Patent application title: REDIRECTED CELLS WITH MHC CHIMERIC RECEPTORS AND METHODS OF USE IN IMMUNOTHERAPY
Inventors:
Michael S Kuhns (Tucson, AZ, US)
Thomas Serwold (Boston, MA, US)
IPC8 Class: AC07K1474FI
USPC Class:
1 1
Class name:
Publication date: 2021-10-07
Patent application number: 20210309714
Abstract:
Chimeric receptors featuring major histocompatibility molecules grafted
onto T cell receptor molecules and surrogate co-receptors featuring cell
surface receptor ligands fused with signaling molecule domains. The
chimeric receptors can be used to redirect cells, altering their
specificity. T cells expressing chimeric receptors may bind to TCRs of
target T cells for which their chimeric receptors are specific. Surrogate
co-receptors may be used to help enhance TCR-CD3 signaling as part of
this modular receptor system. The chimeric receptors and surrogate
coreceptors may be used to help eliminate autoreactive T cells or program
T cells to desired effector functions.Claims:
1. An engineered cell, comprising: a. A chimeric receptor module (MHCR)
that comprises: i) an extracellular domain of a major histocompatibility
complex (MHC); ii) a T-cell receptor (TCR) portion comprising a
transmembrane domain of a TCR, and a cytoplasmic domain of a TCR; and b.
A surrogate coreceptor (SCR) that comprises: i) an extracellular region
of a cell surface receptor ligand; ii) a transmembrane region; and iii) a
kinase.
2. The engineered cell of claim 1, wherein the extracellular domain of the MHC is directly bound to the TCR portion.
3. The engineered cell of claim 1, wherein an antigenic peptide is bound to the extracellular domain of the MHC.
4. The engineered cell of claim 1, wherein the extracellular domain of the MHC is derived from an MHC selected from the group consisting of: HLA-A, HLA-B, HLA-C, Beta2-microglobulin, HLA-DPA, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, and H2-EK beta.
5. The engineered cell of claim 1, wherein the transmembrane domain and the cytoplasmic domain of the TCR are derived from a TCR selected from the group consisting of: TRAC, TRBC1, TRBC2, TRDC, TRGC1, and TRGC2.
6. The engineered cell of claim 1, wherein the cell surface receptor ligand is a T-cell surface receptor ligand.
7. The engineered cell of claim 1, wherein the T-cell surface receptor ligand is selected from the group consisting of: a CD28 ligand, a CTLA-4 ligand, an ICOS ligand, an OX40 ligand, and a CD2 ligand.
8. The engineered cell of claim 1, wherein the T-cell surface receptor ligand is selected from the group consisting of: CD80 and CD86.
9. The engineered cell of claim 1, wherein the kinase is a Src kinase.
10. The engineered cell of claim 9, wherein said Src kinase is Lck or Fyn.
11. The engineered cell of claim 6, wherein the T-cell surface ligand is CD80, and the kinase is Lck.
12. The engineered cell of claim 6, wherein the T-cell surface ligand is CD86, and the kinase is Lck.
13. The engineered cell of claim 1, wherein said engineered cell is a T cell, NK cell, or NK T cell.
Description:
CROSS REFERENCE
[0001] This application is a Divisional and claims benefit of U.S. patent application Ser. No. 15/738,467 filed Dec. 20, 2017 which is a 371 application and claims benefit of International Patent Application No. PCT/US16/40177 filed Jun. 29, 2016, which claims benefit of U.S. Provisional Patent Application No. 62/186,865 filed Jun. 30, 2015, the specification(s) of which is/are incorporated herein in their entirety by reference.
REFERENCE TO SEQUENCE LISTING
[0003] Applicant asserts that the paper copy of the Sequence Listing is identical to the Sequence Listing in computer readable form found on the accompanying computer file, entitled UNIA_15_04_PCT_US_DIV_Sequence_Listing_ST25, and is identical to that forming part of the international application as filed. The content of the sequence listing is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0004] The present invention relates to T cells and T cell receptors, more particularly to redirected T cells with engineered receptors, more particularly to redirected cells expressing a chimeric receptor comprising a major histocompatibility complex (MHC) molecule, including redirected cells further comprising a surrogate coreceptor, e.g., as components of a modular chimeric receptor system.
BACKGROUND OF THE INVENTION
[0005] T cells normally recognize and respond to peptide antigens embedded within major histocompatibility complex molecules (pMHCs) of antigen presenting cells (APCs) via their TCR-CD3 complex (see FIG. 1A). This eight-subunit TCR-CD3 complex is composed of the TCR, which is the receptor module that binds the pMHC, and the CD3.gamma..epsilon., CD3.delta..epsilon., and CD3.zeta..zeta. signaling modules that connect the TCR to the intracellular signaling machinery (see FIG. 1B). The intracellular domains of the CD3 subunits contain immunoreceptor tyrosine-based activation motifs (ITAMs) that are phosphorylated by the Src kinases, e.g., Lck, Fyn. CD3.gamma., CD3.delta., and CD3.epsilon. each contain one ITAM while CD3.zeta. contains three ITAMs for a total of ten in a single complex. The TCR-CD3 complex does not appear to have any intrinsic Src kinase activity. In fact, coreceptors (e.g., CD4, CD8) appear to sequester Lck away from the TCR-CD3 complex until both a coreceptor and a TCR bind a pMHC. The Lck associated with the coreceptor is then brought into close proximity to the CD3 ITAMs to phosphorylate tyrosines within these motifs and initiate signaling.
[0006] Ectopic T cell receptors (TCRs) have been introduced into T cells in an effort to reprogram or alter T cell specificity. However, in some cases, the introduction of ectopic TCRs has been found to lead to cross-pairing events with endogenous TCRs, resulting in novel TCRs with autoimmune specificities. This lead to the use of chimeric antigen receptors (CARs), which are typically designed with (a) an extracellular domain consisting of a single-chain variable fragment (scFv) of a monoclonal antibody directed against a target antigen; (b) a transmembrane domain that does not mediate interactions with other protein subunits; and (c) an intracellular domain consisting of the CD3.zeta. intracellular signaling domain as well as signaling domains from a variety of other signaling molecules (e.g., CD28, CD27, ICOS, 4-1BB, OX40). Without wishing to limit the present invention to any theory or mechanism, it is believed that CARs do not sufficiently take advantage of the modularity of the existing signaling apparatus, which is optimized to direct T cell activation and effector functions. CARs are likely to be delivering incomplete signals that could have unintended consequences or side effects.
[0007] The present invention features novel chimeric receptors (e.g., "MHCRs") comprising a portion of a MHC molecule (e.g., class I, class II, non-classical MHC) and a portion of the TCR. In some embodiments, the MHCR comprises a portion of an antigen peptide. The present invention also features cells, such as T cells, expressing said MHCRs (cells expressing a MHCR are herein referred to as "redirected cells"). The MHCRs are adapted to recognize and bind to appropriate (specific) TCRs. Redirected cells (e.g., redirected T cells) expressing a MHCR would mimic antigen presenting cells (APCs), the cells that normally express MHC molecules. In some cases, binding of a TCR of a target T cell to the MHCR of the redirected cell may then result in destruction of the target T cell; thus, in this case, the redirected cells may function as "anti-T cell" T cells. The present invention is not limited to redirected cells functioning to destroy a target. For example, in some embodiments, the redirected cell is adapted to help reprogram a target cell, e.g., the redirected cell may deliver instructions to the target cell.
[0008] The present invention also features engineered cells expressing both an MHCR and an SCR. It was surprisingly discovered that engineered cells co-expressing an MHCR and an SCR had enhanced effects (e.g., increased IL-2 expression, see FIG. 5) as compared to engineered cells expressing a MHCR without co-expression of an SCR. Without wishing to limit the present invention to any theory or mechanism, it is believed that the use of an SCR in combination with a MHCR enhances signaling and/or other downstream effects. Without wishing to limit the present invention to any theory or mechanism, it is believed that the combination of the MHCR and SCR may provide a synergistic effect, e.g., effects of the combination of the MHCR and SCR may provide effects greater than those of the MHCR and SCR individually.
[0009] Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.
SUMMARY OF THE INVENTION
[0010] The present invention features novel chimeric receptors for engineering redirected cells. For example, the present invention features an engineered cell co-expressing on its surface a chimeric receptor (MHCR) comprising a major histocompatibility complex (MHC) portion (derived from a MHC protein) directly or indirectly fused to a T cell receptor (TCR) portion (derived from a TCR protein); and a surrogate co-receptor (SCR) comprising a cell surface receptor ligand portion directly or indirectly fused to a signaling molecule portion. In some embodiments, the MHCR is adapted to bind to a TCR of a target cell and the SCR is adapted to bind to a cell surface receptor of the target cell. In some embodiments, binding of the MHCR to the TCR of the target cell and binding of the SCR to the cell surface receptor of the target cell (i) initiates a signaling cascade effective for eliminating the target cell or (ii) instructs the target cell to differentiate to a specific effector function. In some embodiments, the cell (e.g., genetically engineered cell) is a T cell (e.g., CD4+, CD8+); however, the present invention is not limited to T cells.
[0011] In some embodiments, the TCR portion comprises a transmembrane domain of the TCR protein and the MHC portion comprises an extracellular domain of the MHC protein. In some embodiments, the TCR portion comprises at least a portion of a transmembrane domain of the TCR protein and the MHC portion comprises at least a portion of an extracellular domain of the MHC protein. In some embodiments, the TCR portion comprises at least a portion of a transmembrane domain and at least a portion of a cytoplasmic domain of a TCR protein, and the MHC portion comprises at least a portion of an extracellular domain of the MHC protein.
[0012] In some embodiments, the MHC portion of the MHCR is N-terminal to the TCR portion of the MHCR. In some embodiments, the MHC portion is directly fused to the TCR portion. In some embodiments, the MHC portion is indirectly fused to the TCR portion via a linker. In some embodiments, the MHCR further comprises a peptide antigen integrated into the MHC portion, or directly or indirectly fused to the MHC portion. In some embodiments, the peptide antigen is linked to the MHC portion via a linker. In some embodiments, the linker comprises a glycine-rich peptide. In some embodiments, the SCR further comprises a transmembrane domain positioned in between the cell surface receptor ligand portion and the signaling molecule portion. In some embodiments, the MHC protein, the TCR protein, or both the MHC protein and the TCR protein are mammalian proteins (e.g., human, mouse, cat, dog, etc. In some embodiments, the signaling molecule portion has kinase or phosphatase activity. In some embodiments, the signaling molecule portion comprises a Src kinase.
[0013] In some embodiments, the MHC protein comprises HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, H2-EK beta, a fragment thereof, or a combination thereof. In some embodiments, the MHC molecule comprises HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, H2-EK beta, a peptide that is at least 90% identical to HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, or H2-EK beta, a fragment thereof, or a combination thereof. In some embodiments, the TCR molecule comprises TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, TCC4, a fragment thereof, or a combination thereof. In some embodiments, the TCR molecule comprises TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, TCC4, a peptide that is at least 90% identical to TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, or TCC4, a fragment thereof, or a combination thereof. In some embodiments, the cell surface receptor ligand portion of the SCR comprises a CD28 ligand, a CTLA-4 ligand, an ICOS ligand, an OX40 ligand, a PD-1 ligand, or a CD2 ligand. In some embodiments, the CD28 ligand comprises CD80, CD86, or both CD80 and CD86. In some embodiments, the MHCR is adapted to complex with a CD3 subunit. In some embodiments, the engineered cell further co-expresses a second SCR.
[0014] The present invention also features a chimeric receptor (MHCR) as described above. For example, the MHCR may comprise a major histocompatibility complex (MHC) portion derived from a MHC protein directly or indirectly fused to a T cell receptor (TCR) portion derived from a TCR protein, wherein the MHCR is adapted to bind to a TCR of a target cell.
[0015] The present invention also features a method of eliminating a target cell or reprogramming a target cell (the target cell comprising a TCR). In some embodiments, the method comprises introducing a genetically engineered cell that expresses on its surface a chimeric receptor (MHCR) according to the present invention to the target cell, wherein the MHCR is specific for the TCR of the target cell, wherein upon binding of the MHCR to the TCR the genetically engineered cell (a) initiates a signaling cascade that eliminates the target cell, or (b) instructs the target cell to differentiate to a specific effector function. In some embodiments, the method is for immunotherapy. In some embodiments, the target cell is an autoreactive T cell.
[0016] The present invention also features vectors encoding MHCRs of the present invention. The present invention also features vectors encoding SCRs of the present invention.
[0017] Then present invention also features an engineered cell co-expressing on its surface a chimeric receptor (MHCR) comprising a major histocompatibility complex (MHC) portion derived from an extracellular domain of a mammalian MHC protein directly or indirectly linked to a transmembrane domain of a T cell receptor (TCR) portion derived from a mammalian TCR protein, wherein the MHC portion is N-terminal to the TCR portion; and a surrogate coreceptor (SCR) comprising a cell surface receptor ligand portion indirectly linked to a signaling molecule portion by a transmembrane domain, wherein the signaling molecule portion has kinase or phosphatase activity. The MHCR may be adapted to bind to a TCR of a target cell and the SCR may be adapted to bind to a cell surface receptor of the target cell.
