sapiens 23Met Ala Trp Glu Ala Arg Arg Glu Pro Gly Pro Arg Arg Ala Ala Val 1 5 10 15 Arg Glu Thr Val Met Leu Leu Leu Cys Leu Gly Val Pro Thr Gly Arg 20 25 30 Pro Tyr Asn Val Asp Thr Glu Ser Ala Leu Leu Tyr Gln Gly Pro His 35 40 45 Asn Thr Leu Phe Gly Tyr Ser Val Val Leu His Ser His Gly Ala Asn 50 55 60 Arg Trp Leu Leu Val Gly Ala Pro Thr Ala Asn Trp Leu Ala Asn Ala 65 70 75 80 Ser Val Ile Asn Pro Gly Ala Ile Tyr Arg Cys Arg Ile Gly Lys Asn 85 90 95 Pro Gly Gln Thr Cys Glu Gln Leu Gln Leu Gly Ser Pro Asn Gly Glu 100 105 110 Pro Cys Gly Lys Thr Cys Leu Glu Glu Arg Asp Asn Gln Trp Leu Gly 115 120 125 Val Thr Leu Ser Arg Gln Pro Gly Glu Asn Gly Ser Ile Val Thr Cys 130 135 140 Gly His Arg Trp Lys Asn Ile Phe Tyr Ile Lys Asn Glu Asn Lys Leu 145 150 155 160 Pro Thr Gly Gly Cys Tyr Gly Val Pro Pro Asp Leu Arg Thr Glu Leu 165 170 175 Ser Lys Arg Ile Ala Pro Cys Tyr Gln Asp Tyr Val Lys Lys Phe Gly 180 185 190 Glu Asn Phe Ala Ser Cys Gln Ala Gly Ile Ser Ser Phe Tyr Thr Lys 195 200 205 Asp Leu Ile Val Met Gly Ala Pro Gly Ser Ser Tyr Trp Thr Gly Ser 210 215 220 Leu Phe Val Tyr Asn Ile Thr Thr Asn Lys Tyr Lys Ala Phe Leu Asp 225 230 235 240 Lys Gln Asn Gln Val Lys Phe Gly Ser Tyr Leu Gly Tyr Ser Val Gly 245 250 255 Ala Gly His Phe Arg Ser Gln His Thr Thr Glu Val Val Gly Gly Ala 260 265 270 Pro Gln His Glu Gln Ile Gly Lys Ala Tyr Ile Phe Ser Ile Asp Glu 275 280 285 Lys Glu Leu Asn Ile Leu His Glu Met Lys Gly Lys Lys Leu Gly Ser 290 295 300 Tyr Phe Gly Ala Ser Val Cys Ala Val Asp Leu Asn Ala Asp Gly Phe 305 310 315 320 Ser Asp Leu Leu Val Gly Ala Pro Met Gln Ser Thr Ile Arg Glu Glu 325 330 335 Gly Arg Val Phe Val Tyr Ile Asn Ser Gly Ser Gly Ala Val Met Asn 340 345 350 Ala Met Glu Thr Asn Leu Val Gly Ser Asp Lys Tyr Ala Ala Arg Phe 355 360 365 Gly Glu Ser Ile Val Asn Leu Gly Asp Ile Asp Asn Asp Gly Phe Glu 370 375 380 Asp Val Ala Ile Gly Ala Pro Gln Glu Asp Asp Leu Gln Gly Ala Ile 385 390 395 400 Tyr Ile Tyr Asn Gly Arg Ala Asp Gly Ile Ser Ser Thr Phe Ser Gln 405 410 415 Arg Ile Glu Gly Leu Gln Ile Ser Lys Ser Leu Ser Met Phe Gly Gln 420 425 430 Ser Ile Ser Gly Gln Ile Asp Ala Asp Asn Asn Gly Tyr Val Asp Val 435 440 445 Ala Val Gly Ala Phe Arg Ser Asp Ser Ala Val Leu Leu Arg Thr Arg 450 455 460 Pro Val Val Ile Val Asp Ala Ser Leu Ser His Pro Glu Ser Val Asn 465 470 475 480 Arg Thr Lys Phe Asp Cys Val Glu Asn Gly Trp Pro Ser Val Cys Ile 485 490 495 Asp Leu Thr Leu Cys Phe Ser Tyr Lys Gly Lys Glu Val Pro Gly Tyr 500 505 510 Ile Val Leu Phe Tyr Asn Met Ser Leu Asp Val Asn Arg Lys Ala Glu 515 520 525 Ser Pro Pro Arg Phe Tyr Phe Ser Ser Asn Gly Thr Ser Asp Val Ile 530 535 540 Thr Gly Ser Ile Gln Val Ser Ser Arg Glu Ala Asn Cys Arg Thr His 545 550 555 560 Gln Ala Phe Met Arg Lys Asp Val Arg Asp Ile Leu Thr Pro Ile Gln 565 570 575 Ile Glu Ala Ala Tyr His Leu Gly Pro His Val Ile Ser Lys Arg Ser 580 585 590 Thr Glu Glu Phe Pro Pro Leu Gln Pro Ile Leu Gln Gln Lys Lys Glu 595 600 605 Lys Asp Ile Met Lys Lys Thr Ile Asn Phe Ala Arg Phe Cys Ala His 610 615 620 Glu Asn Cys Ser Ala Asp Leu Gln Val Ser Ala Lys Ile Gly Phe Leu 625 630 635 640 Lys Pro His Glu Asn Lys Thr Tyr Leu Ala Val Gly Ser Met Lys Thr 645 650 655 Leu Met Leu Asn Val Ser Leu Phe Asn Ala Gly Asp Asp Ala Tyr Glu 660 665 670 Thr Thr Leu His Val Lys Leu Pro Val Gly Leu Tyr Phe Ile Lys Ile 675 680 685 Leu Glu Leu Glu Glu Lys Gln Ile Asn Cys Glu Val Thr Asp Asn Ser 690 695 700 Gly Val Val Gln Leu Asp Cys Ser Ile Gly Tyr Ile Tyr Val Asp His 705 710 715 720 Leu Ser Arg Ile Asp Ile Ser Phe Leu Leu Asp Val Ser Ser Leu Ser 725 730 735 Arg Ala Glu Glu Asp Leu Ser Ile Thr Val His Ala Thr Cys Glu Asn 740 745 750 Glu Glu Glu Met Asp Asn Leu Lys His Ser Arg Val Thr Val Ala Ile 755 760 765 Pro Leu Lys Tyr Glu Val Lys Leu Thr Val His Gly Phe Val Asn Pro 770 775 780 Thr Ser Phe Val Tyr Gly Ser Asn Asp Glu Asn Glu Pro Glu Thr Cys 785 790 795 800 Met Val Glu Lys Met Asn Leu Thr Phe His Val Ile Asn Thr Gly Asn 805 810 815 Ser Met Ala Pro Asn Val Ser Val Glu Ile Met Val Pro Asn Ser Phe 820 825 830 Ser Pro Gln Thr Asp Lys Leu Phe Asn Ile Leu Asp Val Gln Thr Thr 835 840 845 Thr Gly Glu Cys His Phe Glu Asn Tyr Gln Arg Val Cys Ala Leu Glu 850 855 860 Gln Gln Lys Ser Ala Met Gln Thr Leu Lys Gly Ile Val Arg Phe Leu 865 870 875 880 Ser Lys Thr Asp Lys Arg Leu Leu Tyr Cys Ile Lys Ala Asp Pro His 885 890 895 Cys Leu Asn Phe Leu Cys Asn Phe Gly Lys Met Glu Ser Gly Lys Glu 900 905 910 Ala Ser Val His Ile Gln Leu Glu Gly Arg Pro Ser Ile Leu Glu Met 915 920 925 Asp Glu Thr Ser Ala Leu Lys Phe Glu Ile Arg Ala Thr Gly Phe Pro 930 935 940 Glu Pro Asn Pro Arg Val Ile Glu Leu Asn Lys Asp Glu Asn Val Ala 945 950 955 960 His Val Leu Leu Glu Gly Leu His His Gln Arg Pro Lys Arg Tyr Phe 965 970 975 Thr Ile Val Ile Ile Ser Ser Ser Leu Leu Leu Gly Leu Ile Val Leu 980 985 990 Leu Leu Ile Ser Tyr Val Met Trp Lys Ala Gly Phe Phe Lys Arg Gln 995 1000 1005 Tyr Lys Ser Ile Leu Gln Glu Glu Asn Arg Arg Asp Ser Trp Ser 1010 1015 1020 Tyr Ile Asn Ser Lys Ser Asn Asp Asp 1025 1030 24257PRThomo sapiens 24Met Ala Pro Ala Met Glu Ser Pro Thr Leu Leu Cys Val Ala Leu Leu 1 5 10 15 Phe Phe Ala Pro Asp Gly Val Leu Ala Val Pro Gln Lys Pro Lys Val 20 25 30 Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr 35 40 45 Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp 50 55 60 Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile 65 70 75 80 Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln 85 90 95 Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp 100 105 110 Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu 115 120 125 Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile 130 135 140 Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn 145 150 155 160 Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys 165 170 175 Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile 180 185 190 Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Phe Phe Ile 195 200 205 Pro Leu Leu Val Val Ile Leu Phe Ala Val Asp Thr Gly Leu Phe Ile 210 215 220 Ser Thr Gln Gln Gln Val Thr Phe Leu Leu Lys Ile Lys Arg Thr Arg 225 230 235 240 Lys Gly Phe Arg Leu Leu Asn Pro His Pro Lys Pro Asn Pro Lys Asn 245 250 255 Asn 25574PRThomo sapiens 25Met Glu Leu Leu Ile Leu Lys Ala Asn

Ala Ile Thr Thr Ile Leu Thr 1 5 10 15 Ala Val Thr Phe Cys Phe Ala Ser Gly Gln Asn Ile Thr Glu Glu Phe 20 25 30 Tyr Gln Ser Thr Cys Ser Ala Val Ser Lys Gly Tyr Leu Ser Ala Leu 35 40 45 Arg Thr Gly Trp Tyr Thr Ser Val Ile Thr Ile Glu Leu Ser Asn Ile 50 55 60 Lys Glu Asn Lys Cys Asn Gly Thr Asp Ala Lys Val Lys Leu Ile Lys 65 70 75 80 Gln Glu Leu Asp Lys Tyr Lys Asn Ala Val Thr Glu Leu Gln Leu Leu 85 90 95 Met Gln Ser Thr Pro Pro Thr Asn Asn Arg Ala Arg Arg Glu Leu Pro 100 105 110 Arg Phe Met Asn Tyr Thr Leu Asn Asn Ala Lys Lys Thr Asn Val Thr 115 120 125 Leu Ser Lys Lys Arg Lys Arg Arg Phe Leu Gly Phe Leu Leu Gly Val 130 135 140 Gly Ser Ala Ile Ala Ser Gly Val Ala Val Ser Lys Val Leu His Leu 145 150 155 160 Glu Gly Glu Val Asn Lys Ile Lys Ser Ala Leu Leu Ser Thr Asn Lys 165 170 175 Ala Val Val Ser Leu Ser Asn Gly Val Ser Val Leu Thr Ser Lys Val 180 185 190 Leu Asp Leu Lys Asn Tyr Ile Asp Lys Gln Leu Leu Pro Ile Val Asn 195 200 205 Lys Gln Ser Cys Ser Ile Ser Asn Ile Glu Thr Val Ile Glu Phe Gln 210 215 220 Gln Lys Asn Asn Arg Leu Leu Glu Ile Thr Arg Glu Phe Ser Val Asn 225 230 235 240 Ala Gly Val Thr Thr Pro Val Ser Thr Tyr Met Leu Thr Asn Ser Glu 245 250 255 Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp Gln Lys Lys 260 265 270 Leu Met Ser Asn Asn Val Gln Ile Val Arg Gln Gln Ser Tyr Ser Ile 275 280 285 Met Ser Ile Ile Lys Glu Glu Val Leu Ala Tyr Val Val Gln Leu Pro 290 295 300 Leu Tyr Gly Val Ile Asp Thr Pro Cys Trp Lys Leu His Thr Ser Pro 305 310 315 320 Leu Cys Thr Thr Asn Thr Lys Glu Gly Ser Asn Ile Cys Leu Thr Arg 325 330 335 Thr Asp Arg Gly Trp Tyr Cys Asp Asn Ala Gly Ser Val Ser Phe Phe 340 345 350 Pro Gln Ala Glu Thr Cys Lys Val Gln Ser Asn Arg Val Phe Cys Asp 355 360 365 Thr Met Asn Ser Leu Thr Leu Pro Ser Glu Ile Asn Leu Cys Asn Val 370 375 380 Asp Ile Phe Asn Pro Lys Tyr Asp Cys Lys Ile Met Thr Ser Lys Thr 385 390 395 400 Asp Val Ser Ser Ser Val Ile Thr Ser Leu Gly Ala Ile Val Ser Cys 405 410 415 Tyr Gly Lys Thr Lys Cys Thr Ala Ser Asn Lys Asn Arg Gly Ile Ile 420 425 430 Lys Thr Phe Ser Asn Gly Cys Asp Tyr Val Ser Asn Lys Gly Met Asp 435 440 445 Thr Val Ser Val Gly Asn Thr Leu Tyr Tyr Val Asn Lys Gln Glu Gly 450 455 460 Lys Ser Leu Tyr Val Lys Gly Glu Pro Ile Ile Asn Phe Tyr Asp Pro 465 470 475 480 Leu Val Phe Pro Ser Asp Glu Phe Asp Ala Ser Ile Ser Gln Val Asn 485 490 495 Glu Lys Ile Asn Gln Ser Leu Ala Phe Ile Arg Lys Ser Asp Glu Leu 500 505 510 Leu His Asn Val Asn Ala Gly Lys Ser Thr Thr Asn Ile Met Ile Thr 515 520 525 Thr Ile Ile Ile Val Ile Ile Val Ile Leu Leu Ser Leu Ile Ala Val 530 535 540 Gly Leu Leu Leu Tyr Cys Lys Ala Arg Ser Thr Pro Val Thr Leu Ser 545 550 555 560 Lys Asp Gln Leu Ser Gly Ile Asn Asn Ile Ala Phe Ser Asn 565 570 26468PRThomo sapiens 26Met Leu Ala Val Gly Cys Ala Leu Leu Ala Ala Leu Leu Ala Ala Pro 1 5 10 15 Gly Ala Ala Leu Ala Pro Arg Arg Cys Pro Ala Gln Glu Val Ala Arg 20 25 30 Gly Val Leu Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys Pro 35 40 45 Gly Val Glu Pro Glu Asp Asn Ala Thr Val His Trp Val Leu Arg Lys 50 55 60 Pro Ala Ala Gly Ser His Pro Ser Arg Trp Ala Gly Met Gly Arg Arg 65 70 75 80 Leu Leu Leu Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys 85 90 95 Tyr Arg Ala Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val 100 105 110 Pro Pro Glu Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser 115 120 125 Asn Val Val Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr 130 135 140 Lys Ala Val Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp 145 150 155 160 Phe Gln Glu Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys 165 170 175 Gln Leu Ala Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met 180 185 190 Cys Val Ala Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln Thr Phe 195 200 205 Gln Gly Cys Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val 210 215 220 Thr Ala Val Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp 225 230 235 240 Pro His Ser Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg 245 250 255 Tyr Arg Ala Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp 260 265 270 Leu Gln His His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His 275 280 285 Val Val Gln Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser 290 295 300 Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser 305 310 315 320 Pro Pro Ala Glu Asn Glu Val Ser Thr Pro Met Gln Ala Leu Thr Thr 325 330 335 Asn Lys Asp Asp Asp Asn Ile Leu Phe Arg Asp Ser Ala Asn Ala Thr 340 345 350 Ser Leu Pro Val Gln Asp Ser Ser Ser Val Pro Leu Pro Thr Phe Leu 355 360 365 Val Ala Gly Gly Ser Leu Ala Phe Gly Thr Leu Leu Cys Ile Ala Ile 370 375 380 Val Leu Arg Phe Lys Lys Thr Trp Lys Leu Arg Ala Leu Lys Glu Gly 385 390 395 400 Lys Thr Ser Met His Pro Pro Tyr Ser Leu Gly Gln Leu Val Pro Glu 405 410 415 Arg Pro Arg Pro Thr Pro Val Leu Val Pro Leu Ile Ser Pro Pro Val 420 425 430 Ser Pro Ser Ser Leu Gly Ser Asp Asn Thr Ser Ser His Asn Arg Pro 435 440 445 Asp Ala Arg Asp Pro Arg Ser Pro Tyr Asp Ile Ser Asn Thr Asp Tyr 450 455 460 Phe Phe Pro Arg 465 271255PRThomo sapiens 27Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu 1 5 10 15 Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 20 25 30 Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 35 40 45 Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 50 55 60 Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val 65 70 75 80 Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 85 90 95 Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 100 105 110 Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 115 120 125 Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 130 135 140 Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln 145 150 155 160 Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 165 170 175 Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 180 185 190 His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 195 200 205 Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 210 215 220 Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys 225 230 235 240 Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 245 250 255 His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 260 265 270 Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 275 280 285 Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 290 295 300 Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln 305 310 315 320 Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 325 330 335 Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 340 345 350 Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 355 360 365 Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 370 375 380 Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe 385 390 395 400 Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 405 410 415 Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg 420 425 430 Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu 435 440 445 Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 450 455 460 Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val 465 470 475 480 Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr 485 490 495 Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His 500 505 510 Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys 515 520 525 Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys 530 535 540 Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys 545 550 555 560 Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys 565 570 575 Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp 580 585 590 Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu 595 600 605 Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln 610 615 620 Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys 625 630 635 640 Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser 645 650 655 Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly 660 665 670 Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg 675 680 685 Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly 690 695 700 Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu 705 710 715 720 Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys 725 730 735 Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile 740 745 750 Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu 755 760 765 Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg 770 775 780 Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu 785 790 795 800 Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg 805 810 815 Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly 820 825 830 Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala 835 840 845 Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe 850 855 860 Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp 865 870 875 880 Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg 885 890 895 Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val 900 905 910 Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala 915 920 925 Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro 930 935 940 Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met 945 950 955 960 Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe 965 970 975 Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu 980 985 990 Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu 995 1000 1005 Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr 1010 1015 1020 Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly 1025 1030 1035 Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg 1040 1045 1050 Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu 1055 1060 1065 Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser 1070 1075 1080 Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu 1085 1090 1095 Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser 1100 1105 1110 Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val 1115 1120 1125 Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro 1130 1135 1140 Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro 1145 1150 1155 Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu 1160 1165 1170 Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly 1175 1180 1185 Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala 1190 1195 1200 Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp 1205 1210 1215 Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro 1220 1225 1230 Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr 1235 1240 1245 Leu Gly

Leu Asp Val Pro Val 1250 1255 28798PRThomo sapiens 28Met Val Ala Leu Pro Met Val Leu Val Leu Leu Leu Val Leu Ser Arg 1 5 10 15 Gly Glu Ser Glu Leu Asp Ala Lys Ile Pro Ser Thr Gly Asp Ala Thr 20 25 30 Glu Trp Arg Asn Pro His Leu Ser Met Leu Gly Ser Cys Gln Pro Ala 35 40 45 Pro Ser Cys Gln Lys Cys Ile Leu Ser His Pro Ser Cys Ala Trp Cys 50 55 60 Lys Gln Leu Asn Phe Thr Ala Ser Gly Glu Ala Glu Ala Arg Arg Cys 65 70 75 80 Ala Arg Arg Glu Glu Leu Leu Ala Arg Gly Cys Pro Leu Glu Glu Leu 85 90 95 Glu Glu Pro Arg Gly Gln Gln Glu Val Leu Gln Asp Gln Pro Leu Ser 100 105 110 Gln Gly Ala Arg Gly Glu Gly Ala Thr Gln Leu Ala Pro Gln Arg Val 115 120 125 Arg Val Thr Leu Arg Pro Gly Glu Pro Gln Gln Leu Gln Val Arg Phe 130 135 140 Leu Arg Ala Glu Gly Tyr Pro Val Asp Leu Tyr Tyr Leu Met Asp Leu 145 150 155 160 Ser Tyr Ser Met Lys Asp Asp Leu Glu Arg Val Arg Gln Leu Gly His 165 170 175 Ala Leu Leu Val Arg Leu Gln Glu Val Thr His Ser Val Arg Ile Gly 180 185 190 Phe Gly Ser Phe Val Asp Lys Thr Val Leu Pro Phe Val Ser Thr Val 195 200 205 Pro Ser Lys Leu Arg His Pro Cys Pro Thr Arg Leu Glu Arg Cys Gln 210 215 220 Ser Pro Phe Ser Phe His His Val Leu Ser Leu Thr Gly Asp Ala Gln 225 230 235 240 Ala Phe Glu Arg Glu Val Gly Arg Gln Ser Val Ser Gly Asn Leu Asp 245 250 255 Ser Pro Glu Gly Gly Phe Asp Ala Ile Leu Gln Ala Ala Leu Cys Gln 260 265 270 Glu Gln Ile Gly Trp Arg Asn Val Ser Arg Leu Leu Val Phe Thr Ser 275 280 285 Asp Asp Thr Phe His Thr Ala Gly Asp Gly Lys Leu Gly Gly Ile Phe 290 295 300 Met Pro Ser Asp Gly His Cys His Leu Asp Ser Asn Gly Leu Tyr Ser 305 310 315 320 Arg Ser Thr Glu Phe Asp Tyr Pro Ser Val Gly Gln Val Ala Gln Ala 325 330 335 Leu Ser Ala Ala Asn Ile Gln Pro Ile Phe Ala Val Thr Ser Ala Ala 340 345 350 Leu Pro Val Tyr Gln Glu Leu Ser Lys Leu Ile Pro Lys Ser Ala Val 355 360 365 Gly Glu Leu Ser Glu Asp Ser Ser Asn Val Val Gln Leu Ile Met Asp 370 375 380 Ala Tyr Asn Ser Leu Ser Ser Thr Val Thr Leu Glu His Ser Ser Leu 385 390 395 400 Pro Pro Gly Val His Ile Ser Tyr Glu Ser Gln Cys Glu Gly Pro Glu 405 410 415 Lys Arg Glu Gly Lys Ala Glu Asp Arg Gly Gln Cys Asn His Val Arg 420 425 430 Ile Asn Gln Thr Val Thr Phe Trp Val Ser Leu Gln Ala Thr His Cys 435 440 445 Leu Pro Glu Pro His Leu Leu Arg Leu Arg Ala Leu Gly Phe Ser Glu 450 455 460 Glu Leu Ile Val Glu Leu His Thr Leu Cys Asp Cys Asn Cys Ser Asp 465 470 475 480 Thr Gln Pro Gln Ala Pro His Cys Ser Asp Gly Gln Gly His Leu Gln 485 490 495 Cys Gly Val Cys Ser Cys Ala Pro Gly Arg Leu Gly Arg Leu Cys Glu 500 505 510 Cys Ser Val Ala Glu Leu Ser Ser Pro Asp Leu Glu Ser Gly Cys Arg 515 520 525 Ala Pro Asn Gly Thr Gly Pro Leu Cys Ser Gly Lys Gly His Cys Gln 530 535 540 Cys Gly Arg Cys Ser Cys Ser Gly Gln Ser Ser Gly His Leu Cys Glu 545 550 555 560 Cys Asp Asp Ala Ser Cys Glu Arg His Glu Gly Ile Leu Cys Gly Gly 565 570 575 Phe Gly Arg Cys Gln Cys Gly Val Cys His Cys His Ala Asn Arg Thr 580 585 590 Gly Arg Ala Cys Glu Cys Ser Gly Asp Met Asp Ser Cys Ile Ser Pro 595 600 605 Glu Gly Gly Leu Cys Ser Gly His Gly Arg Cys Lys Cys Asn Arg Cys 610 615 620 Gln Cys Leu Asp Gly Tyr Tyr Gly Ala Leu Cys Asp Gln Cys Pro Gly 625 630 635 640 Cys Lys Thr Pro Cys Glu Arg His Arg Asp Cys Ala Glu Cys Gly Ala 645 650 655 Phe Arg Thr Gly Pro Leu Ala Thr Asn Cys Ser Thr Ala Cys Ala His 660 665 670 Thr Asn Val Thr Leu Ala Leu Ala Pro Ile Leu Asp Asp Gly Trp Cys 675 680 685 Lys Glu Arg Thr Leu Asp Asn Gln Leu Phe Phe Phe Leu Val Glu Asp 690 695 700 Asp Ala Arg Gly Thr Val Val Leu Arg Val Arg Pro Gln Glu Lys Gly 705 710 715 720 Ala Asp His Thr Gln Ala Ile Val Leu Gly Cys Val Gly Gly Ile Val 725 730 735 Ala Val Gly Leu Gly Leu Val Leu Ala Tyr Arg Leu Ser Val Glu Ile 740 745 750 Tyr Asp Arg Arg Glu Tyr Ser Arg Phe Glu Lys Glu Gln Gln Gln Leu 755 760 765 Asn Trp Lys Gln Asp Ser Asn Pro Leu Tyr Lys Ser Ala Ile Thr Thr 770 775 780 Thr Ile Asn Pro Arg Phe Gln Glu Ala Asp Ser Pro Thr Leu 785 790 795 29285PRThomo sapiens 29Met Asp Asp Ser Thr Glu Arg Glu Gln Ser Arg Leu Thr Ser Cys Leu 1 5 10 15 Lys Lys Arg Glu Glu Met Lys Leu Lys Glu Cys Val Ser Ile Leu Pro 20 25 30 Arg Lys Glu Ser Pro Ser Val Arg Ser Ser Lys Asp Gly Lys Leu Leu 35 40 45 Ala Ala Thr Leu Leu Leu Ala Leu Leu Ser Cys Cys Leu Thr Val Val 50 55 60 Ser Phe Tyr Gln Val Ala Ala Leu Gln Gly Asp Leu Ala Ser Leu Arg 65 70 75 80 Ala Glu Leu Gln Gly His His Ala Glu Lys Leu Pro Ala Gly Ala Gly 85 90 95 Ala Pro Lys Ala Gly Leu Glu Glu Ala Pro Ala Val Thr Ala Gly Leu 100 105 110 Lys Ile Phe Glu Pro Pro Ala Pro Gly Glu Gly Asn Ser Ser Gln Asn 115 120 125 Ser Arg Asn Lys Arg Ala Val Gln Gly Pro Glu Glu Thr Val Thr Gln 130 135 140 Asp Cys Leu Gln Leu Ile Ala Asp Ser Glu Thr Pro Thr Ile Gln Lys 145 150 155 160 Gly Ser Tyr Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Arg Gly Ser 165 170 175 Ala Leu Glu Glu Lys Glu Asn Lys Ile Leu Val Lys Glu Thr Gly Tyr 180 185 190 Phe Phe Ile Tyr Gly Gln Val Leu Tyr Thr Asp Lys Thr Tyr Ala Met 195 200 205 Gly His Leu Ile Gln Arg Lys Lys Val His Val Phe Gly Asp Glu Leu 210 215 220 Ser Leu Val Thr Leu Phe Arg Cys Ile Gln Asn Met Pro Glu Thr Leu 225 230 235 240 Pro Asn Asn Ser Cys Tyr Ser Ala Gly Ile Ala Lys Leu Glu Glu Gly 245 250 255 Asp Glu Leu Gln Leu Ala Ile Pro Arg Glu Asn Ala Gln Ile Ser Leu 260 265 270 Asp Gly Asp Val Thr Phe Phe Gly Ala Leu Lys Leu Leu 275 280 285 30269PRThomo sapiens 30Met Ala Glu Val Pro Glu Leu Ala Ser Glu Met Met Ala Tyr Tyr Ser 1 5 10 15 Gly Asn Glu Asp Asp Leu Phe Phe Glu Ala Asp Gly Pro Lys Gln Met 20 25 30 Lys Cys Ser Phe Gln Asp Leu Asp Leu Cys Pro Leu Asp Gly Gly Ile 35 40 45 Gln Leu Arg Ile Ser Asp His His Tyr Ser Lys Gly Phe Arg Gln Ala 50 55 60 Ala Ser Val Val Val Ala Met Asp Lys Leu Arg Lys Met Leu Val Pro 65 70 75 80 Cys Pro Gln Thr Phe Gln Glu Asn Asp Leu Ser Thr Phe Phe Pro Phe 85 90 95 Ile Phe Glu Glu Glu Pro Ile Phe Phe Asp Thr Trp Asp Asn Glu Ala 100 105 110 Tyr Val His Asp Ala Pro Val Arg Ser Leu Asn Cys Thr Leu Arg Asp 115 120 125 Ser Gln Gln Lys Ser Leu Val Met Ser Gly Pro Tyr Glu Leu Lys Ala 130 135 140 Leu His Leu Gln Gly Gln Asp Met Glu Gln Gln Val Val Phe Ser Met 145 150 155 160 Ser Phe Val Gln Gly Glu Glu Ser Asn Asp Lys Ile Pro Val Ala Leu 165 170 175 Gly Leu Lys Glu Lys Asn Leu Tyr Leu Ser Cys Val Leu Lys Asp Asp 180 185 190 Lys Pro Thr Leu Gln Leu Glu Ser Val Asp Pro Lys Asn Tyr Pro Lys 195 200 205 Lys Lys Met Glu Lys Arg Phe Val Phe Asn Lys Ile Glu Ile Asn Asn 210 215 220 Lys Leu Glu Phe Glu Ser Ala Gln Phe Pro Asn Trp Tyr Ile Ser Thr 225 230 235 240 Ser Gln Ala Glu Asn Met Pro Val Phe Leu Gly Gly Thr Lys Gly Gly 245 250 255 Gln Asp Ile Thr Asp Phe Thr Met Gln Phe Val Ser Ser 260 265 31317PRThomo sapiens 31Met Arg Arg Ala Ser Arg Asp Tyr Thr Lys Tyr Leu Arg Gly Ser Glu 1 5 10 15 Glu Met Gly Gly Gly Pro Gly Ala Pro His Glu Gly Pro Leu His Ala 20 25 30 Pro Pro Pro Pro Ala Pro His Gln Pro Pro Ala Ala Ser Arg Ser Met 35 40 45 Phe Val Ala Leu Leu Gly Leu Gly Leu Gly Gln Val Val Cys Ser Val 50 55 60 Ala Leu Phe Phe Tyr Phe Arg Ala Gln Met Asp Pro Asn Arg Ile Ser 65 70 75 80 Glu Asp Gly Thr His Cys Ile Tyr Arg Ile Leu Arg Leu His Glu Asn 85 90 95 Ala Asp Phe Gln Asp Thr Thr Leu Glu Ser Gln Asp Thr Lys Leu Ile 100 105 110 Pro Asp Ser Cys Arg Arg Ile Lys Gln Ala Phe Gln Gly Ala Val Gln 115 120 125 Lys Glu Leu Gln His Ile Val Gly Ser Gln His Ile Arg Ala Glu Lys 130 135 140 Ala Met Val Asp Gly Ser Trp Leu Asp Leu Ala Lys Arg Ser Lys Leu 145 150 155 160 Glu Ala Gln Pro Phe Ala His Leu Thr Ile Asn Ala Thr Asp Ile Pro 165 170 175 Ser Gly Ser His Lys Val Ser Leu Ser Ser Trp Tyr His Asp Arg Gly 180 185 190 Trp Ala Lys Ile Ser Asn Met Thr Phe Ser Asn Gly Lys Leu Ile Val 195 200 205 Asn Gln Asp Gly Phe Tyr Tyr Leu Tyr Ala Asn Ile Cys Phe Arg His 210 215 220 His Glu Thr Ser Gly Asp Leu Ala Thr Glu Tyr Leu Gln Leu Met Val 225 230 235 240 Tyr Val Thr Lys Thr Ser Ile Lys Ile Pro Ser Ser His Thr Leu Met 245 250 255 Lys Gly Gly Ser Thr Lys Tyr Trp Ser Gly Asn Ser Glu Phe His Phe 260 265 270 Tyr Ser Ile Asn Val Gly Gly Phe Phe Lys Leu Arg Ser Gly Glu Glu 275 280 285 Ile Ser Ile Glu Val Ser Asn Pro Ser Leu Leu Asp Pro Asp Gln Asp 290 295 300 Ala Thr Tyr Phe Gly Ala Phe Lys Val Arg Asp Ile Asp 305 310 315 32223PRThomo sapiens 32Met Ala Cys Leu Gly Phe Gln Arg His Lys Ala Gln Leu Asn Leu Ala 1 5 10 15 Thr Arg Thr Trp Pro Cys Thr Leu Leu Phe Phe Leu Leu Phe Ile Pro 20 25 30 Val Phe Cys Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala 35 40 45 Ser Ser Arg Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly 50 55 60 Lys Ala Thr Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln 65 70 75 80 Val Thr Glu Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr 85 90 95 Phe Leu Asp Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val 100 105 110 Asn Leu Thr Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile 115 120 125 Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly 130 135 140 Asn Gly Thr Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser 145 150 155 160 Asp Phe Leu Leu Trp Ile Leu Ala Ala Val Ser Ser Gly Leu Phe Phe 165 170 175 Tyr Ser Phe Leu Leu Thr Ala Val Ser Leu Ser Lys Met Leu Lys Lys 180 185 190 Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu 195 200 205 Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn 210 215 220 33189PRThomo sapiens 33Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr 1 5 10 15 Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln 20 25 30 Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His 35 40 45 Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr 50 55 60 Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln 65 70 75 80 Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly 85 90 95 Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu 100 105 110 Pro Ser Leu Leu Pro Asp Ser Pro Val Gly Gln Leu His Ala Ser Leu 115 120 125 Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr 130 135 140 Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu 145 150 155 160 Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala 165 170 175 Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro 180 185 34288PRThomo sapiens 34Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln 1 5 10 15 Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp 20 25 30 Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp 35 40 45 Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val 50 55 60 Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala 65 70 75 80 Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg 85 90 95 Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg 100 105 110 Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu 115 120 125 Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val 130 135 140 Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro 145 150 155 160 Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly 165 170 175 Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys 180 185 190 Ser Arg Ala Ala Arg Gly Thr Ile