[0018] The present invention also features an engineered T-cell co-expressing on its surface: a chimeric receptor (MHCR) comprising a major histocompatibility complex (MHC) portion derived from an extracellular domain of a mammalian MHC protein directly or indirectly linked to a transmembrane domain of a T cell receptor (TCR) portion derived from a mammalian TCR protein, the MHC portion being N-terminal to the TCR portion, the MHC portion being selected from HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, and H2-EK beta, the TCR portion being selected from TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, TCC4; and a surrogate coreceptor (SCR) comprising a cell surface receptor ligand portion indirectly linked to a signaling molecule portion by a transmembrane domain, the signaling molecule portion having kinase or phosphatase activity. The MHCR may be adapted to bind to a TCR of a target cell and the SCR may be adapted to bind to a cell surface receptor of the target cell.
[0019] In some embodiments, the MHC molecule comprises at least a portion of an extracellular domain of a MHC protein. In some embodiments, the TCR molecule comprises at least a portion of a cytoplasmic domain of a TCR protein, at least a portion of a transmembrane domain of a TCR protein, at least a portion of an extracellular domain of a TCR protein, or a combination thereof. In some embodiments, the chimeric receptor is adapted to bind to a TCR. In some embodiments, the chimeric receptor is adapted to complex with at least one CD3 subunit.
[0020] The present invention also features a surrogate co-receptor (SCR) comprising a cell surface receptor ligand portion directly or indirectly fused to a signaling molecule portion via a transmembrane domain, wherein the SCR is adapted to bind to a cell surface receptor of a target cell. In some embodiments, the cell surface receptor ligand portion is indirectly fused to the signaling molecule portion via a linker.
[0021] The present invention also features genetically engineered cells (e.g., redirected cells) that express on their surfaces a chimeric receptor according to the present invention. In some embodiments, the cell is a T cell (e.g., CD8+ T cell, CD4+ T cell, etc.). In some embodiments, the cell co-expresses one or more SCRs according to the present invention. In some embodiments, the chimeric receptor is complexed with at least one CD3 subunit.
[0022] The present invention also features a method of eliminating a target cell or reprogramming a target cell (said target cell comprising a TCR). In some embodiments, the method comprises introducing a genetically engineered cell that expresses on its surface a chimeric receptor to the target cell, wherein the chimeric receptor is specific for the TCR of the target cell. In some embodiments, binding of the chimeric receptor on the genetically engineered cell to the TCR of the target cell initiates a signaling cascade that eliminates the target cell. In some embodiments, binding of the chimeric receptor of the genetically engineered cell to the TCR of the target cell instructs the target cell to differentiate to a specific effector function (e.g. Th1, Th2, Th17, Tfh, Treg or cytotoxic T cell). In some embodiments, the chimeric receptor (e.g., MHCR) is expressed on a Treg and binding of the chimeric receptor to the TCR of a target cell inhibits the target cell's function (e.g., redirect the Treg function against an autoimmune cell). In some embodiments, the genetically engineered cell co-expresses a SCR. In some embodiments, the SCR comprises a cell surface receptor ligand specific for a cell surface receptor on the target cell. In some embodiments, binding of the chimeric receptor to the TCR and binding of the cell surface receptor ligand of the SCR to the cell surface receptor of the target cell initiates a signaling cascade that eliminates the target cell, or instructs the target cell to differentiate to a specific effector function.
[0023] In some embodiments, the method is for immunotherapy. In some embodiments, the genetically engineered cell is surgically introduced to a host (e.g., a mammal). In some embodiments, the target cell is an autoreactive T cell.
[0024] The present invention also features nucleotide sequences encoding the chimeric receptors of the present invention. The present invention also features vectors encoding the chimeric receptors of the present invention. The present invention also features nucleotide sequences encoding the SCRs of the present invention. The present invention also features vectors encoding the SCRs of the present invention.
[0025] Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The patent application or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
[0027] The features and advantages of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:
[0028] FIG. 1A shows molecules involved in T cell activation. Engagement of the TCR with pMHC (MHC with a peptide antigen) initiates T cell activation.
[0029] FIG. 1B shows the molecular components of the lpha-beta-TCR-CD3 complex. The TCR transfers pMHC-specific information to the CD3 subunits and inside the T cell. Triangles represent the inner and outer leafs of the cell membrane. Red and blue dots and ovals represent the transmembrane charge interactions that drive subunit assembly of the complexes (from Kuhns et al., 2006, Immunity 24:133-139).
[0030] FIG. 2A shows a redirected T cell expressing a MHCR (pMHCR with peptide antigen) of the present invention. The MHCR in complex with CD3 subunits is bound to a target T cell's TCR.
[0031] FIG. 2B shows non-limiting examples of MHCR configurations (and the schematics are not limiting with respect to N-terminal and C-terminal orientation). TCR refers to the T cell receptor portion; MHC refers to the major histocompatibility portion, antigen refers to the antigen portion, and L refers to a linker. The present invention is not limited to these configurations. For example, in some embodiments the antigen portion is integrated into the MHC portion. In some embodiments, the MHC portion is N-terminal to the TCR portion (see orientation of sequences below).
[0032] FIG. 3A is a schematic view of a chimeric surrogate coreceptor (SCR), e.g., one comprising CD80/CD86-Lck.
[0033] FIG. 3B shows a redirected T cell expressing a MHCR (pMHCR) and two surrogate coreceptors (SCRs). The MHCR, bound to a target T cell's TCR, is complexed with CD3. The SCRs are bound to the target T cell's coreceptors (CD28, CTLA-4). Binding of the SCRs to coreceptors on the target T cell may help initiate CD3 signaling similar to that seen in normal T cell activation.
[0034] FIG. 4 shows expression of pMHCR-CD3 complexes on T cell hybridomas. 58.alpha..sup.-.beta..sup.- cells that lack endogenous TCRs were transduced with a pMHCR composed of MCC:I-E.sup.k. The proportional expression (diagonal) of I-E.sup.k and CD3 subunits suggests surface co-dependent expression of the epitopes.
[0035] FIG. 5 shows TCR-specific IL-2 production by pMHCR-CD3 expressing T cell hybridomas. 58.alpha..sup.-.beta..sup.- cells that lack endogenous TCRs were transduced with a pMHCR composed of MCC:I-E.sup.k as well as a CD80-Lck surrogate coreceptor (SCR). The cells were co-cultured with parental M12 B cells, or M12 cells stably transduced to express the MCC:I-E.sup.k-specific 2B4 TCR alone or with CD28. The increased IL-2 expression in the presence of CD28 indicates that the surrogate coreceptor (SCR) enhances pMHCR-CD3 signaling.
[0036] FIG. 6 shows TCR-specific killing of CD4 T cells by redirected CTLs. Purified CD8 T cells from B10.A mice were activated in vitro and transduced with a MCC:I-E.sup.k pMHCR (agonist) or an HB:I-E.sup.k pMHCR (null) as well as a CD80-Lck surrogate coreceptor. The redirected CTLs were then co-cultured at the indicated ratios with naive ex vivo 5c.c7 TCR transgenic CD4 T cells overnight. Killing was evaluated by flow cytometry using count beads relative to the 0:1 samples.
DETAILED DESCRIPTION OF THE INVENTION
[0037] Chimeric MHC Receptors (MHCRs)
[0038] The present invention features chimeric receptors (e.g., "MHCRs") comprising at least a MHC portion (e.g., class I, class II, non-classical, a combination thereof, etc.) and a TCR portion (e.g., .alpha..beta., .gamma..delta. TCR, etc.) (see FIG. 2B(i)). For example, the MHCR may comprise a MHC portion and a TCR portion, a MHC and a TCR portion optionally separated by a linker (see FIG. 2B (iii) and (iv)). A linker may be any appropriate linker such as but not limited to a peptide linker. In some embodiments, the MHCR further comprises a peptide antigen (see FIG. 2B (ii)); a MHCR comprising a peptide antigen may herein be referred to as a "pMHCR". Note that MHC portions and/or TCR portions may be from any appropriate species including but not limited to human, monkey, mouse, rat, rabbit, or the like, e.g., any other appropriate mammalian species. The components and configurations of the MHRCs of the present invention are not limited to those shown in FIG. 2B. For example, the MHCR may comprise a TCR portion and a MHC portion; a TCR portion and a MHC portion separated by a linker; a TCR portion and a MHC portion and an antigen portion; a TCR portion and a MHC portion and an antigen portion, wherein the TCR portion and MHC portion are separated by a linker; a TCR portion and a MHC portion and an antigen portion, wherein the MHC portion and antigen portion are separated by a linker; a TCR portion and a MHC portion and an antigen portion, wherein the TCR and MHC portion are separated by a linker and the MHC portion and the antigen portion are separate by a linker; etc.
[0039] The MHC portion may comprise one or more MHC proteins (e.g., HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1), one or more fragments thereof, or combinations thereof. For reference, non-limiting MHC sequences (human, mouse) are listed below in Table 1.1 and Table 1.2. Note that MHC genes are highly polymorphic, and thus the present invention is not limited to the sequences in Table 1.1 And Table 1.2. The present invention includes MHC polymorphisms and any other appropriate variant of MHC proteins.