Gly Ala Arg Arg Thr Gly Gln Pro 195 200 205 Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly 210 215 220 Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro 225 230 235 240 Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly 245 250 255 Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg 260 265 270 Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu 275 280 285 359PRTartificial sequencemAb-specific epitope 35Cys Pro Tyr Ser Asn Pro Ser Leu Cys 1 5 3624PRThomo sapiens 36Asn Ser Glu Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp 1 5 10 15 Gln Lys Lys Leu Met Ser Asn Asn 20 3712PRTartificial sequencemAb-specific epitope 37Cys Gln Phe Asp Leu Ser Thr Arg Arg Leu Lys Cys 1 5 10 3812PRTartificial sequencemAb-specific epitope 38Cys Gln Tyr Asn Leu Ser Ser Arg Ala Leu Lys Cys 1 5 10 3912PRTartificial sequencemAb-specific epitope 39Cys Val Trp Gln Arg Trp Gln Lys Ser Tyr Val Cys 1 5 10 4012PRTartificial sequencemAb-specific epitope 40Cys Met Trp Asp Arg Phe Ser Arg Trp Tyr Lys Cys 1 5 10 4125PRThomo sapiens 41Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp 1 5 10 15 Lys Leu Ala Ala Phe Pro Glu Asp Arg 20 25 4219PRThomo sapiens 42Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln 1 5 10 15 Ile Lys Glu 43557PRTmurine 43Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met 1 5 10 15 Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp 20 25 30 Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln 35 40 45 Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu 50 55 60 Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile 65 70 75 80 Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu 85 90 95 Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr 100 105 110 Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp 115 120 125 Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro 130 135 140 Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala 145 150 155 160 Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro 165 170 175 Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro 180 185 190 Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser 195 200 205 Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser 210 215 220 Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp 225 230 235 240 Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala 245 250 255 Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu 260 265 270 Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly 275 280 285 Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu 290 295 300 Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg 305 310 315 320 Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val 325 330 335 Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu 340 345 350 Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala 355 360 365 Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp 370 375 380 Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly 385 390 395 400 Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu 405 410 415 Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu 420 425 430 Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly 435 440 445 Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu 450 455 460 Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser 465 470 475 480 Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Ala 485 490 495 Gly Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro 500 505 510 Gln Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp 515 520 525 Ala Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala 530 535 540 Trp Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg 545 550 555 44300PRTmurine 44Met Ala Asn Cys Glu Phe Ser Pro Val Ser Gly Asp Lys Pro Cys Cys 1 5 10 15 Arg Leu Ser Arg Arg Ala Gln Leu Cys Leu Gly Val Ser Ile Leu Val 20 25 30 Leu Ile Leu Val Val Val Leu Ala Val Val Val Pro Arg Trp Arg Gln 35 40 45 Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg Phe Pro Glu Thr Val Leu 50 55 60 Ala Arg Cys Val Lys Tyr Thr Glu Ile His Pro Glu Met Arg His Val 65 70 75 80 Asp Cys Gln Ser Val Trp Asp Ala Phe Lys Gly Ala Phe Ile Ser Lys 85 90 95 His Pro Cys Asn Ile Thr Glu Glu Asp Tyr Gln Pro Leu Met Lys Leu 100 105 110 Gly Thr Gln Thr Val Pro Cys Asn Lys Ile Leu Leu Trp Ser Arg Ile 115 120 125 Lys Asp Leu Ala His Gln Phe Thr Gln Val Gln Arg Asp Met Phe Thr 130 135 140 Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala Asp Asp Leu Thr Trp Cys 145 150 155 160 Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr Gln Ser Cys Pro Asp Trp 165 170 175 Arg Lys Asp Cys Ser Asn Asn Pro Val Ser Val Phe Trp Lys Thr Val 180 185 190 Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp Val Val His Val Met Leu 195 200 205 Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys Asn Ser Thr Phe Gly Ser 210 215 220 Val Glu Val His Asn Leu Gln Pro Glu Lys Val Gln Thr Leu Glu Ala 225 230 235 240 Trp Val Ile His Gly Gly Arg Glu Asp Ser Arg Asp Leu Cys Gln Asp 245 250 255 Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile Ser Lys Arg Asn Ile Gln 260 265 270 Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp Lys Phe Leu Gln Cys Val 275 280 285 Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser Glu Ile 290 295 300 45378PRTmurine 45Met Val Leu Leu Trp Leu Thr Leu Leu Leu Ile Ala Leu Pro Cys Leu 1 5 10 15 Leu Gln Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met 20 25 30 Lys Ala Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr 35 40 45 Asp Ile Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn 50 55 60 Asn Ser Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn 65 70 75 80 Tyr Thr Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe 85 90 95 Pro Glu Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys 100 105 110 Trp Ile His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro 115 120 125 Gly Ala Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn 130 135 140 Arg Arg Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly 145 150 155 160 Thr Arg Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly 165 170 175 Ser Gln Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly 180 185 190 Ile Pro Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu 195 200 205 Thr Pro Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met 210 215 220 His Trp Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu 225 230 235 240 Gln Ile Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp 245 250 255 Arg Thr Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile 260 265 270 Arg Ala Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro 275 280 285 Gln Arg Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp 290 295 300 Arg Thr Ser Leu Leu Ile Ala Leu Gly Thr Leu Leu Ala Leu Val Cys 305 310 315 320 Val Phe Val Ile Cys Arg Arg Tyr Leu Val Met Gln Arg Leu Phe Pro 325 330 335 Arg Ile Pro His Met Lys Asp Pro Ile Gly Asp Ser Phe Gln Asn Asp 340 345 350 Lys Leu Val Val Trp Glu Ala Gly Lys Ala Gly Leu Glu Glu Cys Leu 355 360 365 Val Thr Glu Val Gln Val Val Gln Lys Thr 370 375 46335PRTmurine 46Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln 1 5 10 15 Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser 20 25 30 Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val 35 40 45 Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln 50 55 60 Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg 65 70 75 80 Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys 85 90 95 Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu 100 105 110 Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu 115 120 125 Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr 130 135 140 Cys Val Thr Asn Leu Thr Cys Cys Met Glu His Gly Glu Glu Asp Val 145 150 155 160 Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn 165 170 175 Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr 180 185 190 Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro 195 200 205 Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser 210 215 220 Ser Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu 225 230 235 240 Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln Glu 245 250 255 Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu Thr Pro 260 265 270 Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp Thr Ile Pro 275 280 285 His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala Asn Thr Val Tyr 290 295 300 Ser Thr Val Glu Ile Pro Lys Lys Met Glu Asn Pro His Ser Leu Leu 305 310 315 320 Thr Met Pro Asp Thr Pro Arg Leu Phe Ala Tyr Glu Asn Val Ile 325 330 335 47184PRTmurine 47Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser 1 5 10 15 Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr 20 25 30 Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser 35 40 45 Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu 50 55 60 Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile 65 70 75 80 Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu 85 90 95 Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu 100 105 110 Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys 115 120 125 Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe 130 135 140 Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys 145 150 155 160 Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu 165 170 175 Ile Glu Lys Ser Ile Ser Ala Arg 180 48993PRTmurine 48Met Pro Ala Leu Ala Arg Asp Gly Gly Gln Leu Pro Leu Leu Val Val 1 5 10 15 Phe Ser Ala Met Ile Phe Gly Thr Ile Thr Asn Gln Asp Leu Pro Val 20 25 30 Ile Lys Cys Val Leu Ile Asn His Lys Asn Asn Asp Ser Ser Val Gly 35 40 45 Lys Ser Ser Ser Tyr Pro Met Val Ser Glu Ser Pro Glu Asp Leu Gly 50 55 60 Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr Val Tyr Glu Ala Ala Ala 65 70 75 80 Val Glu Val Asp Val Ser Ala Ser Ile Thr Leu Gln Val Leu Val Asp 85 90 95 Ala Pro Gly Asn Ile Ser Cys Leu Trp Val Phe Lys His Ser Ser Leu 100 105 110 Asn Cys Gln Pro His Phe Asp Leu Gln Asn Arg Gly Val Val Ser Met 115 120 125 Val Ile Leu Lys Met Thr Glu Thr Gln Ala Gly Glu Tyr Leu Leu Phe 130 135 140 Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile Leu Phe Thr Val Ser Ile 145 150 155 160 Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg Pro Tyr Phe Arg Lys Met 165 170 175 Glu Asn Gln Asp Ala Leu Val Cys Ile Ser Glu Ser Val Pro Glu Pro 180 185 190 Ile Val Glu Trp Val Leu Cys Asp Ser Gln Gly Glu Ser Cys Lys Glu 195 200 205 Glu Ser Pro Ala Val Val Lys Lys Glu Glu Lys Val Leu His Glu Leu 210 215 220 Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg Asn Glu Leu Gly Arg Glu 225 230 235 240 Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn Gln Thr Pro Gln Thr Thr 245 250 255 Leu Pro Gln Leu Phe Leu Lys Val Gly Glu Pro Leu Trp Ile Arg Cys 260 265 270 Lys Ala Val His Val Asn His Gly Phe Gly Leu Thr Trp Glu Leu

Glu 275 280 285 Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe Glu Met Ser Thr Tyr Ser 290 295 300 Thr Asn Arg Thr Met Ile Arg Ile Leu Phe Ala Phe Val Ser Ser Val 305 310 315 320 Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys Ser Ser Ser Lys His Pro 325 330 335 Ser Gln Ser Ala Leu Val Thr Ile Val Glu Lys Gly Phe Ile Asn Ala 340 345 350 Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp Gln Tyr Glu Glu Phe Cys 355 360 365 Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln Ile Arg Cys Thr Trp Thr 370 375 380 Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln Lys Gly Leu Asp Asn Gly 385 390 395 400 Tyr Ser Ile Ser Lys Phe Cys Asn His Lys His Gln Pro Gly Glu Tyr 405 410 415 Ile Phe His Ala Glu Asn Asp Asp Ala Gln Phe Thr Lys Met Phe Thr 420 425 430 Leu Asn Ile Arg Arg Lys Pro Gln Val Leu Ala Glu Ala Ser Ala Ser 435 440 445 Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro Leu Pro Ser Trp Thr Trp 450 455 460 Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys Thr Glu Glu Ile Thr Glu 465 470 475 480 Gly Val Trp Asn Arg Lys Ala Asn Arg Lys Val Phe Gly Gln Trp Val 485 490 495 Ser Ser Ser Thr Leu Asn Met Ser Glu Ala Ile Lys Gly Phe Leu Val 500 505 510 Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr Ser Cys Glu Thr Ile Leu 515 520 525 Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile Gln Asp Asn Ile Ser Phe 530 535 540 Tyr Ala Thr Ile Gly Val Cys Leu Leu Phe Ile Val Val Leu Thr Leu 545 550 555 560 Leu Ile Cys His Lys Tyr Lys Lys Gln Phe Arg Tyr Glu Ser Gln Leu 565 570 575 Gln Met Val Gln Val Thr Gly Ser Ser Asp Asn Glu Tyr Phe Tyr Val 580 585 590 Asp Phe Arg Glu Tyr Glu Tyr Asp Leu Lys Trp Glu Phe Pro Arg Glu 595 600 605 Asn Leu Glu Phe Gly Lys Val Leu Gly Ser Gly Ala Phe Gly Lys Val 610 615 620 Met Asn Ala Thr Ala Tyr Gly Ile Ser Lys Thr Gly Val Ser Ile Gln 625 630 635 640 Val Ala Val Lys Met Leu Lys Glu Lys Ala Asp Ser Ser Glu Arg Glu 645 650 655 Ala Leu Met Ser Glu Leu Lys Met Met Thr Gln Leu Gly Ser His Glu 660 665 670 Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Leu Ser Gly Pro Ile Tyr 675 680 685 Leu Ile Phe Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Tyr Leu Arg 690 695 700 Ser Lys Arg Glu Lys Phe His Arg Thr Trp Thr Glu Ile Phe Lys Glu 705 710 715 720 His Asn Phe Ser Phe Tyr Pro Thr Phe Gln Ser His Pro Asn Ser Ser 725 730 735 Met Pro Gly Ser Arg Glu Val Gln Ile His Pro Asp Ser Asp Gln Ile 740 745 750 Ser Gly Leu His Gly Asn Ser Phe His Ser Glu Asp Glu Ile Glu Tyr 755 760 765 Glu Asn Gln Lys Arg Leu Glu Glu Glu Glu Asp Leu Asn Val Leu Thr 770 775 780 Phe Glu Asp Leu Leu Cys Phe Ala Tyr Gln Val Ala Lys Gly Met Glu 785 790 795 800 Phe Leu Glu Phe Lys Ser Cys Val His Arg Asp Leu Ala Ala Arg Asn 805 810 815 Val Leu Val Thr His Gly Lys Val Val Lys Ile Cys Asp Phe Gly Leu 820 825 830 Ala Arg Asp Ile Met Ser Asp Ser Asn Tyr Val Val Arg Gly Asn Ala 835 840 845 Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Leu Phe Glu Gly Ile 850 855 860 Tyr Thr Ile Lys Ser Asp Val Trp Ser Tyr Gly Ile Leu Leu Trp Glu 865 870 875 880 Ile Phe Ser Leu Gly Val Asn Pro Tyr Pro Gly Ile Pro Val Asp Ala 885 890 895 Asn Phe Tyr Lys Leu Ile Gln Asn Gly Phe Lys Met Asp Gln Pro Phe 900 905 910 Tyr Ala Thr Glu Glu Ile Tyr Ile Ile Met Gln Ser Cys Trp Ala Phe 915 920 925 Asp Ser Arg Lys Arg Pro Ser Phe Pro Asn Leu Thr Ser Phe Leu Gly 930 935 940 Cys Gln Leu Ala Asp Ala Glu Glu Ala Met Tyr Gln Asn Val Asp Gly 945 950 955 960 Arg Val Ser Glu Cys Pro His Thr Tyr Gln Asn Arg Arg Pro Phe Ser 965 970 975 Arg Glu Met Asp Leu Gly Leu Leu Ser Pro Gln Ala Gln Val Glu Asp 980 985 990 Ser 49364PRTmurine 49Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala 1 5 10 15 Met Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln 20 25 30 Glu Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro 35 40 45 Tyr Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly 50 55 60 Ala Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln 65 70 75 80 Glu Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro 85 90 95 Ser Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp 100 105 110 Asn Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser 115 120 125 Tyr Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg 130 135 140 Pro Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn 145 150 155 160 Leu Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile 165 170 175 Phe Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr 180 185 190 His Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr 195 200 205 Asn Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu 210 215 220 Arg Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr 225 230 235 240 Gly Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly 245 250 255 Val Val His Gly Ala Ile Gly Gly Ala Gly Val Thr Ala Leu Leu Ala 260 265 270 Leu Cys Leu Cys Leu Ile Phe Phe Ile Val Lys Thr His Arg Arg Lys 275 280 285 Ala Ala Arg Thr Ala Val Gly Arg Asn Asp Thr His Pro Thr Thr Gly 290 295 300 Ser Ala Ser Pro Lys His Gln Lys Lys Ser Lys Leu His Gly Pro Thr 305 310 315 320 Glu Thr Ser Ser Cys Ser Gly Ala Ala Pro Thr Val Glu Met Asp Glu 325 330 335 Glu Leu His Tyr Ala Ser Leu Asn Phe His Gly Met Asn Pro Ser Lys 340 345 350 Asp Thr Ser Thr Glu Tyr Ser Glu Val Arg Thr Gln 355 360 50193PRTmurine 50Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly 1 5 10 15 Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile 20 25 30 Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu 35 40 45 Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His 50 55 60 Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala 65 70 75 80 Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu 85 90 95 Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu 100 105 110 Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu 115 120 125 Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg 130 135 140 Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro 145 150 155 160 Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu 165 170 175 Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg 180 185 190 Pro 51943PRTmurine 51Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Gly Asn Tyr 20 25 30 Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser 35 40 45 Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly 50 55 60 Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp 65 70 75 80 Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr 85 90 95 Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp 100 105 110 Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu 115 120 125 Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro 130 135 140 Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg 145 150 155 160 Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu 165 170 175 Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly 180 185 190 Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile 195 200 205 Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile 210 215 220 Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His 225 230 235 240 Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys 245 250 255 Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys 260 265 270 Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys 275 280 285 Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys 290 295 300 Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp 305 310 315 320 Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn 325 330 335 Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu 340 345 350 Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly 355 360 365 Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val 370 375 380 Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe 385 390 395 400 Met Arg Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu 405 410 415 Gln Glu Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro 420 425 430 Asn Gln Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile 435 440 445 Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp 450 455 460 Ile Pro Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu 465 470 475 480 Arg Glu Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala 485 490 495 Tyr Val Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly 500 505 510 Ile Cys Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe 515 520 525 Gly Cys Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser 530 535 540 Gln Tyr Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr 545 550 555 560 Leu Glu Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val 565 570 575 Leu Val Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala 580 585 590 Lys Leu Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys 595 600 605 Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr 610 615 620 Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu 625 630 635 640 Met Thr Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile 645 650 655 Ser Ser Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys 660 665 670 Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala 675 680 685 Asp Ser Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met 690 695 700 Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met 705 710 715 720 His Leu Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp 725 730 735 Glu Glu Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro 740 745 750 Gln Gln Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu 755 760 765 Ser Ser Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp 770 775 780 Arg Asn Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln 785 790 795 800 Arg Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 805 810 815 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro Lys 820 825 830 Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln Pro Leu 835 840 845 Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro His Ser Thr 850 855 860 Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln Pro Thr Cys Val 865 870 875 880 Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala Gln Lys Gly Ser His 885 890 895 Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln Gln Asp Phe Phe Pro Lys 900 905 910 Glu Ala Lys Pro Asn Gly Ile Phe Lys Gly Ser Thr Ala Glu Asn Ala 915 920 925 Glu Tyr Leu Arg Val Ala Pro Gln Ser Ser Glu Phe Ile Gly Ala 930 935 940 52497PRTmurine 52Met Gln Asp Pro Ala Ser Thr Cys Val Pro Glu Pro Ala Ser Gln His 1 5 10 15 Thr Leu Arg Ser Gly Pro Gly Cys Leu Gln Gln Pro Glu Gln Gln Gly 20 25 30 Val Arg Asp Pro Gly Gly Ile Trp Ala Lys Leu Gly Ala Ala Glu Ala 35 40 45 Ser Ala Glu Arg Leu Gln Gly Arg Arg Ser Arg Gly Ala Ser Gly Ser 50 55 60 Glu Pro Gln Gln Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu 65 70 75 80 Pro Ala Val Pro Ser Leu Gly Gly Gly

Gly Gly Cys Ala Leu Pro Val 85 90 95 Ser Gly Ala Ala Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly 100 105 110 Ala Ser Ala Tyr Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro 115 120 125 Pro Pro Pro Pro Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro 130 135 140 Ser Trp Gly Gly Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe 145 150 155 160 Thr Val His Phe Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg 165 170 175 Tyr Gly Pro Phe Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln 180 185 190 Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser 195 200 205 Gln Pro Ala Ile Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly 210 215 220 Thr Pro Ser Tyr Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro 225 230 235 240 Asn His Ser Phe Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu 245 250 255 Gly Glu Gln Gln Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr 260 265 270 Pro Thr Asp Ser Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro 275 280 285 Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met 290 295 300 Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly His Ser Thr 305 310 315 320 Gly Tyr Glu Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln 325 330 335 Tyr Arg Ile His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg 340 345 350 Arg Val Pro Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr 355 360 365 Ser Glu Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg 370 375 380 Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly 385 390 395 400 Glu Lys Pro Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser 405 410 415 Arg Ser Asp Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys 420 425 430 Pro Phe Gln Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His 435 440 445 Leu Lys Thr His Thr Arg Thr His Thr Gly Glu Lys Pro Phe Ser Cys 450 455 460 Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val 465 470 475 480 Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala 485 490 495 Leu 53118PRTartificial sequenceCD19-1 VH chain 53Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 20 25 30 Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val 115 54107PRTartificial sequenceCD19-1 VL chain 54Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr 100 105 55119PRTartificial sequenceCD19-2 VH chain 55Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Leu Thr Val 115 56112PRTartificial sequenceCD19-2 VL chain 56Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 57115PRTmurine 57Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 58107PRTmurine 58Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly 1 5 10 15 Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Asp 20 25 30 Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile 35 40 45 Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser 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 Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 59118PRTmurine 59Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser 115 60111PRTmurine 60Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn 85 90 95 Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 61113PRTmurine 61Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His Lys Phe Met 1 5 10 15 Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln 20 25 30 Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 65 70 75 80 Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr 85 90 95 Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg 62127PRTmurine 62Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly 100 105 110 Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 125 63119PRTmurine 63Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser 1 5 10 15 Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser Ile Thr Ser Gly Tyr 20 25 30 Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser 85 90 95 Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr Thr Leu 100 105 110 Thr Val Ser Ser Ala Arg Ser 115 64113PRTmurine 64Asp Ile Met Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Glu Lys Phe Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly 20 25 30 Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala 65 70 75 80 Ile Ser Ser Val Met Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110 Lys 65115PRTmurine 65Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Ser Lys Ala Thr Leu Thr Val Asp Asn Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Val Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 100 105 110 Thr Val Ser 115 66111PRTmurine 66Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His 65 70 75 80 Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys 85 90 95 Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 67117PRTmurine 67Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Phe Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile Asn Trp Val Asn Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Leu Gln Leu Asn Asn Leu Thr Ser Glu Asn Ser Ala Val Tyr Phe Cys 85 90 95 Ala Ser Gly Tyr Glu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115 68108PRTmurine 68Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Ile Ile Asn Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr 65 70 75 80 Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 69120PRTmurine 69Glu Val Lys Leu Gln Glu

Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Asp Tyr 20 25 30 Val Val His Trp Leu Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Val Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Arg Tyr Glu Val Tyr Gly Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 70115PRTmurine 70Asp Ile Val Leu Thr Gln Ser Pro Thr Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Asn Tyr Ile 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Asp Ser Pro Leu Arg Trp Ile Phe 35 40 45 Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Thr Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Arg Ser Tyr Pro Leu Thr 85 90 95 Phe Gly Asp Gly Thr Arg Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro 100 105 110 Thr Val Ser 115 71118PRTmurine 71Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Ile Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Tyr Pro Gly Asn Asp Asp Ile Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Arg Leu Arg Tyr Phe Asp Val Trp Gly Ala Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 72113PRTmurine 72Asn Ile Met Leu Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Phe Ser 20 25 30 Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ser Glu Asp Leu Ala Ile Tyr Tyr Cys His Gln 85 90 95 Tyr Leu Ser Ser Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg 73115PRTmurine 73Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Ser Lys Ala Thr Leu Thr Val Asp Asn Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Val Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 100 105 110 Thr Val Ser 115 74111PRTmurine 74Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His 65 70 75 80 Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys 85 90 95 Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 75117PRTmurine 75Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Phe Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Asp Ile Asn Trp Val Asn Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Leu Gln Leu Asn Asn Leu Thr Ser Glu Asn Ser Ala Val Tyr Phe Cys 85 90 95 Ala Ser Gly Tyr Glu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115 76108PRTmurine 76Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Ile Ile Asn Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr 65 70 75 80 Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 77120PRTmurine 77Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asn Pro Asn Asn Gly Val Thr Leu Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Met Ile Thr Asn Tyr Val Met Asp Tyr Trp Gly Gln 100 105 110 Val Thr Ser Val Thr Val Ser Ser 115 120 78108PRTmurine 78Ser Ile Val Met Thr Gln Thr Pro Thr Phe Leu Leu Val Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Thr Leu Leu Ile 35 40 45 Ser Tyr Thr Ser Ser Arg Tyr Ala Gly Val Pro Asp Arg Phe Ile Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Leu Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Asn Ser Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 79119PRTmurine 79Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe 20 25 30 Gly Met Asn Trp Val Lys Gln Gly Pro Gly Glu Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Arg Tyr Ala Glu Glu Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Thr Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Asp Trp Asp Gly Ala Tyr Phe Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser 115 80107PRTmurine 80Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Asn Phe Ala Thr Asn Arg Tyr Thr Gly Val Pro Asn Arg Phe Thr Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Leu Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 81117PRTmurine 81Gln Val Gln Leu Gln Gln Ser Arg Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Gly Ser Asn Ser Ile Tyr Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Met Gly Gly Asn Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 82108PRTmurine 82Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Thr Leu Thr Cys Thr Ala Ser Ser Ser Val Asn Ser Asn 20 25 30 Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu 65 70 75 80 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Tyr His Arg Ser Pro 85 90 95 Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 83122PRTmurine 83Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Gln Trp Asp Tyr Asp Val Arg Ala Met Asn Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 84107PRTmurine 84Asp Ile Val Met Thr Gln Ser His Ile Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asp Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg Leu Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 85118PRTmurine 85Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asp Tyr 20 25 30 Glu Met His Trp Val Ile Gln Thr Pro Val His Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Ile Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Gly Tyr Tyr Asp Tyr Asp Ser Phe Thr Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 86107PRTmurine 86Asp Ile Val Met Thr Gln Ser Gln Lys Ile Met Ser Thr Thr Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ala Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asp Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 87119PRTmurine 87Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Arg Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Arg Asn Ile Leu Tyr Leu 65 70 75 80 Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Gly 85 90 95 Arg Tyr Asp Tyr Asp Gly Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 88107PRTmurine 88Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Pro Asp Ile Asn Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Gly Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Tyr 65 70 75 80 Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Tyr 85