TABLE-US-00001 TABLE 1.1 Examples of Human MHC Protein Sequences SEQ ID NO. Description Amino Acid Sequence 1 Uniprot P01891 MAVMAPRTLV LLLSGALALT QTWAGSHSMR HLA-A gene YFYTSVSRPG RGEPRFIAVG YVDDTQFVRF (MHC I) DSDAASQRME PRAPWIEQEG PEYWDRNTRN VKAQSQTDRV DLGTLRGYYN QSEAGSHTIQ MMYGCDVGSD GRFLRGYRQD AYDGKDYIAL KEDLRSWTAA DMAAQTTKHK WEAAHVAEQW RAYLEGTCVE WLRRYLENGK ETLQRTDAPK THMTHHAVSD HEATLRCWAL SFYPAEITLT WQRDGEDQTQ DTELVETRPA GDGTFQKWVA VVVPSGQEQR YTCHVQHEGL PKPLTLRWEP SSQPTIPIVG IIAGLVLFGA VITGAVVAAV MWRRKSSDRK GGSYSQAASS DSAQGSDVSL TACKV 2 Uniprot P18464 MRVTAPRTVL LLLWGAVALT ETWAGSHSMR HLA-B gene YFYTAMSRPG RGEPRFIAVG YVDDTQFVRF (MHC I) DSDAASPRTE PRAPWIEQEG PEYWDRNTQI FKTNTQTYRE NLRIALRYYN QSEAGSHTWQ TMYGCDVGPD GRLLRGHNQY AYDGKDYIAL NEDLSSWTAA DTAAQITQRK WEAAREAEQL RAYLEGLCVE WLRRHLENGK ETLQRADPPK THVTHHPVSD HEATLRCWAL GFYPAEITLT WQRDGEDQTQ DTELVETRPA GDRTFQKWAA VVVPSGEEQR YTCHVQHEGL PKPLTLRWEP SSQSTIPIVG IVAGLAVLAV VVIGAVVATV MCRRKSSGGK GGSYSQAASS DSAQGSDVSL TA 3 Uniprot Q29963 MRVMAPRTLI LLLSGALALT ETWACSHSMR HLA-C gene YFDTAVSRPG RGEPRFISVG YVDDTQFVRF (MHC I) DSDAASPRGE PRAPWVEQEG PEYWDRETQK YKRQAQADRV NLRKLRGYYN QSEDGSHTLQ WMYGCDLGPD GRLLRGYDQS AYDGKDYIAL NEDLRSWTAA DTAAQITQRK WEAAREAEQW RAYLEGTCVE WLRRYLENGK ETLQRAEHPK THVTHHPVSD HEATLRCWAL GFYPAEITLT WQRDGEDQTQ DTELVETRPA GDGTFQKWAA VVVPSGEEQR YTCHVQHEGL PEPLTLRWEP SSQPTIPIVG IVAGLAVLAV LAVLGAVMAV VMCRRKSSGG KGGSCSQAAS SNSAQGSDES LIACKA 4 Uniprot P20036 MRPEDRMFHI RAVILRALSL AFLLSLRGAG HLA DPA1 AIKADHVSTY AAFVQTHRPT GEFMFEFDED (MHC II) EMFYVDLDKK ETVWHLEEFG QAFSFEAQGG LANIAILNNN LNTLIQRSNH TQATNDPPEV TVFPKEPVEL GQPNTLICHI DKFFPPVLNV TWLCNGELVT EGVAESLFLP RTDYSFHKFH YLTFVPSAED FYDCRVEHWG LDQPLLKHWE AQEPIQMPET TETVLCALGL VLGLVGIIVG TVLIIKSLRS GHDPRAQGTL 5 Uniprot P04440 MMVLQVSAAP RTVALTALLM VLLTSVVQGR HLA DPB1 ATPENYLFQG RQECYAFNGT QRFLERYIYN (MHC II) REEFARFDSD VGEFRAVTEL GRPAAEYWNS QKDILEEKRA VPDRMCRHNY ELGGPMTLQR RVQPRVNVSP SKKGPLQHHN LLVCHVTDFY PGSIQVRWFL NGQEETAGVV STNLIRNGDW TFQILVMLEM TPQQGDVYTC QVEHTSLDSP VTVEWKAQSD SARSKTLTGA GGFVLGLIIC GVGIFMHRRS KKVQRGSA 6 Uniprot P01909 MILNKALMLG ALALTTVMSP CGGEDIVADH HLA DQA1 VASYGVNLYQ SYGPSGQYTH EFDGDEQFYV (MHC II) DLGRKETVWC LPVLRQFRFD PQFALTNIAV LKHNLNSLIK RSNSTAATNE VPEVTVFSKS PVTLGQPNIL ICLVDNIFPP VVNITWLSNG HSVTEGVSET SFLSKSDHSF FKISYLTLLP SAEESYDCKV EHWGLDKPLL KHWEPEIPAP MSELTETVVC ALGLSVGLVG IVVGTVFIIR GLRSVGASRH QGPL 7 Uniprot P01920 MSWKKALRIP GGLRAATVTL MLAMLSTPVA HLA DQB1 EGRDSPEDFV YQFKAMCYFT NGTERVRYVT (MHC II) RYIYNREEYA RFDSDVEVYR AVTPLGPPDA EYWNSQKEVL ERTRAELDTV CRHNYQLELR TTLQRRVEPT VTISPSRTEA LNHHNLLVCS VTDFYPAQIK VRWFRNDQEE TTGVVSTPLI RNGDWTFQIL VMLEMTPQHG DVYTCHVEHP SLQNPITVEW RAQSESAQSK MLSGIGGFVL GLIFLGLGLI IHHRSQKGLL H 8 Uniprot P01903 MAISGVPVLG FFIIAVLMSA QESWAIKEEH VIIQAEFYLN HLA DRA gene PDQSGEFMFD FDGDEIFHVD MAKKETVWRL (MHC II) EEFGRFASFE AQGALANIAV DKANLEIMTK RSNYTPITNV PPEVTVLTNS PVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLP STEDVYDCRV EHWGLDEPLL KHWEFDAPSP LPETTENVVC ALGLTVGLVG IIIGTIFIIK GVRKSNAAER RGPL 9 Uniprot Q30167 MVCLRLPGGS CMAVLTVTLM VLSSPLALAG HLA DRB1 gene DTRPRFLEEV KFECHFFNGT ERVRLLERRV (MHC II) HNQEEYARYD SDVGEYRAVT ELGRPDAEYW NSQKDLLERR RAAVDTYCRH NYGVGESFTV QRRVQPKVTV YPSKTQPLQH HNLLVCSVNG FYPGSIEVRW FRNGQEEKTG VVSTGLIQNG DWTFQTLVML ETVPQSGEVY TCQVEHPSVM SPLTVEWRAR SESAQSKMLS GVGGFVLGLL FLGAGLFIYF RNQKGHSGLP PTGFLS
TABLE-US-00002 TABLE 1.2 Examples of Mouse MHC Protein Sequences SEQ ID NO. Description Amino Acid Sequence 10 Uniprot Q9TQ72 RSRALILGVL ALTTMLSLCG GEDYIEADHV MHC II antigen IE AFYGISVYQS PGDIGQYTFE FDGDELFYVD alpha (H2-Aa) LDKKETVWML PEFGQLTSFD PQGGLQEIAT GKYNLEILIK DSNFTPAANE APQATVFPKS PVLLGQPNTL ICFVDNIFPP VINITWLRNS KSVTDGVYET SFLVNRDHSF HKLSYLTFIP SDDDIYDCKV EHWGLEEPVL KHWEPEIPAP MSELTETVIC ALGLSVGLVG IVVGTIFIIQ GLRSGGTSRH 11 Uniprot O19440 MAQRTLFLLL AAALTMIETR AGPHSMRYFE MHC I antigen TAVFRPGLGE PRFISVGYVD NTQFVSFDSD (H2-B1) AENPRSEPRA PWMEQEGPEY WERETQIAKD NEQSFGWSLR NLIHYYNQSK GGFHTFQRLS GCDMGLDGRL LRGYLQFAYD GRDYITLNED LKTWMAADLV ALITRRKWEQ AGAAELYKFY LEGECVEWLR RYLELGNETL LRTDPPKAHV THHPRPAGDV TLRCWALGFY PADITLTWQL NGEELTQDME LVETRPAGDG TFQKWAAVVV PLGKEQNYTC HVYHEGLPEP LTLRWEPPPS TGSNMVNIAV LVVLGAVIII EAMVAFVLKS SRKIAILPGP AGTKGSSAS 12 Uniprot Q31191 MAPCTLLLLL AAALAPTQTR AARAAARGPV MHC I H2-K gene RRSGSHRAPP PGPHSLSDAD NPRFEPRAPW (Haplotype d) MEQEGPEYWE EQTQRAKSDE QWFRVSLRTA (H2-K1) QRYYNQSKGG SHTFQRMFGC DVGSDWRLLR GYQQFAYDGR DYIALNEDLK TWTAADTAAL ITRRKWEQAG DAEYYRAYLE GECVEWLRRY LELGNETLLR TDSPKAHVTY HPRSQVDVTL RCWALGFYPA DITLTWQLNG EDLTQDMELV ETRPAGDGTF QKWAAVVVPL GKEQNYTCHV HHKGLPEPLT LRWKLPPPTV SNTVIIAVLV VLGAAIVTGA VVAFVMKMRR NTGGKGVNYA LAPGSQTSDL SLPDGKVMVH 13 Uniprot P04230 MVWLPRVPCV AAVILLLTVL SPPMALVRDS H2 Class II RPWFLEYCKS ECHFYNGTQR VRLLERYFYN histocompatibility LEENLRFDSD VGEFHAVTEL GRPDAENWNS antigen E-B beta QPEFLEQKRA EVDTVCRHNY EISDKFLVRR chain RVEPTVTVYP TKTQPLEHHN LLVCSVSDFY PGNIEVRWFR NGKEEKTGIV STGLVRNGDW TFQTLVMLET VPQSGEVYTC QVEHPSLTDP VTVEWKAQST SAQNKMLSGV GGFVLGLLFL GAGLFIYFRN QKGQSGLQPT GLLS 14 Uniprot P04224 MATIGALVLR FFFIAVLMSS QKSWAIKEEH MHC II E-K alpha TIIQAEFYLL PDKRGEFMFD FDGDEIFHVD chain IEKSETIWRL EEFAKFASFE AQGALANIAV (underlined portion is DKANLDVMKE RSNNTPDANV APEVTVLSRS portion used in SEQ PVNLGEPNIL ICFIDKFSPP VVNVTWLRNG ID NO: 30) RPVTEGVSET VFLPRDDHLF RKFHYLTFLP STDDFYDCEV DHWGLEEPLR KHWEFEEKTL LPETKENVVC ALGLFVGLVG IVVGIILIMK GIKKRNVVER RQGAL 15 GenBank ID: MWLPRVPCVAAVILLLTVLSPPVALVRDSRPWFLEY M36939.1 CKSECHFYNGTQRVRLLVRYFYNLEENLRFDSDV MHC II E-K beta GEFRAVTELGRPDAENWNSQPEFLEQKRAEVD chain TVCRHNYEIFDNFLVPRRVEPTVWYPTKTQPLEH (underlined portion is HNLLVCSVSDFYPGNIEVRWFRNGKEEKTGIVSTG used in SEQ ID NO: LVRNGDVVTFQTLVMLETVPQSGEVYTCQVEHPSL 31, 32) TDPVTVEWKAQSTSAQNKMLSGVGGFVLGLLFLG AGLFIYFRNQKGQSGLQPTGLLS
[0040] Referring to Table 1.1, the HLA-A (MHC 1) sequence (SEQ ID NO: 1) includes the signal peptide (amino acids 1-24); amino acids 25-308 are believed to make up the extracellular region, amino acids 309-332 are believed to make up the transmembrane region, and amino acids 333-365 are believed to make up the cytoplasmic region. The HLA-B (MHC 1) sequence (SEQ ID NO: 2) includes the signal peptide (amino acids 1-24); amino acids 25-308 are believed to make up the extracellular region, amino acids 309-332 are believed to make up the transmembrane region, and amino acids 333-362 are believed to make up the cytoplasmic region. The HLA-C(MHC 1) sequence (SEQ ID NO: 3) includes the signal peptide (amino acids 1-24); amino acids 25-308 are believed to make up the extracellular region, amino acids 309-333 are believed to make up the transmembrane region, and amino acids 334-366 are believed to make up the cytoplasmic region. The HLA DPA1 (MHC II) sequence (SEQ ID NO: 4) includes the signal peptide (amino acids 1-28); amino acids 29-222 are believed to make up the extracellular region, amino acids 223-245 are believed to make up the transmembrane region, and amino acids 246-260 are believed to make up the cytoplasmic region. The HLA DPB1 (MHC II) sequence (SEQ ID NO: 5) includes the signal peptide (amino acids 1-29); amino acids 30-225 are believed to make up the extracellular region, amino acids 226-246 are believed to make up the transmembrane region, and amino acids 247-258 are believed to make up the cytoplasmic region. The HLA DQA1 (MHC 11) sequence (SEQ ID NO: 6) includes the signal peptide (amino acids 1-23); amino acids 24-216 are believed to make up the extracellular region, amino acids 217-239 are believed to make up the transmembrane region, and amino acids 240-254 are believed to make up the cytoplasmic region. The HLA DQB1 (MHC II) sequence (SEQ ID NO: 7) includes the signal peptide (amino acids 1-32); amino acids 33-230 are believed to make up the extracellular region, amino acids 231-251 are believed to make up the transmembrane region, and amino acids 252-261 are believed to make up the cytoplasmic region. The HLA DRA (MHC II) sequence (SEQ ID NO: 8) includes the signal peptide (amino acids 1-25); amino acids 26-216 are believed to make up the extracellular region, amino acids 217-239 are believed to make up the transmembrane region, and amino acids 240-254 are believed to make up the cytoplasmic region. The HLA DRB1 (MHC II) sequence (SEQ ID NO: 9) includes the signal peptide (amino acids 1-29); amino acids 30-227 are believed to make up the extracellular region, amino acids 228-250 are believed to make up the transmembrane region, and amino acids 251-266 are believed to make up the cytoplasmic region. The MHC E-K alpha chain (SEQ ID NO: 14) includes the signal peptide (aa 1-25), the extracellular domain (aa 26-216), the transmembrane domain (aa 217-24), and a cytoplasmic portion (aa 243-255).
[0041] As previously discussed, the MHCR of the present invention comprises at least a MHC portion and a TCR portion. In some embodiments, a MHC portion comprises one or more MHC proteins (e.g., HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1, MHC E-K alpha, MHC E-K beta, etc.), fragments thereof, or combinations thereof. For example, in some embodiments, the MHC portion comprises a fragment of any of SEQ ID NO: 1-15.
[0042] In some embodiments, the MHC portion comprises a peptide that is at least 80% identical to a MHC protein or a fragment thereof. In some embodiments, the MHC portion comprises a peptide that is at least 85% identical to a MHC protein or a fragment thereof. In some embodiments, the MHC portion comprises a peptide that is at least 90% identical to a MHC protein or a fragment thereof. In some embodiments, the MHC portion comprises a peptide that is at least 95% identical to a MHC protein or a fragment thereof. In some embodiments, the MHC portion comprises a peptide that is at least 99% identical to a MHC protein or a fragment thereof.
[0043] In some embodiments, a fragment of a MHC protein is from 10 to 25 aa in length. In some embodiments, a fragment of a MHC protein is from 10 to 50 aa in length. In some embodiments, a fragment of a MHC protein is from 10 to 100 aa in length. In some embodiments, a fragment of a MHC protein is from 10 to 150 aa in length. In some embodiments, a fragment of a MHC protein is from 10 to 200 aa in length. In some embodiments, a fragment of a MHC protein is from 10 to 250 aa in length. In some embodiments, a fragment of a MHC protein is from 10 to 300 aa in length. In some embodiments, a fragment of a MHC protein is from 10 to 350 aa in length. In some embodiments, a fragment of a MHC protein is from 25 to 50 as in length. In some embodiments, a fragment of a MHC protein is from 25 to 100 aa in length. In some embodiments, a fragment of a MHC protein is from 25 to 150 aa in length. In some embodiments, a fragment of a MHC protein is from 25 to 200 aa in length. In some embodiments, a fragment of a MHC protein is from 25 to 250 aa in length. In some embodiments, a fragment of a MHC protein is from 25 to 300 aa in length. In some embodiments, a fragment of a MHC protein is from 25 to 350 aa in length. In some embodiments, a fragment of a MHC protein is from 50 to 100 aa in length. In some embodiments, a fragment of a MHC protein is from 50 to 150 aa in length. In some embodiments, a fragment of a MHC protein is from 50 to 200 aa in length. In some embodiments, a fragment of a MHC protein is from 50 to 250 aa in length. In some embodiments, a fragment of a MHC protein is from 50 to 300 as in length. In some embodiments, a fragment of a MHC protein is from 50 to 350 aa in length. In some embodiments, a fragment of a MHC protein is from 100 to 150 aa in length. In some embodiments, a fragment of a MHC protein is from 100 to 200 aa in length. In some embodiments, a fragment of a MHC protein is from 100 to 250 aa in length. In some embodiments, a fragment of a MHC protein is from 100 to 300 as in length. In some embodiments, a fragment of a MHC protein is from 100 to 350 aa in length. In some embodiments, a fragment of a MHC protein is from 150 to 200 aa in length. In some embodiments, a fragment of a MHC protein is from 150 to 250 aa in length. In some embodiments, a fragment of a MHC protein is from 150 to 300 as in length. In some embodiments, a fragment of a MHC protein is from 150 to 350 aa in length. In some embodiments, a fragment of a MHC protein is from 200 to 250 as in length. In some embodiments, a fragment of a MHC protein is from 200 to 300 as in length. In some embodiments, a fragment of a MHC protein is from 200 to 350 as in length. In some embodiments, a fragment of a MHC protein is from 250 to 300 aa in length. In some embodiments, a fragment of a MHC protein is from 250 to 350 as in length. In some embodiments, a fragment of a MHC protein is more than 350 aa in length.
[0044] A TCR portion may comprise one or more TCR proteins (e.g., TCRA, TCRB), one or more fragments thereof, or combinations thereof. For reference, non-limiting TCR sequences (human and mouse) are listed below in Table 2.1 and Table 2.2. The present invention is not limited to the TCR sequences in Table 2.1 and Table 2.2.
TABLE-US-00003 TABLE 2.1 Examples of Human TCR Protein Sequences SEQ ID NO. Description Amino Acid Sequence 16 Uniprot P01848 PNIQNPDPAV YQLRDSKSSD KSVCLFTDFD T cell receptor SQTNVSQSKD SDVYITDKTV LDMRSMDFKS alpha chain NSAVAWSNKS DFACANAFNN SIIPEDTFFP constant region SPESSCDVKL VEKSFETDTN LNFQNLSVIG (TRAC, TCRA) FRILLLKVAG FNLLMTLRLW SS 17 Uniprot P01850 EDLNKVFPPE VAVFEPSEAE ISHTQKATLV T cell receptor CLATGFFPDH VELSWWVNGK EVHSGVSTDP beta-1 chain QPLKEQPALN DSRYCLSSRL RVSATFWQNP constant region RNHFRCQVQF YGLSENDEWT QDRAKPVTQI (TRBC1) VSAEAWGRAD CGFTSVSYQQ GVLSATILYE ILLGKATLYA VLVSALVLMA MVKRKDF 18 Uniprot A0A5B9 DLKNVFPPEV AVFEPSEAEI SHTQKATLVC T cell receptor LATGFYPDHV ELSWWVNGKE beta-2 chain VHSGVSTDPQ PLKEQPALND SRYCLSSRLR constant region VSATFWQNPR NHFRCQVQFY (TRBC2, GLSENDEWTQ DRAKPVTQIV SAEAWGRADC TCRBC2) GFTSESYQQG VLSATILYEI LLGKATLYAV LVSALVLMAM VKRKDSRG 19 Uniprot B7Z8K6 SQPHTKPSVF VMKNGTNVAC LVKEFYPKDI T cell receptor RINLVSSKKI TEFDPAIVIS PSGKYNAVKL delta chain GKYEDSNSVT CSVQHDNKTV HSTDFEVKTD constant region STDHVKPKET ENTKQPSKSC HKPKAIVHTE (TRDC) KVNMMSLTVL GLRMLFAKTV AVNFLLTAKL FFL 20 Uniprot P0CF51 DKQLDADVSP KPTIFLPSIA ETKLQKAGTY T cell receptor LCLLEKFFPD VIKIHWQEKK SNTILGSQEG gamma-1 chain NTMKTNDTYM KFSWLTVPEK SLDKEHRCIV constant region RHENNKNGVD QEIIFPPIKT DVITMDPKDN (TRGC1) CSKDANDTLL LQLTNTSAYY MYLLLLLKSV VYFAIITCCL LRRTAFCCNG EKS 21 Uniprot P03986 DKQLDADVSP KPTIFLPSIA ETKLQKAGTY T cell receptor LCLLEKFFPD IIKIHWQEKK SNTILGSQEG gamma-2 chain NTMKTNDTYM KFSWLTVPEE SLDKEHRCIV constant region RHENNKNGID QEIIFPPIKT DVTIVDPKDS (TRGC2, YSKDANDVIT MDPKDNWSKD ANDTLLLQLT TCRGC2) NTSAYYMYLL LLLKSVVYFA IITCCLLGRT AFCCNGEKS
TABLE-US-00004 TABLE 2.2 Examples of Mouse TCR Protein Sequences SEQ ID NO. Description Amino Acid Sequence 22 Uniprot P01849 PYIQNPEPAV YQLKDPRSQD STLCLFTDFD T cell receptor alpha SQINVPKTME SGTFITDKTV LDMKAMDSKS chain constant region NGAIAWSNQT SFTCQDIFKE TNATYPSSDV (TCRA-mouse) PCDATLTEKS FETDMNLNFQ NLSVMGLRIL (underlined portion LLKVAGFNLL MTLRLWSS refers to sequence also used in SEQ ID NO: 30) 23 Uniprot P01852 EDLRNVTPPK VSLFEPSKAE IANKQKATLV T cell receptor beta-1 CLARGFFPDH VELSWWVNGK EVHSGVSTDP chain constant region QAYKESNYSY CLSSRLRVSATFWHNPRNHF (TCB1-mouse) RCQVQFHGLS EEDKWPEGSP KPVTQNISAE AWGRADCGIT SASYQQGVLS ATILYEILLG KATLYAVLVS TLVVMAMVKR KNS 24 Uniprot P01851 EDLRNVTPPK VSLFEPSKAE IANKQKATLV T cell receptor beta-2 CLARGFFPDH VELSWWVNGK EVHSGVSTDP chain constant region QAYKESNYSY CLSSRLRVSA TFWHNPRNHF (TCB2-mouse) RCQVQFHGLS EEDKWPEGSP KPVTQNISAE (underlined portion AWGRADCGIT SASYHQGVLS ATILYEILLG refers to sequence used KATLYAVLVS GLVLMAMVKK KNS in SEQ ID NO: 31, 32) 25 Uniprot P01853 DKRLDADISP KPTIFLPSVA ETNLHKTGTY T cell receptor gamma LCLLEKFFPD VIRVYWKEKN GNTILDSQEG chain constant region DTLKTKGTYM KFSWLTVPER AMGKEHSCIV C10.5 (TCC1-mouse) KHENNKGGAD QEIFFPSIKK VATTCWQDKN DVLQFQFTST SAYYTYLLLL LKSVIYLAII SFSLLRRTSV CGNEKKS 26 Uniprot P03985 DKKLDADISP KPTIFLPSVA ETNLHKTGTY T cell receptor gamma LCVLEKFFPD VIRVYWKEKK GNTILDSQEG chain constant region DMLKTNDTYM KFSWLTVPER SMGKEHRCIV C7.5 (TCC2-mouse) KHENNKGGAD QEIFFPTIKK VAVSTKPTTC WQDKNDVLQL QFTITSAYYT YLLLLLKSVI YLAIISFSLL RRTSVCCNEK KS 27 Uniprot P06334 PSDKRLDADI SPKPTIFLPS VAETNLHKTG T cell receptor gamma TYLCILEKFF PDVIRVYWKD KNGNTILDSQ chain constant region EGDTLKTKGT YMKFSWLTVP ERSMGKEHRC DFL12 (TCC3-mouse) IVKHENNKGG ADQEIFFPSI KKVATTCWQD KNDVLQLQFM STSAYYTYLL LLLKSVIYLA IISFSLLRRT SVCCNEKRS 28 Uniprot P06335 DKRTDSDFSP KPTIFLPSAA ETNLHKAGTY T cell receptor gamma LCLLEKFFPK VIRVYWKEKD GEKILESQEG chain constant region NTIKTNDRYM KFSWLTVTED SMAKEHSCIV 5/10-13 (TCC4-mouse) KHENNKRGVD QEILFPPIGK AFTTINVNPR DSVLRHENVN NATDLEDCMK GRKDMLQLQV TTTYAFYTYL ILFFKSMVHL AFVVFCLFRR AAMSCDDQRS
[0045] Referring to the TRAC protein (SEQ ID NO: 16) in Table 2, amino acids 118-137 are believed to make up the transmembrane domain, and amino acids 138-142 are believed to make up the cytoplasmic domain. Referring to the TRBC1 protein (SEQ ID NO: 17) in Table 2, amino acids 151-171 are believed to make up the transmembrane domain. Referring to the TRBC2 protein (SEQ ID NO: 18) in Table 2, amino acids 145-167 are believed to make up the transmembrane domain. Referring to the TRDC protein (SEQ ID NO: 19) in Table 2, amino acids 130-152 are believed to make up the transmembrane domain. Referring to the TRGC1 protein (SEQ ID NO: 20) in Table 2, amino acids 139-161 are believed to make up the transmembrane domain. Referring to the TRGC2 protein (SEQ ID NO: 21) in Table 2, amino acids 157-177 are believed to make up the transmembrane domain, and amino acids 178-189 are believed to make up the cytoplasmic domain.
[0046] As previously discussed, the MHCR of the present invention comprises at least a MHC portion and a TCR portion. In some embodiments, a TCR portion comprises one or more TCR proteins (e.g., TRAC, TRBC1, TRBC2, TRDC, TRCG1, TRCG2, TCRA-mouse, TCB1-mouse, TCB2-mouse, TCC1-mouse, TCC2-mouse, TCC3 mouse, TCC4 mouse, etc.), fragments thereof, or combinations thereof. For example, in some embodiments, the TCR portion comprises a fragment of any of SEQ ID NO: 16-28. (In some embodiments, the fragment is from 5 to 10 aa in length. In some embodiments, the fragment is from 10 to 20 aa in length, in some embodiments, the fragment is from 10 to 30 aa in length. IN some embodiments, the fragment is from 10 to 40 aa in length. In some embodiments, the fragment is from 10 to 50 aa in length, etc.
[0047] In some embodiments, the TCR portion comprises a peptide that is at least 80% identical to a TCR protein (e.g., any of SEQ ID NO: 16-28), or a fragment thereof. In some embodiments, the TCR portion comprises a peptide that is at least 85% identical to a TCR protein (e.g., any of SEQ ID NO: 16-28), or a fragment thereof. In some embodiments, the TCR portion comprises a peptide that is at least 90% identical to a TCR protein (e.g., any of SEQ ID NO: 16-28), or a fragment thereof. In some embodiments, the TCR portion comprises a peptide that is at least 95% identical to a TCR protein (e.g., any of SEQ ID NO: 16-28), or a fragment thereof. In some embodiments, the TCR portion comprises a peptide that is at least 99% identical to a TCR protein (e.g., any of SEQ ID NO: 16-28), or a fragment thereof.
[0048] In some embodiments, a fragment of a TCR protein is from 10 to 25 aa in length. In some embodiments, a fragment of a TCR protein is from 10 to 50 as in length. In some embodiments, a fragment of a TCR protein is from 10 to 100 aa in length. In some embodiments, a fragment of a TCR protein is from 10 to 150 aa in length. In some embodiments, a fragment of a TCR protein is from 25 to 50 aa in length. In some embodiments, a fragment of a TCR protein is from 25 to 100 aa in length. In some embodiments, a fragment of a TCR protein is from 25 to 150 aa in length. In some embodiments, a fragment of a TCR protein is from 50 to 100 aa in length. In some embodiments, a fragment of a TCR protein is from 50 to 150 aa in length. In some embodiments, a fragment of a TCR protein is from 100 to 150 as in length. In some embodiments, a fragment of a TCR protein is more than 150 aa in length.
[0049] In some embodiments, the MHCR comprises a peptide antigen. Any appropriate peptide antigen may be used. The peptide antigen in the pMHCR complex directs the specificity of the pMHCR molecule, therefore the pMHCR molecule will be specific for T cells with TCRs that are specific for that peptide antigen/pMHCR. A non-limiting example of a peptide antigen that may be used with the MHCR is moth cytochrome c peptide (aa 88-103, ANERADLIAYLKQATK (SEQ ID NO: 29)). The peptide antigens used in the Examples (see below) are peptides commonly used as model antigens in mouse models. Any appropriate peptide antigen may be used, and the present invention is not limited to the peptide antigens disclosed herein. For example, in some embodiments, the peptide antigen comprises any immunodominant peptide antigen identified to bind a class I or class 11 MHC. In some embodiments, the peptide antigen comprises any immunodominant peptide antigen identified to bind a class I or class II MHC and elicit a response. A response may include but is not limited to an autoimmune response, an allergic response, an asthma response, or an inappropriate Treg response. The peptide antigen may be any appropriate length.
[0050] In some embodiments, the MHCR comprises at least a portion of a MHC molecule that allows for binding to an appropriate TCR. In some embodiments, the MHCR comprises at least a portion of a MHC molecule that allows for binding to an appropriate TCR and at least a portion of a TCR molecule (e.g., a portion of a TCR molecule that allows for appropriate signaling and/or complexing subunits such as CD3 subunits). In some embodiments, the MHCR comprises a transmembrane domain that is at least partially derived from (i) a MHC molecule, (ii) a TCR molecule, or (iii) both the MHC molecule and TCR molecule. In some embodiments, the MHCR comprises a transmembrane domain, wherein a portion (or all) of the transmembrane domain is not derived from a MHC molecule or a TCR molecule. In some embodiments, the MHCR comprises an extracellular domain that is at least partially derived from (i) a MHC molecule, (ii) a TCR molecule, or (iii) both the MHC molecule and TCR molecule. In some embodiments, the MHCR comprises an extracellular domain, wherein a portion of the extracellular domain is not derived from a MHC molecule or a TCR molecule.