90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys 100 105 89117PRTmurine 89Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ala Gly Gly Phe Thr Asn Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Leu Leu 65 70 75 80 Lys Met Thr Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Arg Gly Ser Ser Tyr Ser Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115 90106PRTmurine 90Glu Ile Val Leu Ser Gln Ser Pro Ala Ile Thr Ala Ala Ser Leu Gly 1 5 10 15 Gln Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Asn Val Ser Tyr Ile 20 25 30 His Trp Tyr Gln Gln Arg Ser Gly Thr Ser Pro Arg Pro Trp Ile Tyr 35 40 45 Glu Ile Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Ile Tyr Tyr Cys Gln Gln Trp Asn Tyr Pro Leu Ile Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Gln 100 105 91116PRTmurine 91Glu Val Gln Val Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Gly Ser Ser Gly Trp Ser Glu Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 92107PRTmurine 92Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile Val Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His His Ser Tyr Pro Leu 85 90 95 Thr Ser Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 93118PRTmurine 93Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Leu Lys Leu Ser Cys Val Thr Ser Gly Phe Thr Phe Arg Lys Phe 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Ser Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Thr Gly Gly Tyr Asn Thr Tyr Tyr Ser Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Thr Arg Gly Tyr Ser Ser Thr Ser Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val 115 94108PRTmurine 94Asp Ile Glu Leu Thr Gln Ser Pro Ala Ser Leu Ser Val Ala Thr Gly 1 5 10 15 Glu Lys Val Thr Ile Arg Cys Met Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Pro Pro Lys Phe Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Ser 50 55 60 Ser Gly Thr Gly Thr Asp Phe Val Phe Thr Ile Glu Asn Thr Leu Ser 65 70 75 80 Glu Asp Val Gly Asp Tyr Tyr Cys Leu Gln Ser Phe Asn Val Pro Leu 85 90 95 Thr Phe Gly Asp Gly Thr Lys Leu Glu Lys Ala Leu 100 105 95119PRTmurine 95Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 96112PRTmurine 96Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Ser Gln Ser 85 90 95 Ser Ile Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 97119PRTmurine 97Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 98112PRTmurine 98Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Glu Thr 85 90 95 Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 99117PRTmurine 99Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe 50 55 60 Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115 100111PRTmurine 100Asp Ile Val Leu Thr Gly Ser Pro Pro Ser Leu Ala Met Ser Leu Gly 1 5 10 15 Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu 20 25 30 Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp 65 70 75 80 Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg 85 90 95 Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 101117PRTmurine 101Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr 20 25 30 Ser Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Arg Ile Asn Thr Glu Thr Gly Glu Pro Leu Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Val Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Phe Phe Cys 85 90 95 Ser Asn Asp Tyr Leu Tyr Ser Cys Asp Tyr Trp Gly Arg Gly Thr Thr 100 105 110 Leu Thr Val Ser Ser 115 102111PRTmurine 102Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly 1 5 10 15 Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu 20 25 30 Gly Ser His Leu Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp 65 70 75 80 Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg 85 90 95 Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 103119PRTmurine 103Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Thr Pro Ser Leu 50 55 60 Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Ala Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 104107PRTmurine 104Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 105120PRTmurine 105Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Met Ile Ala Thr Arg Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 106107PRTmurine 106Asp Ile Val Met Thr Gln Ser Gln Lys Ser Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ile Thr Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Asn Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 107121PRTmurine 107Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Lys Val Tyr Tyr Gly Ser Asn Pro Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 108107PRTmurine 108Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser

Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 109120PRTmurine 109Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Ser Thr Met Ile Ala Thr Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 110107PRTmurine 110Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser Met Ala Ile Gly 1 5 10 15 Glu Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Ser 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Val Phe Thr Ile Glu Asn Met Leu Ser 65 70 75 80 Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 111120PRTmurine 111Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Ser Thr Met Ile Ala Thr Gly Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 112108PRTmurine 112Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser 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 Thr Pro Pro 85 90 95 Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 113141PRTmurine 113Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Val Ser Gly Thr Gly Gly 1 5 10 15 Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Asp Tyr Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu 50 55 60 Glu Trp Ile Gly Asp Ile Ile Pro Ser Asn Gly Ala Thr Phe Tyr Asn 65 70 75 80 Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Ser 85 90 95 Thr Ala Tyr Met His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Thr Arg Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr 115 120 125 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser 130 135 140 114134PRTmurine 114Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser 1 5 10 15 Gly Thr Cys Gly Asp Phe Val Met Thr Gln Ser Pro Ser Ser Leu Thr 20 25 30 Val Thr Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Leu Gln 50 55 60 Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg 65 70 75 80 Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr 100 105 110 Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr 115 120 125 Lys Leu Glu Ile Lys Arg 130 115140PRTmurine 115Trp Thr Trp Arg Phe Leu Phe Val Val Ala Ala Ala Thr Gly Val Gln 1 5 10 15 Ser Gln Val Gln Leu Leu Gln Ser Gly Ala Glu Val Lys Lys Pro Gly 20 25 30 Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr 35 40 45 Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp 50 55 60 Met Gly Gly Ile Ile Pro Ile Phe Gly Ile Val Asn Tyr Ala Gln Lys 65 70 75 80 Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala 85 90 95 Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 100 105 110 Cys Ala Arg Gly Gly Gly Ser Gly Pro Asp Val Leu Asp Ile Trp Gly 115 120 125 Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr 130 135 140 116132PRTmurine 116Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Pro Gly Ala Arg Cys Val Ile Trp Met Thr Gln Ser Pro Ser Leu 20 25 30 Leu Ser Ala Ser Thr Gly Asp Arg Val Thr Ile Ser Cys Arg Met Ser 35 40 45 Gln Gly Ile Arg Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Glu Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Tyr Tyr Ser Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val 130 117115PRTmurine 117Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 118107PRTmurine 118Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly 1 5 10 15 Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Asp 20 25 30 Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile 35 40 45 Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser 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 Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 119118PRTmurine 119Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser 115 120111PRTmurine 120Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn 85 90 95 Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 121127PRTmurine 121Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly 100 105 110 Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 125 122113PRTmurine 122Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His Lys Phe Met 1 5 10 15 Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln 20 25 30 Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 65 70 75 80 Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr 85 90 95 Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg 123119PRTmurine 123Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser 1 5 10 15 Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser Ile Thr Ser Gly Tyr 20 25 30 Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser 85 90 95 Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr Thr Leu 100 105 110 Thr Val Ser Ser Ala Arg Ser 115 124113PRTmurine 124Asp Ile Met Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Glu Lys Phe Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly 20 25 30 Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala 65 70 75 80 Ile Ser Ser Val Met Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110 Lys 125464PRTartificial sequenceanti-BCMA-CAR 125Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 130 135 140 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser 145 150 155 160 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 165 170 175 Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg 180 185 190 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 195 200 205 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser 210 215 220 Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ala Pro 225 230 235 240 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 245 250 255 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 260 265 270 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile 275 280 285 Trp Ala Pro Leu Ala Gly Thr

Cys Gly Val Leu Leu Leu Ser Leu Val 290 295 300 Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe 305 310 315 320 Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly 325 330 335 Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg 340 345 350 Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln 355 360 365 Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp 370 375 380 Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro 385 390 395 400 Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp 405 410 415 Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg 420 425 430 Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr 435 440 445 Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 450 455 460 126498PRTartificial sequenceanti-BCMA-CAR 126Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 130 135 140 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser 145 150 155 160 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 165 170 175 Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg 180 185 190 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 195 200 205 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser 210 215 220 Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp 225 230 235 240 Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu 245 250 255 Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys 260 265 270 Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 275 280 285 Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 290 295 300 Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 305 310 315 320 Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 325 330 335 Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr 340 345 350 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 355 360 365 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 370 375 380 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 385 390 395 400 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 405 410 415 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 420 425 430 Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 435 440 445 Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu 450 455 460 Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 465 470 475 480 Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 485 490 495 Arg Glu 127513PRTartificial sequenceanti-BCMA-CAR 127Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 130 135 140 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser 145 150 155 160 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 165 170 175 Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg 180 185 190 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 195 200 205 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser 210 215 220 Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp 225 230 235 240 Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu 245 250 255 Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys 260 265 270 Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala 275 280 285 Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile 290 295 300 Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala 305 310 315 320 Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr 325 330 335 Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu 340 345 350 Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile 355 360 365 Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp 370 375 380 Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 385 390 395 400 Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 405 410 415 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 420 425 430 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 435 440 445 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 450 455 460 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 465 470 475 480 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 485 490 495 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 500 505 510 Glu 128522PRTartificial sequenceanti-BCMA-CAR 128Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 130 135 140 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser 145 150 155 160 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 165 170 175 Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg 180 185 190 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 195 200 205 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser 210 215 220 Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp 225 230 235 240 Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu 245 250 255 Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser 260 265 270 Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys 275 280 285 Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro 290 295 300 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 305 310 315 320 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 325 330 335 Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly 340 345 350 Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg 355 360 365 Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 370 375 380 Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 385 390 395 400 Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser 405 410 415 Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 420 425 430 Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 435 440 445 Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln 450 455 460 Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 465 470 475 480 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 485 490 495 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 500 505 510 Leu His Met Gln Ala Leu Pro Pro Arg Glu 515 520 129500PRTartificial sequenceanti-BCMA-CAR 129Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly 20 25 30 Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln 35 40 45 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 50 55 60 Ser Ser Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 65 70 75 80 Glu Trp Val Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala 85 90 95 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 100 105 110 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 115 120 125 Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr 130 135 140 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 145 150 155 160 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 165 170 175 Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln 180 185 190 Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 195 200 205 Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile 210 215 220 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 225 230 235 240 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 245 250 255 Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 260 265 270 Lys Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 275 280 285 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 290 295 300 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 305 310 315 320 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 325 330 335 Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu 340 345 350 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 355 360 365 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 370 375 380 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 385 390 395 400 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 405 410 415 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 420 425 430 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 435 440 445 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 450 455 460 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 465 470 475 480 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 485 490 495 Pro Pro Arg Glu 500 130466PRTartificial sequenceanti-BCMA-CAR 130Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70

75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser 115 120 125 Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 130 135 140 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val 145 150 155 160 Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln 210 215 220 Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser 225 230 235 240 Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 245 250 255 Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 260 265 270 Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 275 280 285 Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 290 295 300 Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr 305 310 315 320 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 325 330 335 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 340 345 350 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 355 360 365 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 370 375 380 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 385 390 395 400 Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 405 410 415 Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu 420 425 430 Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 435 440 445 Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 450 455 460 Arg Glu 465 131472PRTartificial sequenceanti-BCMA-CAR 131Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser 115 120 125 Leu Cys Ser Gly Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser 130 135 140 Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys 145 150 155 160 Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg 180 185 190 Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr 210 215 220 Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr 225 230 235 240 Lys Val Glu Ile Lys Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro 245 250 255 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 260 265 270 Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 275 280 285 Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys 290 295 300 Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly 305 310 315 320 Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val 325 330 335 Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu 340 345 350 Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp 355 360 365 Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn 370 375 380 Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg 385 390 395 400 Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly 405 410 415 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 420 425 430 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 435 440 445 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 450 455 460 Met Gln Ala Leu Pro Pro Arg Glu 465 470 132491PRTartificial sequenceanti-BCMA-CAR 132Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser 20 25 30 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 35 40 45 Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln 50 55 60 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly 65 70 75 80 Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 85 90 95 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 100 105 110 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp 115 120 125 Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Cys 130 135 140 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu 145 150 155 160 Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr 165 170 175 Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp 180 185 190 Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala 195 200 205 Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser 210 215 220 Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe 225 230 235 240 Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly 245 250 255 Gln Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Thr Thr Thr Pro Ala 260 265 270 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 275 280 285 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 290 295 300 Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 305 310 315 320 Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 325 330 335 Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 340 345 350 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 355 360 365 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 370 375 380 Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn 385 390 395 400 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 405 410 415 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro 420 425 430 Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala 435 440 445 Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His 450 455 460 Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp 465 470 475 480 Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 485 490 133497PRTartificial sequenceanti-BCMA-CAR 133Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser 20 25 30 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 35 40 45 Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln 50 55 60 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly 65 70 75 80 Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 85 90 95 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 100 105 110 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp 115 120 125 Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly 145 150 155 160 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 165 170 175 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser 180 185 190 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 195 200 205 Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg 210 215 220 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 225 230 235 240 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser 245 250 255 Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp 260 265 270 Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile 275 280 285 Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala 290 295 300 Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr 305 310 315 320 Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu 325 330 335 Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile 340 345 350 Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp 355 360 365 Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 370 375 380 Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 385 390 395 400 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 405 410 415 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 420 425 430 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 435 440 445 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 450 455 460 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 465 470 475 480 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 495 Glu 134490PRTartificial sequenceanti-BCMA-CAR 134Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser 115 120 125 Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 130 135 140 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val 145 150 155 160 Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln 210 215 220 Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser 225 230 235 240 Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser 245 250 255 Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro 260 265 270 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 275 280 285 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 290 295 300 Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly 305 310 315 320 Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg 325 330 335 Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 340 345 350 Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 355 360 365 Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser 370 375 380 Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 385 390 395 400 Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 405 410 415 Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln 420 425 430 Glu Gly Leu Tyr Asn Glu Leu

Gln Lys Asp Lys Met Ala Glu Ala Tyr 435 440 445 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 450 455 460 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 465 470 475 480 Leu His Met Gln Ala Leu Pro Pro Arg Glu 485 490 135496PRTartificial sequenceanti-BCMA-CAR 135Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser 115 120 125 Leu Cys Ser Gly Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser 130 135 140 Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys 145 150 155 160 Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg 180 185 190 Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr 210 215 220 Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr 225 230 235 240 Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys 245 250 255 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro 260 265 270 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 275 280 285 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 290 295 300 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile 305 310 315 320 Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val 325 330 335 Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe 340 345 350 Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly 355 360 365 Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg 370 375 380 Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln 385 390 395 400 Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp 405 410 415 Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro 420 425 430 Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp 435 440 445 Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg 450 455 460 Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr 465 470 475 480 Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 485 490 495 136514PRTartificial sequenceanti-BCMA-CAR 136Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser 20 25 30 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 35 40 45 Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln 50 55 60 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly 65 70 75 80 Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 85 90 95 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 100 105 110 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp 115 120 125 Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr 145 150 155 160 Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu 165 170 175 Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr 180 185 190 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser 195 200 205 Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 210 215 220 Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala 225 230 235 240 Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln 245 250 255 Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly 260 265 270 Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser 275 280 285 Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 290 295 300 Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 305 310 315 320 Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 325 330 335 Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 340 345 350 Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr 355 360 365 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 370 375 380 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 385 390 395 400 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 405 410 415 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 420 425 430 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 435 440 445 Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln 450 455 460 Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu 465 470 475 480 Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr 485 490 495 Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro 500 505 510 Arg Glu 137515PRTartificial sequenceanti-BCMA-CAR 137Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser 20 25 30 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 35 40 45 Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln 50 55 60 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly 65 70 75 80 Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 85 90 95 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 100 105 110 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp 115 120 125 Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Cys 130 135 140 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu 145 150 155 160 Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr 165 170 175 Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp 180 185 190 Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala 195 200 205 Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser 210 215 220 Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe 225 230 235 240 Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly 245 250 255 Gln Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly 260 265 270 Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly 275 280 285 Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro 290 295 300 Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro 305 310 315 320 Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp 325 330 335 Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu 340 345 350 Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu 355 360 365 Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu 370 375 380 Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys 385 390 395 400 Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 405 410 415 Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu 420 425 430 Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly 435 440 445 Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 450 455 460 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 465 470 475 480 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 485 490 495 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 500 505 510 Pro Arg Glu 515 138521PRTartificial sequenceanti-BCMA-CAR 138Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser 20 25 30 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 35 40 45 Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln 50 55 60 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly 65 70 75 80 Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 85 90 95 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 100 105 110 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp 115 120 125 Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly 145 150 155 160 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 165 170 175 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser 180 185 190 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 195 200 205 Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg 210 215 220 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 225 230 235 240 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser 245 250 255 Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp 260 265 270 Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu 275 280 285 Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg 290 295 300 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 305 310 315 320 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 325 330 335 Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr 340 345 350 Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg 355 360 365 Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro 370 375 380 Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu 385 390 395 400 Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala 405 410 415 Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu 420 425 430 Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly 435 440 445 Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu 450 455 460 Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser 465 470 475 480 Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly 485 490 495 Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu 500 505 510 His Met Gln Ala Leu Pro Pro Arg Glu 515 520 139504PRTartificial sequenceanti-BCMA-CAR 139Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 130 135 140 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser 145 150 155 160 Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 165 170 175 Leu Leu Met

Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg 180 185 190 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 195 200 205 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser 210 215 220 Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp 225 230 235 240 Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu 245 250 255 Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys 260 265 270 Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro 275 280 285 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 290 295 300 Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 305 310 315 320 Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys 325 330 335 Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly 340 345 350 Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val 355 360 365 Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu 370 375 380 Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp 385 390 395 400 Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn 405 410 415 Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg 420 425 430 Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly 435 440 445 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 450 455 460 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 465 470 475 480 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 485 490 495 Met Gln Ala Leu Pro Pro Arg Glu 500 140547PRTartificial sequenceanti-BCMA-CAR 140Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser 20 25 30 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 35 40 45 Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln 50 55 60 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly 65 70 75 80 Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 85 90 95 Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 100 105 110 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp 115 120 125 Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr 145 150 155 160 Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu 165 170 175 Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr 180 185 190 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser 195 200 205 Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 210 215 220 Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala 225 230 235 240 Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln 245 250 255 Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly 260 265 270 Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser 275 280 285 Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser 290 295 300 Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu 305 310 315 320 Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro 325 330 335 Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro 340 345 350 Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp 355 360 365 Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu 370 375 380 Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu 385 390 395 400 Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu 405 410 415 Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys 420 425 430 Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 435 440 445 Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu 450 455 460 Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly 465 470 475 480 Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 485 490 495 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 500 505 510 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 515 520 525 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 530 535 540 Pro Arg Glu 545 141523PRTartificial sequenceanti-BCMA-CAR 141Glu 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 Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser 115 120 125 Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu 130 135 140 Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val 145 150 155 160 Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 165 170 175 Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln 210 215 220 Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser 225 230 235 240 Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser 245 250 255 Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe 260 265 270 Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala 275 280 285 Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala 290 295 300 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 305 310 315 320 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 325 330 335 Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 340 345 350 Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 355 360 365 Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 370 375 380 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 385 390 395 400 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 405 410 415 Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn 420 425 430 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 435 440 445 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro 450 455 460 Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala 465 470 475 480 Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His 485 490 495 Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp 500 505 510 Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 515 520 142467PRTartificial sequenceanti-CD123-CAR 142Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu 130 135 140 Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu 145 150 155 160 Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu 180 185 190 Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe 195 200 205 Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys 225 230 235 240 Leu Glu Leu Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 245 250 255 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 260 265 270 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 275 280 285 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 290 295 300 Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu 305 310 315 320 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 325 330 335 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 340 345 350 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 355 360 365 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 370 375 380 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 385 390 395 400 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 405 410 415 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 420 425 430 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 435 440 445 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 450 455 460 Pro Pro Arg 465 143518PRTartificial sequenceCD123 protein 143Met Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met Lys 1 5 10 15 Ala Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr Asp 20 25 30 Ile Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn Asn 35 40 45 Ser Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn Tyr 50 55 60 Thr Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe Pro 65 70 75 80 Glu Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys Trp 85 90 95 Ile His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro Gly 100 105 110 Ala Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn Arg 115 120 125 Arg Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly Thr 130 135 140 Arg Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly Ser 145 150 155 160 Gln Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly Ile 165 170 175 Pro Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu Thr 180 185 190 Pro Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met His 195 200 205 Trp Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu Gln 210 215 220 Ile Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp Arg 225 230 235 240 Thr Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile Arg 245 250 255 Ala Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro Gln 260 265 270 Arg Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp Arg 275 280 285 Gly Gly Gly Gly Ala Gly Gly Gly Gly Cys Lys Pro Cys Ile Cys Thr 290 295 300 Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp 305 310 315 320 Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp 325 330 335 Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp 340 345 350 Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn 355 360 365 Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp 370 375 380 Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro 385 390 395 400 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala 405 410 415 Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys

Asp 420 425 430 Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile 435 440 445 Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn 450 455 460 Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys 465 470 475 480 Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys 485 490 495 Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu 500 505 510 Ser His Ser Pro Gly Lys 515 14416PRTartificial sequencemAb-specific epitope 144Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser 1 5 10 15 145469PRTartificial sequenceanti-BCMA-CAR 145Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser 130 135 140 Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser 145 150 155 160 Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu 165 170 175 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn 180 185 190 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala 195 200 205 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val 210 215 220 Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr 245 250 255 Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala 260 265 270 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe 275 280 285 Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val 290 295 300 Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys 305 310 315 320 Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr 325 330 335 Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu 340 345 350 Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro 355 360 365 Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly 370 375 380 Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro 385 390 395 400 Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr 405 410 415 Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 420 425 430 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln 435 440 445 Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln 450 455 460 Ala Leu Pro Pro Arg 465 146485PRTartificial sequenceBC30-LM 146Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser 130 135 140 Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser 145 150 155 160 Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu 165 170 175 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn 180 185 190 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala 195 200 205 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val 210 215 220 Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr 245 250 255 Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr 260 265 270 Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala 275 280 285 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe 290 295 300 Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val 305 310 315 320 Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys 325 330 335 Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr 340 345 350 Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu 355 360 365 Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro 370 375 380 Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly 385 390 395 400 Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro 405 410 415 Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr 420 425 430 Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 435 440 445 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln 450 455 460 Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln 465 470 475 480 Ala Leu Pro Pro Arg 485 147491PRTartificial sequenceBC30-LML 147Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser 130 135 140 Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser 145 150 155 160 Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu 165 170 175 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn 180 185 190 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala 195 200 205 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val 210 215 220 Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr 245 250 255 Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr Thr Thr Pro 260 265 270 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 275 280 285 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 290 295 300 Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu 305 310 315 320 Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr 325 330 335 Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe 340 345 350 Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg 355 360 365 Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser 370 375 380 Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr 385 390 395 400 Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys 405 410 415 Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn 420 425 430 Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 435 440 445 Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly 450 455 460 His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr 465 470 475 480 Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 148500PRTartificial sequenceBC30-LMLM 148Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser 130 135 140 Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser 145 150 155 160 Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu 165 170 175 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn 180 185 190 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala 195 200 205 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val 210 215 220 Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr 245 250 255 Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser 260 265 270 Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro 275 280 285 Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys 290 295 300 Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala 305 310 315 320 Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu 325 330 335 Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys 340 345 350 Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr 355 360 365 Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly 370 375 380 Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 385 390 395 400 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 405 410 415 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 420 425 430 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 435 440 445 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 450 455 460 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 465 470 475 480 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 485 490 495 Leu Pro Pro Arg 500 149506PRTartificial sequenceBC30-LMLML 149Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr 20 25 30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser 130 135 140 Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser 145 150 155 160 Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu 165 170 175 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn 180 185 190 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala 195 200 205 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val

Gly Val 210 215 220 Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr 245 250 255 Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser 260 265 270 Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr Thr Thr Pro Ala 275 280 285 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 290 295 300 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 305 310 315 320 Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 325 330 335 Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 340 345 350 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 355 360 365 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 370 375 380 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 385 390 395 400 Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn 405 410 415 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 420 425 430 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro 435 440 445 Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala 450 455 460 Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His 465 470 475 480 Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp 485 490 495 Ala Leu His Met Gln Ala Leu Pro Pro Arg 500 505 150136PRTartificial sequenceBC30-RQR8 150Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu 1 5 10 15 Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro 20 25 30 Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys 35 40 45 Ser Gly Gly Gly Gly Ser Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro 50 55 60 Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro 65 70 75 80 Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp 85 90 95 Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu 100 105 110 Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn Arg Arg Arg Val 115 120 125 Cys Lys Cys Pro Arg Pro Val Val 130 135 151284PRTartificial sequenceBCMA protein 151Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser 1 5 10 15 Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr 20 25 30 Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser 35 40 45 Val Lys Gly Thr Asn Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Cys 50 55 60 Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe 65 70 75 80 Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val 85 90 95 Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe 100 105 110 Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro 115 120 125 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro 130 135 140 Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val 145 150 155 160 Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 165 170 175 Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys 180 185 190 Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp 195 200 205 Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro 210 215 220 Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser 225 230 235 240 Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala 245 250 255 Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His 260 265 270 His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 275 280 152490PRTartificial sequencepolypeptide 152Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu 130 135 140 Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu 145 150 155 160 Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu 180 185 190 Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe 195 200 205 Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys 225 230 235 240 Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys 245 250 255 Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro 260 265 270 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 275 280 285 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 290 295 300 Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly 305 310 315 320 Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg 325 330 335 Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 340 345 350 Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 355 360 365 Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser 370 375 380 Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 385 390 395 400 Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 405 410 415 Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln 420 425 430 Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 435 440 445 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 450 455 460 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 465 470 475 480 Leu His Met Gln Ala Leu Pro Pro Arg Glu 485 490 153496PRTartificial sequencepolypeptide 153Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu 130 135 140 Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu 145 150 155 160 Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu 180 185 190 Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe 195 200 205 Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys 225 230 235 240 Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys 245 250 255 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro 260 265 270 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 275 280 285 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 290 295 300 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile 305 310 315 320 Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val 325 330 335 Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe 340 345 350 Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly 355 360 365 Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg 370 375 380 Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln 385 390 395 400 Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp 405 410 415 Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro 420 425 430 Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp 435 440 445 Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg 450 455 460 Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr 465 470 475 480 Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 485 490 495 154505PRTartificial sequencepolypeptide 154Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu 130 135 140 Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu 145 150 155 160 Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu 180 185 190 Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe 195 200 205 Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys 225 230 235 240 Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys 245 250 255 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro 260 265 270 Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg 275 280 285 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 290 295 300 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 305 310 315 320 Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr 325 330 335 Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg 340 345 350 Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro 355 360 365 Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu 370 375 380 Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala 385 390 395 400 Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu 405 410 415 Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly 420 425 430 Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu 435 440 445 Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser 450 455 460 Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly 465 470 475 480 Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu 485 490 495 His Met Gln Ala Leu Pro Pro Arg Glu 500 505 155511PRTartificial sequencepolypeptide 155Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe

Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu 130 135 140 Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu 145 150 155 160 Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu 180 185 190 Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe 195 200 205 Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys 225 230 235 240 Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys 245 250 255 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro 260 265 270 Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr 275 280 285 Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser 290 295 300 Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly 305 310 315 320 Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp 325 330 335 Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile 340 345 350 Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys 355 360 365 Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys 370 375 380 Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val 385 390 395 400 Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn 405 410 415 Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val 420 425 430 Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg 435 440 445 Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 450 455 460 Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 465 470 475 480 Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 485 490 495 Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 500 505 510 156474PRTartificial sequencepolypeptide 156Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Cys Pro Tyr Ser Asn Pro Ser 115 120 125 Leu Cys Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala 130 135 140 Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala 145 150 155 160 Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn 180 185 190 Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr 195 200 205 Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly 225 230 235 240 Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro 245 250 255 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 260 265 270 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 275 280 285 Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly 290 295 300 Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg 305 310 315 320 Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 325 330 335 Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 340 345 350 Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser 355 360 365 Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 370 375 380 Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 385 390 395 400 Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln 405 410 415 Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 420 425 430 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 435 440 445 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 450 455 460 Leu His Met Gln Ala Leu Pro Pro Arg Glu 465 470 157480PRTartificial sequencepolypeptide 157Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Gly Gly Gly Cys Pro Tyr Ser 115 120 125 Asn Pro Ser Leu Cys Gly Gly Gly Gly Gly Gly Gly Ser Asp Ile Val 130 135 140 Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala 145 150 155 160 Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr 165 170 175 Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu 180 185 190 Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser 195 200 205 Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu 210 215 220 Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro 225 230 235 240 Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro 245 250 255 Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 260 265 270 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 275 280 285 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile 290 295 300 Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val 305 310 315 320 Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe 325 330 335 Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly 340 345 350 Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg 355 360 365 Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln 370 375 380 Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp 385 390 395 400 Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro 405 410 415 Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp 420 425 430 Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg 435 440 445 Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr 450 455 460 Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 465 470 475 480 158487PRTartificial sequencepolypeptide 158Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gln 1 5 10 15 Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr 20 25 30 Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly 35 40 45 Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly 50 55 60 Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys 65 70 75 80 Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu 85 90 95 His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala 100 105 110 Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser 115 120 125 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala 145 150 155 160 Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser 165 170 175 Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro 180 185 190 Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser 195 200 205 Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr 210 215 220 Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys 225 230 235 240 Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu 245 250 255 Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro 260 265 270 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 275 280 285 Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 290 295 300 Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly 305 310 315 320 Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg 325 330 335 Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln 340 345 350 Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu 355 360 365 Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 370 375 380 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 385 390 395 400 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 405 410 415 Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu 420 425 430 Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile 435 440 445 Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr 450 455 460 Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met 465 470 475 480 Gln Ala Leu Pro Pro Arg Glu 485 159493PRTartificial sequencepolypeptide 159Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu 20 25 30 Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr 35 40 45 Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys 50 55 60 Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr 65 70 75 80 Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr 100 105 110 Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln 145 150 155 160 Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser 165 170 175 Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg 195 200 205 Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly 210 215 220 Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp 225 230 235 240 Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe 245 250 255 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr 260 265 270 Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro 275 280 285 Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val 290 295 300 His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro 305 310 315 320 Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu 325 330 335 Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro 340 345 350 Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys 355 360 365 Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe 370 375 380 Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu 385 390 395 400 Tyr Asn Glu Leu