[0051] As an example, in some embodiments, the MHCR comprises at least a portion of the extracellular domain of a MHC molecule (e.g., the extracellular domain of HLA-DRA) and at least a portion of the transmembrane domain of a TCR molecule and at least a portion of the cytoplasmic domain of a TCR molecule. As another example, in some embodiments, the MHCR comprises at least a portion of the extracellular domain of a TCR molecule.
[0052] The present invention also features redirected cells, such as redirected T cells, expressing MHCRs of the present invention, e.g., as described above. Without wishing to limit the present invention to any theory or mechanism, the MHCRs are generally adapted to recognize and bind to appropriate (specific) TCRs. In some embodiments, the MHCR is expressed in a CD8+ T cell (e.g., a cytotoxic T cell, T.sub.C cells, CTLs). In some embodiments, the MHCR is expressed in a CD4+ T cell (e.g., a T helper cell, T.sub.H cell or a regulatory T cell (Treg cell)). The present invention is not limited to the expression of MHCRs in T cells, nor is the present invention limited to expression of MHCRs in CD8+ or CD4+ T cells, e.g., the MHCRs may be expressed in CD8+/CD4+ thymocytes, .gamma..delta.T cells, NK cells, NK T cells, etc. In some embodiments, the MHCR of the redirected T cell complexes or is adapted to complex with CD3 subunits (e.g., forming a MHCR-CD3 complex).
[0053] In some embodiments, the MHCR comprises a MHC portion derived from an extracellular portion of a MHC protein and a TCR portion derived from a transmembrane domain of a TCR protein. In some embodiments, the MHC portion and TCR portion are directly linked. In some embodiments, the MHC portion and TCR portion are separated by a linker. In some embodiments, the linker comprises a glycine-rich linker.
[0054] The present invention is not limited to the MHC portions and TCR portions described herein. For example, the MHC portion may comprise any MHC peptide, e.g., an extracellular domain (or a portion thereof) of any MHC peptide. The TCR portion may comprise any TCR peptide, e.g., a transmembrane domain (or portion thereof) of any TCR peptide. Further, the present invention is not limited to antigens, signaling molecules, and cell surface receptor ligands described herein, e.g., the present invention may be applicable to a wide range of MHC molecules, TCR molecules, antigens, signaling molecules cell surface receptor ligands, etc.
Surrogate Coreceptors (SCRs)
[0055] The present invention also features chimeric surrogate coreceptors (SCR), e.g., receptors that recruit signaling molecules (e.g., kinases such as but not limited to Src kinases (e.g., Lck), phosphatases, etc.). In some embodiments, the SRCs recruit signaling molecules (e.g., kinases) to the MHCR and/or CD3 subunits. The present invention also features cells expressing a SCR. In some embodiments, redirected cells, e.g., redirected T cells, express both a MHCR and a SCR. In some embodiments, cells express more than one type of SCR. Without wishing to limit the present invention to any theory or mechanism, it is believed that certain SCRs may enhance signaling through the pMHCR-CD3 complex.
[0056] In some embodiments, the SCR comprises a cell surface receptor ligand (e.g., T cell surface receptor ligand) fused to a signaling molecule (e.g., kinase (e.g., Lck or other appropriate kinase), phosphatase, etc.). In some embodiments, the cell surface receptor ligand and the kinase are separated by a linker, e.g., a peptide linker or any other appropriate linker. The signaling molecule is not limited to a kinase or a phosphatase.
[0057] In some embodiments, the cell surface receptor ligand (e.g., T cell surface receptor ligand) comprises CD80, CD86, fragments thereof, or combinations thereof. The present invention is not limited to CD80 and CD86; any other appropriate cell surface receptor ligand (or a fragment thereof) may be used. For example, in some embodiments, the cell surface receptor ligand comprises a CD28 ligand, a CTLA-4 ligand, an ICOS ligand, an OX40 ligand, a PD-1 ligand (e.g., PD-1L), a CD2 ligand, etc.
[0058] As an example, in some embodiments, when a T cell is expressing a pMHCR (a MHCR with a peptide antigen), the pMHCR may complex with CD3 subunits, forming a pMHCR-CD3 complex. If the cell is also expressing a CD80-Lck SCR, then when the pMHCR binds a TCR on a target T cell, the CD80-Lck may also bind to CD28 on the same target T cell. Without wishing to limit the present invention to any theory or mechanism, it is believed that then the CD80-Lck SCR should recruit Lck to the pMHCR-CD3 complex to phosphorylate the pMHCR-CD3 ITAMs for robust signaling.
[0059] In some embodiments, the SCR is engineered (e.g., a particular cell surface receptor ligand of the SCR is selected) to target a specific set of target cells. For example, T follicular helper cells express a molecule called PD-1 and these cells provide help to B cells to make autoantibodies in autoimmune diseases such as Lupus. The ligand for PD-1 is PD-1L, so a SCR comprising PD-1L and Lck may be co-expressed with a pMHCR recognized by the TCR of the T follicular helper cell. This may allow for targeting of this specific T follicular helper cell population.
[0060] The present invention also features methods of use of said MHCRs, SCRs, and/or said redirected cells, for example for immunotherapy. In some embodiments, the redirected cells may eliminate autoreactive T cells, regulatory T cells (Tregs) that protect tumor cells by suppressing anti-tumor T cell responses, or any other appropriate T cell. For example, in some embodiments, the MHCR is an auto-antigen MHCR, and the MHCR's target is an autoreactive T cell.
Examples
[0061] Example 1: Redirected T cells targeting CD4 T Helper Cells. Example 1 describes a non-limiting experimental approach to target CD4 T cells. A prototype pMHCR was engineered with a peptide antigen: the moth cytochrome c peptide (SEQ ID NO: 29) was fused to the mouse class II MHC I-E.sup.k (MCC:I-E.sup.k; e.g., see SEQ ID NO: 31). This pMHCR was expressed (e.g., retrovirally expressed) in T cell hybridomas. It was determined that this pMHCR (e.g., pMHCR-CD3 complex) was expressed on the surface of T cell hybridomas (see FIG. 4). IL-2 production was induced after interactions with cognate TCRs (e.g., 5c.c7, 2B4), yet an irrelevant peptide (control peptide antigen) in the pMHCR-CD3 complex rendered it non-stimulatory (data not shown).
[0062] Lck fusions were generated with known ligands for T cell surface receptors. For example, all T cells express CD28. Lck fusions with CD28 ligands (e.g., CD80, CD86) were engineered to generate surrogate coreceptors (SCRs), e.g., CD80-Lck (see SEQ ID NO: 33, SEQ ID NO: 38), e.g., CD86-Lck (see SEQ ID NO: 34, SEQ ID NO: 39). When the pMHCR-CD3 complex was co-expressed with SCR CD80-Lck in hybridomas, these cells produced significantly more IL-2 in response to cells expressing the 2B4 TCR ligand+CD28 than they did in response to cells expressing only the 284 TCR ligand (see FIG. 5). This suggested that signaling through the pMHCR-CD3 complex could be augmented through the use of a SCR.
[0063] MCC:IE.sup.k pMHCR-CD3 and the SCR CD80-Lck or HB:IE.sup.k pMHCR-CD3 (e.g., see SEQ ID NO: 32) and the SCR CD80-Lck were expressed in in vitro differentiated CD8 cytotoxic T cells (CTLs) and their ability to kill 5c.c7 TCR transgenic CD4 T cells expressing the TCR specific for the MCC:IE.sup.k pMHCR was evaluated. Surface expression of the pMHCRs on the redirected CTLs was observed, suggesting that these chimeric receptor modules compete with the endogenous TCR for assembly with the endogenous CD3 subunits (data not shown). CTLs expressing the MCC:IE.sup.k pMHCR robustly killed the target CD4 T cells while those expressing the null HB:IE.sup.k pMHCR did not (see FIG. 6). This suggests that CD8 T cells can be redirected to target and eliminate antigen-specific CD4 T cells.
[0064] Example 2: Redirected T cells targeting CD4 T Helper Cells in Allergic Asthma. Example 2 describes a non-limiting experimental approach to target CD4 T helper cells involved in allergic asthma, e.g., to help eliminate naive Der p 1-specific CD4 T cells from the repertoire prior to House Dust Mite (HDM) sensitization. Without wishing to limit the present invention to any theory or mechanism, it is believed that eliminating allergen-specific CD4 T cells from the repertoire may help prevent the onset of T.sub.H2 immunity upon HDM sensitization.
[0065] A pMHCR (pMHCR-CD3 complex) will be retrovirally expressed in in vitro activated CTLs. The pMHCR will bear a pMHCR comprising either the immunodominant HDM-derived Der p 1 epitope (aa117-127) in the context of I-A.sup.b (Derp1:IA.sup.b) or the immunodominant West Nile Virus peptide from the envelope protein (aa641-655) in the context of I-A.sup.b (E641:IA.sup.b). The E641:IA.sup.b pMHCR cells will serve as a non-specific control population.
[0066] The in vitro activated CTLs will also be transduced with a CD80-Lck SCR to enhance signaling. These redirected CTLs will then be transferred intravenously into C57Bl/6 mice to target and eliminate Derp1:IA.sup.b- or E641:IA.sup.b-specific naive CD4 T cells from the endogenous repertoire. After a certain length of time, e.g., 1 week, the elimination of antigen-specific CD4 T cells will be evaluated. This will be performed via tetramer enrichment experiments using a Derp1:IA.sup.b tetramer and a E641:IA.sup.b tetramer. The presence of the redirected CD8 T cells will also be assessed by flow cytometry by gating on CD3+CD8+IA.sup.b+ T cells since mouse T cells do not express class II MHC.
[0067] After determining if the redirected CTLs eliminate the target population, mice that received redirected CTLs one-week prior will be sensitized with HDM (e.g., intranasally, e.g., with HDM extracts). This will be done even if endogenous CD4 T cells specific for Derp1:IA.sup.b are detected, but only if redirected T cells are still present in the mice. This may help to determine if activation of the CD4 T cells made them more susceptible to targeting by the redirected CTLs.
[0068] Example 3: Redirected T cells targeting CD4 T Helper Cells in Lungs After Sensitization. Example 3 describes a non-limiting experimental approach to target CD4 T helper cells in lungs of HDM-sensitized mice. Without wishing to limit the present invention to any theory or mechanism, it is believed that eliminating allergen-specific CD4 T cells from the lungs of HDM-sensitized mice may help attenuate T.sub.H2 immunity.
[0069] Der p 1-specific CD4 T cells will be targeted similarly to Example 2, but only after HDM sensitization. In brief, mice will be sensitized with HDM according to the protocol described above. They will then receive redirected Derp1:IA.sup.b or E641:IA.sup.b pMHCR-CD3 CTLs on day 14. Various surrogate co-receptors will be employed to explore the efficacy of the technology and approach. For example, the CD80-Lck fusion SCR will be used, as well as others, e.g., a TIM-4-Lck SCR (since the TIM-1 expressed on CD4 T cells is genetically linked with asthma and this combination for targeting might enhance effectiveness). One week after transfer of redirected CTLs, cytokine and cellular analysis will be performed as described above in Example 2 so as to assess the impact of these cells on the lung cytokine milieu and cellularity. The status of the redirected CTLs will also be evaluated.
[0070] Example 4: Attenuation of Der p 1-specific CD4 T cell function in situ. Example 4 describes a non-limiting experimental approach to redirect Tregs against Der p 1-specific CD4 T cells. Without wishing to limit the present invention to any theory or mechanism, it is believed that this may help attenuate function of said CD4 T cells and help diminish T.sub.H2 immunity.
[0071] In vitro generated induced Tregs (iTregs) expressing a MHCR will be tested for efficacy in reducing HDM-induced airway hypersensitivity. Induced Tregs (iTregs) will be generated in vitro and transduced with pMHCR and SCRs as described in Examples 2 and 3 above. These cells will then either be transferred prior to HDM sensitization as in Example 2 or after sensitization as in Example 3. Evaluation of the lung cytokine milieu and cellularity will then be performed as described above.
[0072] Table 3 shows examples of protein sequences for reagents the above examples. Table 4 shows the nucleotide sequences for the proteins in Table 3. Note that in SEQ ID NO: 30, a portion is derived from SEQ ID NO: 14 and a portion is derived from SEQ ID NO: 22. In SEQ ID NO: 31, a portion is derived from SEQ ID NO: 15, a portion is derived from SEQ ID NO: 23, and a portion is derived from SEQ ID NO: 29 (and other residues may correspond to a glycine-rich linking region). In SEQ ID NO: 32, a portion is derived from SEQ ID NO: 15 and a portion is derived from SEQ ID NO: 23 (and other residues may correspond to a glycine-rich linking region).
TABLE-US-00005 TABLE 3 Peptide sequences for reagents in Examples. SEQ ID NO. Description Amino Acid Sequence 30 I-E.sup.k.alpha.-TCR.alpha. MATIGALLLRFFFIAVLMSSQKSWAIKEEHTIIQAEFY Note: underlined LLPPKRGEFMFDFDGDEIFHVDIEKSETIWRLEEFA portion is from SEQ KFASFEAQGALANIAVDKANLDVMKERSNNTPDAN ID NO: 14 (MHC VAPEVTVLSRSPVNLGEPNILICFIDKFSPPVVNVIW portion), bold portion FRNGRPVTEGVSETVFLPRDDHLFRKFHYLTFLPST is from SEQ ID NO: DDFYDCEVDHWGLEEPLRKHWEFEEKTLLPETKE 22 (TCR portion) CDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAG FNLLMTLRLWSS 31 MCC: I-E.sup.k.beta.-TCR.beta. MVWLPRVPCVAAVILLLTVLSPPVALVRDSGSANER (note: italic portion ADLIAYLKQATKEFRSGGGGSLVPRGSGGGGSVDR shows peptide PWFLEYCKSECHFYNGTQRVRLLVRYFYNLEENLR antigen sequence, FDSDVGEFRAVTELGRPDAENWNSQPEFLEQKRA underlined portion is EVDTVCRHNYEIFDNFLVPRRVEPTVIVYPTKTQPL from SEQ ID NO: 15 EHHNLLVCSVSDFYPGNIEVRWFRNGKEEKTGIVS (MHC portion), and TGLVRNGDWTFQTLVMLETVPQSGEVYTCQVEHP bold portion is from SLTDPVTVEWKAQSTSAQNKCGITSASYHQGVLSA SEQ ID NO: 24 (TCR TILYEILLGKATLYAVLVSGLVLMAMVKKKNSAAA portion) 32 HB: I-E.sup.k.beta.-TCR.beta. MVWLPRVPCVAAVILLLTVLSPPVALVRDSGSGKKVI Note: italic portion TAFNEGLKEFRSGGGGSLVPRGSGGGGSVDRPWF shows peptide LEYCKSECHFYNGTQRVRLLVRYFYNLEENLRFDS antigen sequence, DVGEFRAVTELGRPDAENWNSQPEFLEQKRAEVD underlined portion is TVCRHNYEIFDNFLVPRRVEPTVIVYPTKTQPLEHH from SEQ ID NO: 15 NLLVCSVSDFYPGNIEVRWFRNGKEEKTGIVSTGLV (MHC portion), and RNGDWTFQTLVMLETVPQSGEVYTCQVEHPSLTD bold portion is from PVTVEWKAQSTSAQNKCGITSASYHQGVLSATILY SEQ ID NO: 24 (TCR EILLGKATLYAVLVSGLVLMAMVKKKNSAAA portion) 33 CD80-Lck MACNCQLMQDTPLLKFPCPRLILLFVLLIRLSQVSS (mCD80-mLck DVDEQLSKSVKDKVLLPCRYNSPHEDESEDRIYWQ fusion) KHDKVVLSVIAGKLKVWPEYKNRTLYDNTTYSLIILG LVLSDRGTYSCVVQKKERGTYEVKHLALVKLSIKAD FSTPNITESGNPSADTKRITCFASGGFPKPRFSWLE NGRELPGINTTISQDPESELYTISSQLDFNTTRNHTI KCLIKYGDAHVSEDFTWEKPPEDPPDSKNTLVLFG AGFGAVITVVVIVVIIKCFCKHRSCFRRNEASRETNN SLTFGPEEALAEQTVFLTTSHYPIVPLDSKISLPIRNG SEVRDPLVTYEGSLPPASPLQDNLVIALHSYEPSHD GDLGFEKGEQLRILEQSGEVVWKAQSLTTGQEGFIP FNFVAKANSLEPEPWFFKNLSRKDAERQLLAPGNT HGSFLIRESESTAGSFSLSVRDFDQNQGEWKHYKI RNLDNGGFYISPRITFPGLHDLVRHYTNASDGLCTK LSRPCQTQKPQKPVVWEDEWEVPRETLKLVERLGA GQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLA EANLMKQLQHPRLVRLYAVVTQEPIYIITEYMENGSL VDFLKTPSGIKLNVNKLLDMAAQIAEGMAFIEEQNYI HRDLRAANILVSDTLSCKIADFGLARLIEDNEYTARE GAKFPIKWTAPEAINYGTFTIKSDVWSFGILLTEIVTH GRIPYPGMTNPEVIQNLERGYRMVRPDNCPEELYH LMMLCWKERPEDRPTFDYLRSVLDDFFTATEGQY QPQPGT 34 CD86-Lck MDPRCTMGLAILIFVTVLLISDAVSVETQAYFNGTAY (mCD86-mLck LPCPFTKAQNISLSELVVFWQDQQKLVLYEHYLGTE fusion) KLDSVNAKYLGRTSFDRNNWTLRLHNVQIKDMGSY DCFIQKKPPTGSIILQQTLTELSVIANFSEPEIKLAQN VTGNSGINLTCTSKQGHPKPKKMYFLITNSTNEYGD NMQISQDNVTELFSISNSLSLSFPDGVWHMTVVCV LETESMKISSKPLNFTQEFPSPQTYWKEITASVTVAL LLVMLLIIVCHKKPNQPSRPSNTASKLERDSNADRE TINLKELEPQIASAKPNAECTSHYPIVPLDSKISLPIR NGSEVRDPLVTYEGSLPPASPLQDNLVIALHSYEPS HDGDLGFEKGEQLRILEQSGEWWKAQSLTTGQEG FIPFNFVAKANSLEPEPWFFKNLSRKDAERQLLAPG NTHGSFLIRESESTAGSFSLSVRDFDQNQGEVVKH YKIRNLDNGGFYISPRITFPGLHDLVRHYTNASDGL CTKLSRPCQTQKPQKPWWEDEWEVPRETLKLVER LGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPD AFLAEANLMKQLQHPRLVRLYAVVTQEPIYIITEYME NGSLVDFLKTPSGIKLNVNKLLDMAAQIAEGMAFIE EQNYIHRDLRAANILVSDTLSCKIADFGLARLIEDNE YTAREGAKFPIKWTAPEAINYGTFTIKSDVWSFGILL TEIVTHGRIPYPGMTNPEVIQNLERGYRMVRPDNC PEELYHLMMLCWKERPEDRPTFDYLRSVLDDFFTA TEGQYQPQPGT
TABLE-US-00006 TABLE 4 Examples of DNA sequences for encoding the proteins in Table 3. SEQ ID NO. Description Gene Sequence 35 I-E.sup.k.alpha.-TCR.alpha. aataagcttctcgagcgccaccATGGCCACAATTGGAGCCCTGCTGTTAAGATTT fusion TTCTTCATTGCTGTTCTGATGAGCTCCCAGAAGTCATGGGCTATCAAAG AGGAACACACCATCATCCAGGCGGAGTTCTATCTTTTACCAGACAAACG TGGAGAGTTTATGTTTGACTTTGACGGCGATGAGATTTTCCATGTAGAC ATTGAAAAGTCAGAGACCATCTGGAGACTTGAAGAATTTGCAAAGTTTG CCAGCTTTGAGGCTCAGGGTGCACTGGCTAATATAGCTGTGGACAAAG CTAACCTGGATGTCATGAAAGAGCGTTCCAACAACACTCCAGATGCCA ACGTGGCCCCAGAGGTGACTGTACTCTCCAGAAGCCCTGTGAACCTG GGAGAGCCCAACATCCTCATCTGTTTCATTGACAAGTTCTCCCCTCCA GTGGTCAATGTCACCTGGTTCCGGAATGGACGGCCTGTCACCGAAGG CGTGTCAGAGACAGTGTTTCTCCCGAGGGACGATCACCTCTTCCGCAA ATTCCACTATCTGACCTTCCTGCCCTCCACAGATGATTTCTATGACTGTG AGGTGGATCACTGGGGTTTGGAGGAGCCTCTGCGGAAGCACTGGGAG TTTGAAGAGAAAACCCTCCTCCCAGAAACTAAAGAGtgtgatgccacgttgacc gagaaaaGCTTTGAAACAGATATgaacctaaactttcaaaacctgtcaGTTATGGGAC TCCGAATCCtcctgctgaaagtagcgggatttaacCTGCTCATGACGCTgaggctgtggt ccagttgaggatccgcta 36 MCC: I-E.sup.k.beta.-T aatCTCGAGCGCCACCATGGTGTGGCTCCCCAGAGTTCCCTGTGTGGC CR.beta. fusion AGCTGTGATCCTGTTGCTGACAGTGCTGAGCCCTCCAGTGGCTTTGGT CAGAGACTCCGGATCCGCCAACGAGAGGGCCGACCTGATCGCCTACC TGAAGCAGGCCACCAAGGAATTCAGATCCGGAGGCGGAGGCTCCCTG GTGCCTCGGGGCTCCGGAGGCGGAGGCTCCGTCGACAGACCATGGT TTTTGGAATACTGTAAATCTGAGTGTCATTTCTACAACGGGACGCAGCG CGTGCGGCTTCTGGTAAGATACTTCTACAACCTGGAGGAGAACCTGCG CTTCGACAGCGACGTGGGCGAGTTCCGCGCGGTGACCGAGCTGGGG CGGCCAGACGCCGAGAACTGGAACAGCCAGCCGGAGTTCCTGGAGC AAAAGCGGGCCGAGGTGGACACGGTGTGCAGACACAACTATGAGATC TTCGATAACTTCCTTGTGCCGCGGAGAGTTGAGCCTACGGTGACTGTG TACCCCACAAAGACGCAGCCCCTGGAACACCACAACCTCCTGGTCTG CTCTGTGAGTGACTTCTACCCTGGCAACATTGAAGTCAGATGGTTCCG GAATGGCAAGGAGGAGAAAACAGGAATTGTGTCCACGGGCCTGGTCC GAAATGGAGACTGGACCTTCCAGACACTGGTGATGCTGGAGACGGTT CCTCAGAGTGGAGAGGTTTACACCTGCCAGGTGGAGCATCCCAGCCT GACCGACCCTGTCACGGTCGAGTGGAAAGCACAGTCCACATCTGCAC AGAACAAGtgtggaatcactagtgcatcctatcatcagggggttctgtctgcaaccatcctctatgag atcctactggggaaggccaccctatatgctgtgctggtcagtggcctagtgctgatgGCCATGGTC AAGAAAAAAAATTCCgcggccgcatgatgagatctgagctccatagaggcg 37 HB: I-E.sup.k.beta.-TC aatCTCGAGCGCCACCATGGTGTGGCTCCCCAGAGTTCCCTGTGTGGC R.beta. fusion AGCTGTGATCCTGTTGCTGACAGTGCTGAGCCCTCCAGTGGCTTTGGT CAGAGACTCCGGATCCGGCAAGAAGGTGATCACCGCCTTCAACGAGG GCCTGAAGGAATTCAGATCCGGAGGCGGAGGCTCCCTGGTGCCTCGG GGCTCCGGAGGCGGAGGCTCCGTCGACAGACCATGGTMTGGAATA CTGTAAATCTGAGTGTCATTTCTACAACGGGACGCAGCGCGTGCGGCT TCTGGTAAGATACTTCTACAACCTGGAGGAGAACCTGCGCTTCGACAG CGACGTGGGCGAGTTCCGCGCGGTGACCGAGCTGGGGCGGCCAGAC GCCGAGAACTGGAACAGCCAGCCGGAGTTCCTGGAGCAAAAGCGGG CCGAGGTGGACACGGTGTGCAGACACAACTATGAGATCTTCGATAACT TCCTTGTGCCGCGGAGAGTTGAGCCTACGGTGACTGTGTACCCCACA AAGACGCAGCCCCTGGAACACCACAACCTCCTGGTCTGCTCTGTGAG TGACTTCTACCCTGGCAACATTGAAGTCAGATGGTTCCGGAATGGCAA GGAGGAGAAAACAGGAATTGTGTCCACGGGCCTGGTCCGAAATGGAG ACTGGACCTTCCAGACACTGGTGATGCTGGAGACGGTTCCTCAGAGT GGAGAGGTTTACACCTGCCAGGTGGAGCATCCCAGCCTGACCGACCC TGTCACGGTCGAGTGGAAAGCACAGTCCACATCTGCACAGAACAAGtgt ggaatcactagtgcatcctatcatcagggggttctgtctgcaaccatcctctatgagatcctactggggaa ggccaccctatatgctgtgctggtcagtggcctagtgctgatgGCCATGGTCAAGAAAAAAA ATTCCgcggccgcatgatgagatctgagctccatagaggcg 38 CD80-Lck acgtctagatacctcgaggccaccATGGCTTGCAATTGTCAGttgatgcaggatacaccact (mCD80-mL cctcaagtttccatgtccaaggctcattcttctctttgtgctgctgattcgtctttcacaagt- gtcttcagatgttg ck fusion) atgaacaactgtccaagtcagtgaaagataaggtattgctgccttgccgttacaactctcctcatgaagat gagtctgaagaccgaatctactggcaaaaacatgacaaagtggtgctgtctgtcattgctgggaaacta aaagtgtggcccgagtataagaaccggactttatatgacaacactacctactctcttatcatcctgggcct ggtcctttcagaccggggcacatacagctgtgtcgttcaaaagaaggaaagaggaacgtatgaagtta aacacttggctttagtaaagttgtccatcaaagctgacttctctacccccaacataactgagtctggaaac ccatctgcagacactaaaaggattacctgctttgcttccgggggtttcccaaagcctcgcttctcttggttg- g aaaatggaagagaattacctggcatcaatacgacaatttcccaggatcctgaatctgaattgtacaccat tagtagccaactagatttcaatacgactcgcaaccacaccattaagtgtctcattaaatatggagatgctc acgtgtcagaggacttcacctgggaaaaacccccagaagaccctcctgatagcaagaacacacttgt gctctttggggcaggattcggcgcagtaataacagtcgtcgtcatcgttgtcatcatcaaatgcttctgtaa gcacagaagctgtttcagaagaaatgaggcaagcagagaaacaaacaacagccttaccttcgggcc tgaagaagcattagctGAACAGACCGTCTTCCTTaccactagtCACTATCCCATAGT Cccactggacagcaagatctcgctgcccatccggaatggctctgaagtgcgggacccactggtcacct atgagggatctctcccaccagcatccccgctgcaagacaacctggttatcgccctgcacagttatgagc cctcccatgatggagacttgggctttgagaagggtgaacagctccgaatcctggagcagagcggtgag tggtggaaggctcagtccctgacgactggccaagaaggcttcattcccttcaacttcgtggcgaaagca aacagcctggagcctgaaccttggttcttcaagaatctgagccgtaaggacgccgagcggcagcttttg gcgcccgggaacacgcatggatccttcctgatccgggaaagcgaaagcactgcggggtccttttccctg tcggtcagagacttcgaccagaaccagggagaagtggtgaaacattacaagatccgtaacctagaca acggtggcttctacatctcccctcgtatcacttttcccggattgcacgatctagtccgccattacaccaacg- c ctctgatgggctgtgcacaaagttgagccgtccttgccagacccagaagccccagaaaccatggtggg