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp 405 410 415 Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys 420 425 430 Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala 435 440 445 Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys 450 455 460 Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr 465 470 475 480 Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 485 490 160502PRTartificial sequencepolypeptide 160Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gln Ile 20 25 30 Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val 35 40 45 Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met 50 55 60 Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp 65 70 75 80 Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly 85 90 95 Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His 100 105 110 Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 115 120 125 Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val 130 135 140 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 145 150 155 160 Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val 165 170 175 Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val 180 185 190 Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly 195 200 205 Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly 210 215 220 Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu 225 230 235 240 Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln 245 250 255 Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu 260 265 270 Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr 275 280 285 Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala 290 295 300 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe 305 310 315 320 Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val 325 330 335 Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys 340 345 350 Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr 355 360 365 Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu 370 375 380 Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro 385 390 395 400 Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly 405 410 415 Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro 420 425 430 Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr 435 440 445 Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 450 455 460 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln 465 470 475 480 Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln 485 490 495 Ala Leu Pro Pro Arg Glu 500 161508PRTartificial sequencepolypeptide 161Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly 20 25 30 Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys 35 40 45 Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile 50 55 60 Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser 65 70 75 80 Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr 85 90 95 Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala 100 105 110 Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala 115 120 125 Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp 130 135 140 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 145 150 155 160 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser 165 170 175 Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys 180 185 190 Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp 195 200 205 Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala 210 215 220 Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser 225 230 235 240 Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val 245 250 255 Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly 260 265 270 Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro 275 280 285 Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu 290 295 300 Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His 305 310 315 320 Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu 325 330 335 Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr 340 345 350 Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe 355 360 365 Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg 370 375 380 Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser 385 390 395 400 Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr 405 410 415 Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys 420 425 430 Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn 435 440 445 Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 450 455 460 Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly 465 470 475 480 His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr 485 490 495 Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 500 505 162558PRTartificial sequencepolypeptide 162Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser 20 25 30 Gly Pro Glu Leu Ile Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys 35 40 45 Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val Met His Trp Val Lys Gln 50 55 60 Lys Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn 65 70 75 80 Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr 85 90 95 Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr 100 105 110 Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Gly Thr Tyr Tyr Tyr 115 120 125 Gly Ser Arg Val Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 130 135 140 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 145 150 155 160 Ser Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro 165 170 175 Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn 180 185 190 Ser Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln 195 200 205 Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val 210 215 220 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg 225 230 235 240 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln 245 250 255 His Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 260 265 270 Lys Arg Ala Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser 275 280 285 Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln 290 295 300 Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr 305 310 315 320 Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr 325 330 335 Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln 340 345 350 Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala 355 360 365 Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala 370 375 380 Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr 385 390 395 400 Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln 405 410 415 Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser 420 425 430 Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys 435 440 445 Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln 450 455 460 Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu 465 470 475 480 Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg 485 490 495 Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met 500 505 510 Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly 515 520 525 Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp 530 535 540 Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu 545 550 555 163536PRTartificial sequencepolypeptide 163Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Leu Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro 115 120 125 Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Val Met Thr 130 135 140 Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly Glu Ser Val Ser Ile 145 150 155 160 Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser Asn Gly Asn Thr Tyr 165 170 175 Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile 180 185 190 Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly 195 200 205 Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile Ser Arg Val Glu Ala 210 215 220 Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His Leu Glu Tyr Pro Phe 225 230 235 240 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Pro Gly 245 250 255 Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser 260 265 270 Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val 275 280 285 Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr 290 295 300 Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro 305 310 315 320 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 325 330 335 Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 340 345 350 Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys 355 360 365 Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly 370 375 380 Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val 385 390 395 400 Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu 405 410 415 Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp 420 425 430 Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn 435 440 445 Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg 450 455 460 Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly 465 470 475 480 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 485 490 495 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 500 505 510 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 515 520 525 Met Gln Ala Leu Pro Pro Arg Glu 530 535 164554PRTartificial sequencepolypeptide 164Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Gln Leu Val Gln Ser 20 25 30 Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys 35 40 45 Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln 50 55 60 Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr 65 70 75 80 Gly Glu Ser Thr Tyr Ser Ala Asp Phe

Lys Gly Arg Phe Ala Phe Ser 85 90 95 Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys 100 105 110 Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp 115 120 125 Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly 130 135 140 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 145 150 155 160 Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg 165 170 175 Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn 180 185 190 Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu 195 200 205 Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe 210 215 220 Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val 225 230 235 240 Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp 245 250 255 Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp 260 265 270 Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu 275 280 285 Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser 290 295 300 Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys 305 310 315 320 Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro 325 330 335 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 340 345 350 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 355 360 365 Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly 370 375 380 Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg 385 390 395 400 Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 405 410 415 Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 420 425 430 Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser 435 440 445 Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 450 455 460 Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 465 470 475 480 Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln 485 490 495 Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 500 505 510 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 515 520 525 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 530 535 540 Leu His Met Gln Ala Leu Pro Pro Arg Glu 545 550 165532PRTartificial sequencepolypeptide 165Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn 115 120 125 Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro 130 135 140 Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg 145 150 155 160 Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser 180 185 190 Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg 195 200 205 Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala 210 215 220 Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala 225 230 235 240 Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly 245 250 255 Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly 260 265 270 Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val 275 280 285 Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser 290 295 300 Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 305 310 315 320 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 325 330 335 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 340 345 350 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 355 360 365 Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu 370 375 380 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 385 390 395 400 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 405 410 415 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 420 425 430 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 435 440 445 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 450 455 460 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 465 470 475 480 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 485 490 495 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 500 505 510 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 515 520 525 Pro Pro Arg Glu 530 166553PRTartificial sequencepolypeptide 166Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 20 25 30 Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 35 40 45 Ala Ser Gly Phe Thr Phe Asn Asp Tyr Ala Met His Trp Val Arg Gln 50 55 60 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Trp Asn Ser 65 70 75 80 Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 85 90 95 Arg Asp Asn Ala Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg 100 105 110 Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Ile Gln Tyr Gly 115 120 125 Asn Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 130 135 140 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 145 150 155 160 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser 165 170 175 Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser 180 185 190 Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 195 200 205 Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe 210 215 220 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 225 230 235 240 Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp 245 250 255 Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Asp Pro 260 265 270 Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys 275 280 285 Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn 290 295 300 Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro 305 310 315 320 Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg 325 330 335 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 340 345 350 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 355 360 365 Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr 370 375 380 Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg 385 390 395 400 Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro 405 410 415 Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu 420 425 430 Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala 435 440 445 Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu 450 455 460 Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly 465 470 475 480 Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu 485 490 495 Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser 500 505 510 Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly 515 520 525 Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu 530 535 540 His Met Gln Ala Leu Pro Pro Arg Glu 545 550 167531PRTartificial sequencepolypeptide 167Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Ser Gly Gly Ser Cys 115 120 125 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu 130 135 140 Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr 145 150 155 160 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser 180 185 190 Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala 210 215 220 Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe Gly Gln 225 230 235 240 Gly Thr Arg Leu Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly 245 250 255 Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser 260 265 270 Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser 275 280 285 Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu 290 295 300 Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro 305 310 315 320 Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro 325 330 335 Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp 340 345 350 Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu 355 360 365 Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu 370 375 380 Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu 385 390 395 400 Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys 405 410 415 Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 420 425 430 Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu 435 440 445 Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly 450 455 460 Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 465 470 475 480 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 485 490 495 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 500 505 510 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 515 520 525 Pro Arg Glu 530 168552PRTartificial sequencepolypeptide 168Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser 1 5 10 15 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu 20 25 30 Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys 35 40 45 Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg 50 55 60 Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser 65 70 75 80 Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile 85 90 95 Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln 100 105 110 Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly 115 120 125 Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val 130 135 140 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 145 150 155 160 Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu 165 170 175 Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys 180 185 190 Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu 195

200 205 Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser 210 215 220 Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu 225 230 235 240 Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro 245 250 255 Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Ser Asp Pro Gly 260 265 270 Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser 275 280 285 Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val 290 295 300 Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr 305 310 315 320 Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro 325 330 335 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 340 345 350 Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 355 360 365 Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys 370 375 380 Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly 385 390 395 400 Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val 405 410 415 Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu 420 425 430 Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp 435 440 445 Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn 450 455 460 Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg 465 470 475 480 Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly 485 490 495 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 500 505 510 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 515 520 525 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 530 535 540 Met Gln Ala Leu Pro Pro Arg Glu 545 550 169529PRTartificial sequencepolypeptide 169Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 20 25 30 Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro Tyr 115 120 125 Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Gln Met Thr Gln 130 135 140 Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 145 150 155 160 Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu 180 185 190 His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 210 215 220 Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Leu Glu Ile Thr Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys 245 250 255 Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu 260 265 270 Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala 275 280 285 Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala 290 295 300 Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile 305 310 315 320 Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala 325 330 335 Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr 340 345 350 Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu 355 360 365 Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile 370 375 380 Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp 385 390 395 400 Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 405 410 415 Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 420 425 430 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 435 440 445 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 450 455 460 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 465 470 475 480 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 485 490 495 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 500 505 510 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 515 520 525 Glu 170124PRTartificial sequenceHumanized F19 VH chain 170Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 171113PRTartificial sequenceHumanized F19 VL chain 171Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys 172119PRTartificial sequenceFAP5 VH chain 172Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Thr Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 85 90 95 Phe Cys Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 173107PRTartificial sequenceFAP5 VL chain 173Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 17412PRTartificial sequencemAb-specific epitope 174Gly Gln Asn Asp Thr Ser Gln Thr Ser Ser Pro Ser 1 5 10 175112PRTartificial sequenceCD3zeta intracellular signaling domain (ISD) 175Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 1 5 10 15 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 20 25 30 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 35 40 45 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 50 55 60 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 65 70 75 80 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 85 90 95 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 100 105 110 17642PRTartificial sequence41BB intracellular signaling domain (ISD) 176Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 1 5 10 15 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 20 25 30 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 35 40 17742PRTartificial sequence41BB-IC (41BB co-stimulatory domain) 177Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 1 5 10 15 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 20 25 30 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 35 40 17821PRTartificial sequenceCD8alpha signal peptide 178Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro 20 17916PRTartificial sequenceFcgammaRIIIalpha hinge 179Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln 1 5 10 15 18045PRTartificial sequenceCD8alpha hinge 180Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 1 5 10 15 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 20 25 30 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp 35 40 45 181231PRTartificial sequenceIgG1 hinge 181Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15 Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 75 80 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 90 95 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 100 105 110 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 115 120 125 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 165 170 175 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly Lys 225 230 18224PRTartificial sequenceCD8alpha transmembrane (TM) domain 182Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu 1 5 10 15 Ser Leu Val Ile Thr Leu Tyr Cys 20 18352PRTartificial sequenceFcepsilonRI alpha-TM-IC (FcepsilonRI alpha chain transmembrane and intracellular domain) 183Phe Phe Ile Pro Leu Leu Val Val Ile Leu Phe Ala Val Asp Thr Gly 1 5 10 15 Leu Phe Ile Ser Thr Gln Gln Gln Val Thr Phe Leu Leu Lys Ile Lys 20 25 30 Arg Thr Arg Lys Gly Phe Arg Leu Leu Asn Pro His Pro Lys Pro Asn 35 40 45 Pro Lys Asn Asn 50 184215PRTartificial sequenceFcepsilonRIbeta-(-)ITAM (FcepsilonRI beta chain without ITAM) 184Met Asp Thr Glu Ser Asn Arg Arg Ala Asn Leu Ala Leu Pro Gln Glu 1 5 10 15 Pro Ser Ser Val Pro Ala Phe Glu Val Leu Glu Ile Ser Pro Gln Glu 20 25 30 Val Ser Ser Gly Arg Leu Leu Lys Ser Ala Ser Ser Pro Pro Leu His 35 40 45 Thr Trp Leu Thr Val Leu Lys Lys Glu Gln Glu Phe Leu Gly Val Thr 50 55 60 Gln Ile Leu Thr Ala Met Ile Cys Leu Cys Phe Gly Thr Val Val Cys 65 70 75 80 Ser Val Leu Asp Ile Ser His Ile Glu Gly Asp Ile Phe Ser Ser Phe 85 90 95 Lys Ala Gly Tyr Pro Phe Trp Gly Ala Ile Phe Phe Ser Ile Ser Gly 100 105 110 Met Leu Ser Ile Ile Ser Glu Arg Arg Asn Ala Thr Tyr Leu Val Arg 115 120 125 Gly Ser Leu Gly Ala Asn Thr Ala Ser Ser Ile Ala Gly Gly Thr Gly 130 135 140 Ile Thr Ile Leu Ile Ile Asn Leu Lys Lys Ser Leu Ala Tyr Ile His 145 150 155 160 Ile His Ser Cys Gln Lys Phe Phe Glu Thr Lys Cys Phe Met Ala Ser 165 170 175 Phe Ser Thr Glu Ile Val Val Met Met Leu Phe Leu Thr Ile Leu Gly 180 185 190 Leu Gly Ser Ala Val Ser Leu Thr Ile Cys Gly Ala Gly Glu Glu Leu 195 200 205 Lys Gly Asn Lys Val Pro Glu 210 215 18541PRTartificial sequenceCD28-IC (CD28 co-stimulatory domain) 185Arg Ser Lys Arg Ser Arg

Gly Gly His Ser Asp Tyr Met Asn Met Thr 1 5 10 15 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 20 25 30 Pro Arg Asp Phe Ala Ala Tyr Arg Ser 35 40

Claims

1. A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope.

2. The polypeptide according to claim 1, wherein said mAb-specific epitope is located between the VH and VL chains.

3. The polypeptide according to claim 1, wherein said VH and VL chains, and mAb specific-epitope are bound together by at least one linker and to the transmembrane domain of said CAR by a hinge.

4. The polypeptide according to claim 3, wherein the mAb-specific epitope is joined to the VH and VL chains by two linkers.

5. The polypeptide according to claim 1, wherein the mAb-specific epitope is an epitope to be bound by an epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing a CAR comprising such epitope.

6. The polypeptide according to claim 1, wherein the polypeptide comprises one extracellular binding domain, wherein said extracellular binding domain further comprises a hinge, and said polypeptide further comprises a transmembrane domain, and, an intracellular domain.

7. The polypeptide according to claim 1, wherein the extracellular binding domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mAb-specific epitopes.

8. The polypeptide according to claim 1, wherein the extracellular binding domain comprises 1, 2, 3 or, 4 mAb-specific epitopes.

9. The polypeptide according to claim 1, wherein the extracellular binding domain comprises 2, 3 or, 4 mAb-specific epitopes.

10. The polypeptide according to claim 1, wherein the extracellular binding domain comprises the following sequence V1-L1-V2-(L)x-Epitope1-(L)x-; V1-L1-V2-(L)x-Epitope1-(L)x-Epitope2-(L)x-; V1-L1-V2-(L)x-Epitope1-(L)x-Epitope2-(L)x-Epitope3-(L)x-; (L)x-Epitope1-(L)x-V1-L1-V2; (L)x-Epitope1-(L)x-Epitope2-(L)x-V1-L1-V2; Epitope 1-(L)x-Epitope2-(L)x-Epitope3-(L)x-V1-L1-V2; (L)x-Epitope1-(L)x-V1-L1-V2-(L)x-Epitope2-(L)x; (L)x-Epitope1-(L)x-V1-L1-V2-(L)x-Epitope2-(L)x-Epitope3-(L)x-; (L)x-Epitope1-(L)x-V1-L1-V2-(L)x-Epitope2-(L)x-Epitope3-(L)x-Epitope4-(L)- x-; (L)x-Epitope1-(L)x-Epitope2-(L)x-V1-L1-V2-(L)x-Epitope3-(L)x-; (L)x-Epitope1-(L)x-Epitope2-(L)x-V1-L1-V2-(L)x-Epitope3-(L)x-Epitope4-(L)- x-; V1-(L)x-Epitope1-(L)x-V2; V1-(L)x-Epitope1-(L)x-V2-(L)x-Epitope2-(L)x; V1-(L)x-Epitope1-(L)x-V2-(L)x-Epitope2-(L)x-Epitope3-(L)x; V1-(L)x-Epitope1-(L)x-V2-(L)x-Epitope2-(L)x-Epitope3-(L)x-Epitope4-(L)x; (L)x-Epitope1-(L)x-V1-(L)x-Epitope2-(L)x-V2; or, (L)x-Epitope1-(L)x-V1-(L)x-Epitope2-(L)x-V2-(L)x-Epitope3-(L)x; wherein, V1 is VL and V2 is VH or V1 is VH and V2 is VL; L1 is a linker suitable to link the VH chain to the VL chain; L is a linker comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain can be identical or different to other occurrence of L in the same extracellular binding domain; x is 0 or 1 and each occurrence of x is selected independently from the others; and Epitope 1, Epitope 2 and Epitope 3 are mAb-specific epitopes and can be identical or different.