aggacgaatgggaagttcccagggaaacactgaagttggtggagcggctgggagctggccagttcgg ggaagtgtggatggggtactacaacggacacacgaaggtggcggtgaagagtctgaaacaaggga gcatgtcccccgacgccttcctggctgaggctaacctcatgaagcagctgcagcacccgcggctagtcc ggctttatgcagtggtcacccaggaacccatctacatcatcacggaatacatggagaacgggagccta gtagattttctcaagactccctcgggcatcaagttgaatgtcaacaaacttttggacatggcagcccagatt gcagagggcatggcgttcatcgaagaacagaattacatccatcgggacctgcgcgccgccaacatcc tggtgtctgacacgctgagctgcaagattgcagactttggcctggcgcgcctcattgaggacaatgagta cacggcccgggagggggccaaatttcccattaagtggacagcaccagaagccattaactatgggacc ttcaccatcaagtcagacgtgtggtccttcgggatcttgcttacagagatcgtcacccacggtcgaatccct tacccaggaatgaccaaccctgaagtcattcagaacctggagagaggctaccgcatggtgagacctg acaactgtccggaagagctgtaccacctcatgatgctgtgctggaaggagcgcccagaggaccggcc cacgtttgactaccttcggagtgttctggatgacttcttcacagccacagagggcCAGTACCAGCC CCAGCCTggtacctagtgagaattctacatg 39 CD86-Lck tactctagatacctcgaggccaccATGGACCCCAGATGCACCatgggcttggcaatccttatc (mCD86-mL tttgtgacagtcttgctgatctcagatgctgtttccgtggagacgcaagcttatttcaatggg- actgcatatct ck fusion) gccgtgcccatttacaaaggctcaaaacataagcctgagtgagctggtagtattttggcaggaccagca aaagttggttctgtacgagcactatttgggcacagagaaacttgatagtgtgaatgccaagtacctgggc cgcacgagctttgacaggaacaactggactctacgacttcacaatgttcagatcaaggacatgggctcg tatgattgttttatacaaaaaaagccacccacaggatcaattatcctccaacagacattaacagaactgtc agtgatcgccaacttcagtgaacctgaaataaaactggctcagaatgtaacaggaaattctggcataaa tttgacctgcacgtctaagcaaggtcacccgaaacctaagaagatgtattttctgataactaattcaacta atgagtatggtgataacatgcagatatcacaagataatgtcacagaactgttcagtatctccaacagcct ctctctttcattcccggatggtgtgtggcatatgaccgttgtgtgtgttctggaaacggagtcaatgaagat- tt cctccaaacctctcaatttcactcaagagtttccatctcctcaaacgtattggaaggagattacagcttcag ttactgtggccctcctccttgtgatgctgctcatcattgtatgtcacaagaagccgaatcagcctagcaggc ccagcaacacagcctctaagttagagcgggatagtaacgctgacagagagactatcaacctgaagg aacttgaaccccaaattgcttcagcaaaaccaaatgcagagtgtactagtCACTATCCCATAGT Cccactggacagcaagatctcgctgcccatccggaatggctctgaagtgcgggacccactggtcacct atgagggatctctcccaccagcatccccgctgcaagacaacctggttatcgccctgcacagttatgagc cctcccatgatggagacttgggctttgagaagggtgaacagctccgaatcctggagcagagcggtgag tggtggaaggctcagtccctgacgactggccaagaaggcttcattcccttcaacttcgtggcgaaagca aacagcctggagcctgaaccttggttcttcaagaatctgagccgtaaggacgccgagcggcagcttttg gcgcccgggaacacgcatggatccttcctgatccgggaaagcgaaagcactgcggggtccttttccctg tcggtcagagacttcgaccagaaccagggagaagtggtgaaacattacaagatccgtaacctagaca acggtggcttctacatctcccctcgtatcacttttcccggattgcacgatctagtccgccattacaccaacg- c ctctgatgggctgtgcacaaagttgagccgtccttgccagacccagaagccccagaaaccatggtggg aggacgaatgggaagttcccagggaaacactgaagttggtggagcggctgggagctggccagttcgg ggaagtgtggatggggtactacaacggacacacgaaggtggcggtgaagagtctgaaacaaggga gcatgtcccccgacgccttcctggctgaggctaacctcatgaagcagctgcagcacccgcggctagtcc ggctttatgcagtggtcacccaggaacccatctacatcatcacggaatacatggagaacgggagccta gtagattttctcaagactccctcgggcatcaagttgaatgtcaacaaacttttggacatggcagcccagatt gcagagggcatggcgttcatcgaagaacagaattacatccatcgggacctgcgcgccgccaacatcc tggtgtctgacacgctgagctgcaagattgcagactttggcctggcgcgcctcattgaggacaatgagta cacggcccgggagggggccaaatttcccattaagtggacagcaccagaagccattaactatgggacc ttcaccatcaagtcagacgtgtggtccttcgggatcttgcttacagagatcgtcacccacggtcgaatccct tacccaggaatgaccaaccctgaagtcattcagaacctggagagaggctaccgcatggtgagacctg acaactgtccggaagagctgtaccacctcatgatgctgtgctggaaggagcgcccagaggaccggcc cacgtttgactaccttcggagtgttctggatgacttcttcacagccacagagggcCAGTACCAGCC CCAGCCTggtacctagtgagaattctacatg
[0073] The disclosures of the following U.S. patents are incorporated in their entirety by reference herein: U.S. Pat. Application No. 20140219975; U.S. Pat. Nos. 8,450,112; 7,741,465; 6,319,494; CA 2209300; CA 2104957; EP 0574512; U.S. Pat. Nos. 6,407,221; 6,268,411; U.S. Pat. Application No. 20040258697; EP 1292621; EP 2659893; WO 2011101681; WO 2005054292; EP 1379670; U.S. Pat. Nos. 6,056,952; 6,410,319; 8,524,234; 7,871,817.
[0074] As used herein, the term "about" refers to plus or minus 10% of the referenced number.
[0075] Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by reference in its entirety.
[0076] Although there has been shown and described the preferred embodiment of the present invention, it will be readily apparent to those skilled in the art that modifications may be made thereto which do not exceed the scope of the appended claims. Therefore, the scope of the invention is only to be limited by the following claims. In some embodiments, the figures presented in this patent application are drawn to scale, including the angles, ratios of dimensions, etc. In some embodiments, the figures are representative only and the claims are not limited by the dimensions of the figures. In some embodiments, descriptions of the inventions described herein using the phrase "comprising" includes embodiments that could be described as "consisting of", and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase "consisting of" is met.
Sequence CWU
1
1
391365PRTHomo sapiens 1Met Ala Val Met Ala Pro Arg Thr Leu Val Leu Leu Leu
Ser Gly Ala1 5 10 15Leu
Ala Leu Thr Gln Thr Trp Ala Gly Ser His Ser Met Arg Tyr Phe 20
25 30Tyr Thr Ser Val Ser Arg Pro Gly
Arg Gly Glu Pro Arg Phe Ile Ala 35 40
45Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala
50 55 60Ala Ser Gln Arg Met Glu Pro Arg
Ala Pro Trp Ile Glu Gln Glu Gly65 70 75
80Pro Glu Tyr Trp Asp Arg Asn Thr Arg Asn Val Lys Ala
Gln Ser Gln 85 90 95Thr
Asp Arg Val Asp Leu Gly Thr Leu Arg Gly Tyr Tyr Asn Gln Ser
100 105 110Glu Ala Gly Ser His Thr Ile
Gln Met Met Tyr Gly Cys Asp Val Gly 115 120
125Ser Asp Gly Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr Asp
Gly 130 135 140Lys Asp Tyr Ile Ala Leu
Lys Glu Asp Leu Arg Ser Trp Thr Ala Ala145 150
155 160Asp Met Ala Ala Gln Thr Thr Lys His Lys Trp
Glu Ala Ala His Val 165 170
175Ala Glu Gln Trp Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu
180 185 190Arg Arg Tyr Leu Glu Asn
Gly Lys Glu Thr Leu Gln Arg Thr Asp Ala 195 200
205Pro Lys Thr His Met Thr His His Ala Val Ser Asp His Glu
Ala Thr 210 215 220Leu Arg Cys Trp Ala
Leu Ser Phe Tyr Pro Ala Glu Ile Thr Leu Thr225 230
235 240Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln
Asp Thr Glu Leu Val Glu 245 250
255Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Val Ala Val Val
260 265 270Val Pro Ser Gly Gln
Glu Gln Arg Tyr Thr Cys His Val Gln His Glu 275
280 285Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Pro
Ser Ser Gln Pro 290 295 300Thr Ile Pro
Ile Val Gly Ile Ile Ala Gly Leu Val Leu Phe Gly Ala305
310 315 320Val Ile Thr Gly Ala Val Val
Ala Ala Val Met Trp Arg Arg Lys Ser 325
330 335Ser Asp Arg Lys Gly Gly Ser Tyr Ser Gln Ala Ala
Ser Ser Asp Ser 340 345 350Ala
Gln Gly Ser Asp Val Ser Leu Thr Ala Cys Lys Val 355
360 3652362PRTHomo sapiens 2Met Arg Val Thr Ala Pro Arg
Thr Val Leu Leu Leu Leu Trp Gly Ala1 5 10
15Val Ala Leu Thr Glu Thr Trp Ala Gly Ser His Ser Met
Arg Tyr Phe 20 25 30Tyr Thr
Ala Met Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala 35
40 45Val Gly Tyr Val Asp Asp Thr Gln Phe Val
Arg Phe Asp Ser Asp Ala 50 55 60Ala
Ser Pro Arg Thr Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly65
70 75 80Pro Glu Tyr Trp Asp Arg
Asn Thr Gln Ile Phe Lys Thr Asn Thr Gln 85
90 95Thr Tyr Arg Glu Asn Leu Arg Ile Ala Leu Arg Tyr
Tyr Asn Gln Ser 100 105 110Glu
Ala Gly Ser His Thr Trp Gln Thr Met Tyr Gly Cys Asp Val Gly 115
120 125Pro Asp Gly Arg Leu Leu Arg Gly His
Asn Gln Tyr Ala Tyr Asp Gly 130 135
140Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Ser Ser Trp Thr Ala Ala145
150 155 160Asp Thr Ala Ala
Gln Ile Thr Gln Arg Lys Trp Glu Ala Ala Arg Glu 165
170 175Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly
Leu Cys Val Glu Trp Leu 180 185
190Arg Arg His Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Ala Asp Pro
195 200 205Pro Lys Thr His Val Thr His
His Pro Val Ser Asp His Glu Ala Thr 210 215
220Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu
Thr225 230 235 240Trp Gln
Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu
245 250 255Thr Arg Pro Ala Gly Asp Arg
Thr Phe Gln Lys Trp Ala Ala Val Val 260 265
270Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln
His Glu 275 280 285Gly Leu Pro Lys
Pro Leu Thr Leu Arg Trp Glu Pro Ser Ser Gln Ser 290