11. The polypeptide according to claim 10, wherein the extracellular binding domain comprises the following sequence V1-L1-V2-L-Epitope1; V1-L1-V2-L-Epitope1-L; V1-L1-V2-L-Epitope1-L-Epitope2; V1-L1-V2-L-Epitope1-L-Epitope2-L; V1-L1-V2-L-Epitope1-L-Epitope2-L-Epitope3; V1-L1-V2-L-Epitope1-L-Epitope2-L-Epitope3-L; V1-L1-V2-Epitope1; V1-L1-V2-Epitope1-L; V1-L1-V2-Epitope1-L-Epitope2; V1-L1-V2-Epitope1-L-Epitope2-L; V1-L1-V2-Epitope1-L-Epitope2-L-Epitope3; V1-L1-V2-Epitope1-L-Epitope2-L-Epitope3-L; Epitope1-V1-L1-V2; Epitope1-L-V1-L1-V2; L-Epitope1-V1-L1-V2; L-Epitope1-L-V1-L1-V2; Epitope1-L-Epitope2-V1-L1-V2; Epitope1-L-Epitope2-L-V1-L1-V2; L-Epitope1-L-Epitope2-V1-L1-V2; L-Epitope1-L-Epitope2-L-V1-L1-V2; Epitope1-L-Epitope2-L-Epitope3-V1-L1-V2; Epitope1-L-Epitope2-L-Epitope3-L-V1-L1-V2; L-Epitope1-L-Epitope2-L-Epitope3-V1-L1-V2; L-Epitope1-L-Epitope2-L-Epitope3-L-V1-L1-V2; V1-L-Epitope1-L-V2; L-Epitope1-L-V1-L-Epitope2-L-V2; V1-L-Epitope1-L-V2-L-Epitope2-L; V1-L-Epitope1-L-V2-L-Epitope2-L-Epitope3; V1-L-Epitope1-L-V2-L-Epitope2-Epitope3; V1-L-Epitope1-L-V2-L-Epitope2-L-Epitope3-Epitope4; L-Epitope1-L-V1-L-Epitope2-L-V2-L-Epitope3-L; Epitope1-L-V1-L-Epitope2-L-V2-L-Epitope3-L; L-Epitope1-L-V1-L-Epitope2-L-V2-L-Epitope3; L-Epitope1-L-V1-L1-V2-L-Epitope2-L; L-Epitope1-L-V1-L1-V2-L-Epitope2-L-Epitope3; L-Epitope1-L-V1-L1-V2-L-Epitope2-Epitope3, or Epitope1-L-V1-L1-V2-L-Epitope2-L-Epitope3-Epitope4 wherein V1 is VL and V2 is VH or V1 is VH and V2 is VL; L1 is any linker suitable to link the VH chain to the VL chain; L is a linker comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain can be identical or different to other occurrences of L in the same extracellular binding domain, and, Epitope 1, Epitope 2 and Epitope 3 are mAb-specific epitopes and can be identical or different.

12. The polypeptide according to claim 10, wherein L1 is a linker comprising Glycine and/or Serine.

13. The polypeptide according to claim 12, wherein L1 is a linker comprising an amino acid sequence of (Gly-Gly-Gly-Ser)n or (Gly-Gly-Gly-Gly-Ser)n, where n is 1, 2, 3, 4 or 5 or a linker comprising an amino acid sequence of (Gly4Ser)4 or (Gly4Ser)3.

14. The polypeptide according to claim 10, wherein L is a linker comprising Glycine and/or Serine.

15. The polypeptide according to claim 14, wherein L is a linker having an amino acid sequence of SGG, GGS, SGGS (SEQ ID NO. 186), SSGGS (SEQ ID NO. 187), GGGG (SEQ ID NO. 188), SGGGG (SEQ ID NO. 189), GGGGS (SEQ ID NO. 190), SGGGGS (SEQ ID NO. 191), GGGGGS (SEQ ID NO. 192), SGGGGGS (SEQ ID NO. 193), SGGGGG (SEQ ID NO. 194), GSGGGGS (SEQ ID NO. 195), GGGGGGGS (SEQ ID NO. 196), SGGGGGGG (SEQ ID NO. 197), SGGGGGGGS (SEQ ID NO. 198), or SGGGGSGGGGS (SEQ ID NO. 199).

16. The polypeptide according to claim 14, wherein L is a SGGGG (SEQ ID NO. 189), GGGGS (SEQ ID NO. 190), or SGGGGS (SEQ ID NO. 191).

17. The polypeptide according to claim 10, wherein Epitope 1, Epitope 2, Epitope 3 and Epitope 4 are independently selected from mAb-specific epitopes specifically recognized by ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 or ustekinumab.

18. The polypeptide according to claim 10, wherein Epitope 1, Epitope 2, Epitope 3 and Epitope 4 are independently selected from mAb-specific epitopes having an amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174.

19. The polypeptide according to claim 10, wherein Epitope 1 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35.

20. The polypeptide according to claim 10, wherein Epitope 2 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35.

21. The polypeptide according to claim 10, wherein Epitope 3 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 or SEQ ID NO 144.

22. The polypeptide according to claim 10, wherein Epitope 4 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35.

23. The polypeptide according to claim 10, wherein Epitope 1, Epitope 2 and Epitope 4 are a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 and Epitope 3 is a mAb-specific epitope having an amino acid sequence of SEQ ID NO 144.

24. The polypeptide according to claim 1, wherein the mAb-specific epitope is from one polypeptide selected from those listed in Table 1.

25. The polypeptide according to claim 1, wherein the mAb-specific epitope is selected from mAb-specific epitopes specifically recognized by ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and or ustekinumab.

26. The polypeptide according to claim 1, wherein the mAb-specific epitope is selected from mAb-specific epitope having an amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174.

27. The polypeptide according to claim 1, wherein the mAb-specific epitope is has an amino acid sequence of SEQ ID NO 35.

28. The polypeptide according to claim 1, wherein said VH and VL chains have an antigenic target sequence of over 80% identity with SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-3v antigen) or SEQ ID NO 52 (WT1 antigen).

29. The polypeptide according to claim 1, wherein said antigen is a cell surface marker antigen.

30. The polypeptide according to claim 1, wherein said antigen is a tumor-associated surface antigen.

31. The polypeptide according to claim 1, wherein said antigen is ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), CD19, CD20, CD30, CD40, disialoganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal-epithelial mucine, gp36, TAG-72, glycosphingolipids, glioma-associated antigen, .beta.-human chorionic gonadotropin, alphafetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxyl esterase, mut hsp70-2, M-CSF, prostase, prostase specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostein, PSMA, survivin and telomerase, prostate-carcinoma tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, ephrin B2, CD22, insulin growth factor (IGF1)-I, IGF-II, IGFI receptor, mesothelin, a major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, 5T4, ROR1, Nkp30, NKG2D, tumor stromal antigens, the extra domain A (EDA) and extra domain B (EDB) of fibronectin and the A1 domain of tenascin-C (TnC A1) and fibroblast associated protein (fap), LRP6, melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), CD38/CS1, MART1, WT1, MUC1, LMP2, Idiotype, NY-ESO-1, Ras mutant, gp100, proteinase 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, Androgen receptor; a lineage-specific or tissue specific antigen such as CD3, CD4, CD8, CD24, CD25, CD33, CD34, CD70, CD79, CD116, CD117, CD135, CD123, CD133, CD138, CTLA-4, B7-1 (CD80), B7-2 (CD86), endoglin, a major histocompatibility complex (MHC) molecule, BCMA (CD269, TNFRSF 17) or FLT-3.

32. The polypeptide according to claim 1, wherein VH and VL are a VH of SEQ ID NO 65 and a VL of SEQ ID NO 66; a VH of SEQ ID NO 67 and a VL of SEQ ID NO 68; a VH of SEQ ID NO 69 and a VL of SEQ ID NO 70; a VH of SEQ ID NO 71 and a VL of SEQ ID NO 72; a VH of SEQ ID NO 77 and a VL of SEQ ID NO 78; a VH of SEQ ID NO 79 and a VL of SEQ ID NO 80; a VH of SEQ ID NO 81 and a VL of SEQ ID NO 82; a VH of SEQ ID NO 83 and a VL of SEQ ID NO 84; a VH of SEQ ID NO 85 and a VL of SEQ ID NO 86; a VH of SEQ ID NO 87 and a VL of SEQ ID NO 88; a VH of SEQ ID NO 89 and a VL of SEQ ID NO 90; a VH of SEQ ID NO 91 and a VL of SEQ ID NO 92; a VH of SEQ ID NO 93 and a VL of SEQ ID NO 94; a VH of SEQ ID NO 95 and a VL of SEQ ID NO 96; a VH of SEQ ID NO 97 and a VL of SEQ ID NO 98; a VH of SEQ ID NO 99 and a VL of SEQ ID NO 100; a VH of SEQ ID NO 101 and a VL of SEQ ID NO 102; a VH of SEQ ID NO 103 and a VL of SEQ ID NO 104; a VH of SEQ ID NO 105 and a VL of SEQ ID NO 106; a VH of SEQ ID NO 107 and a VL of SEQ ID NO 108; a VH of SEQ ID NO 109 and a VL of SEQ ID NO 110; a VH of SEQ ID NO 111 and a VL of SEQ ID NO 112; aVH of SEQ ID NO 113 and a VL of SEQ ID NO 114; aVH of SEQ ID NO 115 and a VL of SEQ ID NO 116; a VH of SEQ ID NO 117 and a VL of SEQ ID NO 118; a VH of SEQ ID NO 119 and a VL of SEQ ID NO 120; a VH of SEQ ID NO 121 and a VL of SEQ ID NO 122; or, a VH of SEQ ID NO 123 and a VL of SEQ ID NO 124, a VH of SEQ ID NO 170 and a VL of SEQ ID NO 171; a VH of SEQ ID NO 172 and a VL of SEQ ID NO 173; or a VH of SEQ ID NO 174 and a VL of SEQ ID NO 175.

33. The polypeptide according to claim 3, wherein the hinge comprises a PD-1 hinge, an IgG4 hinge, a CD8alpha hinge or a Fc.gamma.RIII alpha hinge.

34. The polypeptide according to claim 3, wherein the transmembrane domain comprises the transmembrane region(s) of the alpha, beta or zeta chain of the T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154.

35. The polypeptide according to claim 3, wherein the transmembrane domain comprises the transmembrane region(s) of PD-1 or CD8 alpha.

36. The polypeptide according to claim 3, wherein the transmembrane domain comprises the transmembrane region(s) of CD8 alpha.

37. The polypeptide according to claim 6, wherein the intracellular domain comprises a CD3zeta signaling domain.

38. The polypeptide according to claim 6, wherein the intracellular domain comprises a 4-1BB domain.

39. The polypeptide according to claim 1, wherein the CAR is a single-chain CAR.

40. The polypeptide according to claim 1, wherein the said polypeptide shares over 80% sequence identity with or is identical to SEQ ID NO 1 to 10, SEQ ID NO 125 to 141 or SEQ ID no 145 to 150 or SEQ ID NO 152 to 169.

41. The polypeptide according to claim 1, wherein the CAR is a multi-chain CAR.

42. A polynucleotide encoding the polypeptide according to claim 1.

43. The polynucleotide according to claim 42, wherein said CAR comprises a CD3 zeta signaling domain and co-stimulatory domain from 4-1BB.

44. An expression vector comprising the nucleic acid of claim 42.

45. An engineered immune cell expressing at its cell surface a polypeptide according to claim 1.

46. The engineered immune cell according to claim 45, wherein said cell is derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes.

47. The engineered immune cell according to claim 45, formulated as a medicament.

48. A method for engineering an immune cell, comprising introducing into said cell at least one polynucleotide encoding the CAR according to claim 1.

49. The method for engineering an immune cell of claim 48, wherein immune cell is a T-cell.

50. A method for in vitro sorting engineered immune cell expressing at its cell surface a polypeptide comprising at least one mAb-specific epitope according to claim 1 comprising contacting a population of immune cells comprising said engineered immune cells with a monoclonal antibody specific for the mAb-specific epitope; selecting the cells that bind to the monoclonal antibody to obtain a population of cells enriched in engineered immune cell.

51. The method according to claim 50, wherein the monoclonal antibody specific for the mAb-specific epitope is conjugated to a fluorophore and the step of selecting the cells that bind to the monoclonal antibody is done by Fluorescence Activated Cell Sorting (FACS).

52. The method according to claim 50, wherein the monoclonal antibody specific for the mAb-specific epitope is conjugated to a magnetic particle and the step of selecting the cells that bind to the monoclonal antibody is done by Magnetic Activated Cell Sorting (MACS).

53. The method according to claim 50, wherein the polypeptide comprises an mAb-specific epitope having an amino acid sequence of SEQ ID NO 35 and the monoclonal antibody is rituximab.

54. The method according to claim 50, wherein the polypeptide comprises an mAb-specific epitope having an amino acid sequence of SEQ ID NO 144 and the antibody used to contact the population of immune cells is QBEND-10.

55. The method according to claim 50, wherein the population of cells enriched in engineered immune cell comprises at least 70%, 75%, 80%, 85%, 90%, or 95% of CAR-expressing immune cells.

56. A method for in vivo depleting an engineered immune cell expressing at its cell surface a polypeptide comprising at least one mAb-specific epitope according to claim 1 in a patient, comprising contacting said engineered immune cell with at least one epitope-specific mAb.

57. The method according to claim 56, wherein the mAb-specific epitope is a CD20 epitope or mimotope and the epitope-specific mAb is rituximab.

58. The method according to claim 57, wherein the mAb-specific epitope has an amino acid sequence of SEQ ID NO 35.

59. The method according to claim 56, wherein the epitope-specific mAb is conjugated by a molecule able to activate the complement system.

60. The method according to claim 56, wherein a cytotoxic drug is coupled to the epitope-specific mAb.

61. A method for in vivo depleting an engineered immune cell expressing at its cell surface a polypeptide comprising at least one mAb-specific epitope according to claim 1 in a patient, comprising contacting said engineered immune cell with bi-specific mAb (BsAb) able to bind both the mAb-specific epitope borne on said cells and to an surface antigen borne on an effector (and cytotoxic) cell.

62. The method according to claim 48, wherein said immune cell is a T-cell.