295 300Thr Ile Pro Ile Val Gly Ile Val Ala Gly Leu Ala
Val Leu Ala Val305 310 315
320Val Val Ile Gly Ala Val Val Ala Thr Val Met Cys Arg Arg Lys Ser
325 330 335Ser Gly Gly Lys Gly
Gly Ser Tyr Ser Gln Ala Ala Ser Ser Asp Ser 340
345 350Ala Gln Gly Ser Asp Val Ser Leu Thr Ala
355 3603366PRTHomo sapiens 3Met Arg Val Met Ala Pro Arg
Thr Leu Ile Leu Leu Leu Ser Gly Ala1 5 10
15Leu Ala Leu Thr Glu Thr Trp Ala Cys Ser His Ser Met
Arg Tyr Phe 20 25 30Asp Thr
Ala Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser 35
40 45Val Gly Tyr Val Asp Asp Thr Gln Phe Val
Arg Phe Asp Ser Asp Ala 50 55 60Ala
Ser Pro Arg Gly Glu Pro Arg Ala Pro Trp Val Glu Gln Glu Gly65
70 75 80Pro Glu Tyr Trp Asp Arg
Glu Thr Gln Lys Tyr Lys Arg Gln Ala Gln 85
90 95Ala Asp Arg Val Asn Leu Arg Lys Leu Arg Gly Tyr
Tyr Asn Gln Ser 100 105 110Glu
Asp Gly Ser His Thr Leu Gln Trp Met Tyr Gly Cys Asp Leu Gly 115
120 125Pro Asp Gly Arg Leu Leu Arg Gly Tyr
Asp Gln Ser Ala Tyr Asp Gly 130 135
140Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala145
150 155 160Asp Thr Ala Ala
Gln Ile Thr Gln Arg Lys Trp Glu Ala Ala Arg Glu 165
170 175Ala Glu Gln Trp Arg Ala Tyr Leu Glu Gly
Thr Cys Val Glu Trp Leu 180 185
190Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Ala Glu His
195 200 205Pro Lys Thr His Val Thr His
His Pro Val Ser Asp His Glu Ala Thr 210 215
220Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu
Thr225 230 235 240Trp Gln
Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu
245 250 255Thr Arg Pro Ala Gly Asp Gly
Thr Phe Gln Lys Trp Ala Ala Val Val 260 265
270Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln
His Glu 275 280 285Gly Leu Pro Glu
Pro Leu Thr Leu Arg Trp Glu Pro Ser Ser Gln Pro 290
295 300Thr Ile Pro Ile Val Gly Ile Val Ala Gly Leu Ala
Val Leu Ala Val305 310 315
320Leu Ala Val Leu Gly Ala Val Met Ala Val Val Met Cys Arg Arg Lys
325 330 335Ser Ser Gly Gly Lys
Gly Gly Ser Cys Ser Gln Ala Ala Ser Ser Asn 340
345 350Ser Ala Gln Gly Ser Asp Glu Ser Leu Ile Ala Cys
Lys Ala 355 360 3654260PRTHomo
sapiens 4Met Arg Pro Glu Asp Arg Met Phe His Ile Arg Ala Val Ile Leu Arg1
5 10 15Ala Leu Ser Leu
Ala Phe Leu Leu Ser Leu Arg Gly Ala Gly Ala Ile 20
25 30Lys Ala Asp His Val Ser Thr Tyr Ala Ala Phe
Val Gln Thr His Arg 35 40 45Pro
Thr Gly Glu Phe Met Phe Glu Phe Asp Glu Asp Glu Met Phe Tyr 50
55 60Val Asp Leu Asp Lys Lys Glu Thr Val Trp
His Leu Glu Glu Phe Gly65 70 75
80Gln Ala Phe Ser Phe Glu Ala Gln Gly Gly Leu Ala Asn Ile Ala
Ile 85 90 95Leu Asn Asn
Asn Leu Asn Thr Leu Ile Gln Arg Ser Asn His Thr Gln 100
105 110Ala Thr Asn Asp Pro Pro Glu Val Thr Val
Phe Pro Lys Glu Pro Val 115 120
125Glu Leu Gly Gln Pro Asn Thr Leu Ile Cys His Ile Asp Lys Phe Phe 130
135 140Pro Pro Val Leu Asn Val Thr Trp
Leu Cys Asn Gly Glu Leu Val Thr145 150
155 160Glu Gly Val Ala Glu Ser Leu Phe Leu Pro Arg Thr
Asp Tyr Ser Phe 165 170
175His Lys Phe His Tyr Leu Thr Phe Val Pro Ser Ala Glu Asp Phe Tyr
180 185 190Asp Cys Arg Val Glu His
Trp Gly Leu Asp Gln Pro Leu Leu Lys His 195 200
205Trp Glu Ala Gln Glu Pro Ile Gln Met Pro Glu Thr Thr Glu
Thr Val 210 215 220Leu Cys Ala Leu Gly
Leu Val Leu Gly Leu Val Gly Ile Ile Val Gly225 230
235 240Thr Val Leu Ile Ile Lys Ser Leu Arg Ser
Gly His Asp Pro Arg Ala 245 250
255Gln Gly Thr Leu 2605258PRTHomo sapiens 5Met Met Val
Leu Gln Val Ser Ala Ala Pro Arg Thr Val Ala Leu Thr1 5
10 15Ala Leu Leu Met Val Leu Leu Thr Ser
Val Val Gln Gly Arg Ala Thr 20 25
30Pro Glu Asn Tyr Leu Phe Gln Gly Arg Gln Glu Cys Tyr Ala Phe Asn
35 40 45Gly Thr Gln Arg Phe Leu Glu
Arg Tyr Ile Tyr Asn Arg Glu Glu Phe 50 55
60Ala Arg Phe Asp Ser Asp Val Gly Glu Phe Arg Ala Val Thr Glu Leu65
70 75 80Gly Arg Pro Ala
Ala Glu Tyr Trp Asn Ser Gln Lys Asp Ile Leu Glu 85
90 95Glu Lys Arg Ala Val Pro Asp Arg Met Cys
Arg His Asn Tyr Glu Leu 100 105
110Gly Gly Pro Met Thr Leu Gln Arg Arg Val Gln Pro Arg Val Asn Val
115 120 125Ser Pro Ser Lys Lys Gly Pro
Leu Gln His His Asn Leu Leu Val Cys 130 135
140His Val Thr Asp Phe Tyr Pro Gly Ser Ile Gln Val Arg Trp Phe
Leu145 150 155 160Asn Gly
Gln Glu Glu Thr Ala Gly Val Val Ser Thr Asn Leu Ile Arg
165 170 175Asn Gly Asp Trp Thr Phe Gln
Ile Leu Val Met Leu Glu Met Thr Pro 180 185
190Gln Gln Gly Asp Val Tyr Thr Cys Gln Val Glu His Thr Ser
Leu Asp 195 200 205Ser Pro Val Thr
Val Glu Trp Lys Ala Gln Ser Asp Ser Ala Arg Ser 210
215 220Lys Thr Leu Thr Gly Ala Gly Gly Phe Val Leu Gly
Leu Ile Ile Cys225 230 235
240Gly Val Gly Ile Phe Met His Arg Arg Ser Lys Lys Val Gln Arg Gly
245 250 255Ser Ala6254PRTHomo
sapiens 6Met Ile Leu Asn Lys Ala Leu Met Leu Gly Ala Leu Ala Leu Thr Thr1
5 10 15Val Met Ser Pro
Cys Gly Gly Glu Asp Ile Val Ala Asp His Val Ala 20
25 30Ser Tyr Gly Val Asn Leu Tyr Gln Ser Tyr Gly
Pro Ser Gly Gln Tyr 35 40 45Thr
His Glu Phe Asp Gly Asp Glu Gln Phe Tyr Val Asp Leu Gly Arg 50
55 60Lys Glu Thr Val Trp Cys Leu Pro Val Leu
Arg Gln Phe Arg Phe Asp65 70 75
80Pro Gln Phe Ala Leu Thr Asn Ile Ala Val Leu Lys His Asn Leu
Asn 85 90 95Ser Leu Ile
Lys Arg Ser Asn Ser Thr Ala Ala Thr Asn Glu Val Pro 100
105 110Glu Val Thr Val Phe Ser Lys Ser Pro Val
Thr Leu Gly Gln Pro Asn 115 120
125Ile Leu Ile Cys Leu Val Asp Asn Ile Phe Pro Pro Val Val Asn Ile 130
135 140Thr Trp Leu Ser Asn Gly His Ser
Val Thr Glu Gly Val Ser Glu Thr145 150
155 160Ser Phe Leu Ser Lys Ser Asp His Ser Phe Phe Lys
Ile Ser Tyr Leu 165 170
175Thr Leu Leu Pro Ser Ala Glu Glu Ser Tyr Asp Cys Lys Val Glu His
180 185 190Trp Gly Leu Asp Lys Pro
Leu Leu Lys His Trp Glu Pro Glu Ile Pro 195 200
205Ala Pro Met Ser Glu Leu Thr Glu Thr Val Val Cys Ala Leu
Gly Leu 210 215 220Ser Val Gly Leu Val
Gly Ile Val Val Gly Thr Val Phe Ile Ile Arg225 230
235 240Gly Leu Arg Ser Val Gly Ala Ser Arg His
Gln Gly Pro Leu 245 2507261PRTHomo sapiens
7Met Ser Trp Lys Lys Ala Leu Arg Ile Pro Gly Gly Leu Arg Ala Ala1
5 10 15Thr Val Thr Leu Met Leu
Ala Met Leu Ser Thr Pro Val Ala Glu Gly 20 25
30Arg Asp Ser Pro Glu Asp Phe Val Tyr Gln Phe Lys Ala
Met Cys Tyr 35 40 45Phe Thr Asn
Gly Thr Glu Arg Val Arg Tyr Val Thr Arg Tyr Ile Tyr 50
55 60Asn Arg Glu Glu Tyr Ala Arg Phe Asp Ser Asp Val
Glu Val Tyr Arg65 70 75
80Ala Val Thr Pro Leu Gly Pro Pro Asp Ala Glu Tyr Trp Asn Ser Gln
85 90 95Lys Glu Val Leu Glu Arg
Thr Arg Ala Glu Leu Asp Thr Val Cys Arg 100
105 110His Asn Tyr Gln Leu Glu Leu Arg Thr Thr Leu Gln
Arg Arg Val Glu 115 120 125Pro Thr
Val Thr Ile Ser Pro Ser Arg Thr Glu Ala Leu Asn His His 130
135 140Asn Leu Leu Val Cys Ser Val Thr Asp Phe Tyr
Pro Ala Gln Ile Lys145 150 155
160Val Arg Trp Phe Arg Asn Asp Gln Glu Glu Thr Thr Gly Val Val Ser
165 170 175Thr Pro Leu Ile
Arg Asn Gly Asp Trp Thr Phe Gln Ile Leu Val Met 180
185 190Leu Glu Met Thr Pro Gln His Gly Asp Val Tyr
Thr Cys His Val Glu 195 200 205His
Pro Ser Leu Gln Asn Pro Ile Thr Val Glu Trp Arg Ala Gln Ser 210
215 220Glu Ser Ala Gln Ser Lys Met Leu Ser Gly
Ile Gly Gly Phe Val Leu225 230 235
240Gly Leu Ile Phe Leu Gly Leu Gly Leu Ile Ile His His Arg Ser
Gln 245 250 255Lys Gly Leu
Leu His 2608254PRTHomo sapiens 8Met Ala Ile Ser Gly Val Pro
Val Leu Gly Phe Phe Ile Ile Ala Val1 5 10
15Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu
His Val Ile 20 25 30Ile Gln
Ala Glu Phe Tyr Leu Asn Pro Asp Gln Ser Gly Glu Phe Met 35
40 45Phe Asp Phe Asp Gly Asp Glu Ile Phe His
Val Asp Met Ala Lys Lys 50 55 60Glu
Thr Val Trp Arg Leu Glu Glu Phe Gly Arg Phe Ala Ser Phe Glu65
70 75 80Ala Gln Gly Ala Leu Ala
Asn Ile Ala Val Asp Lys Ala Asn Leu Glu 85
90 95Ile Met Thr Lys Arg Ser Asn Tyr Thr Pro Ile Thr
Asn Val Pro Pro 100 105 110Glu
Val Thr Val Leu Thr Asn Ser Pro Val Glu Leu Arg Glu Pro Asn 115
120 125Val Leu Ile Cys Phe Ile Asp Lys Phe
Thr Pro Pro Val Val Asn Val 130 135
140Thr Trp Leu Arg Asn Gly Lys Pro Val Thr Thr Gly Val Ser Glu Thr145
150 155 160Val Phe Leu Pro
Arg Glu Asp His Leu Phe Arg Lys Phe His Tyr Leu 165
170 175Pro Phe Leu Pro Ser Thr Glu Asp Val Tyr
Asp Cys Arg Val Glu His 180 185
190Trp Gly Leu Asp Glu Pro Leu Leu Lys His Trp Glu Phe Asp Ala Pro
195 200 205Ser Pro Leu Pro Glu Thr Thr
Glu Asn Val Val Cys Ala Leu Gly Leu 210 215
220Thr Val Gly Leu Val Gly Ile Ile Ile Gly Thr Ile Phe Ile Ile
Lys225 230 235 240Gly Val
Arg Lys Ser Asn Ala Ala Glu Arg Arg Gly Pro Leu 245
2509266PRTHomo sapiens 9Met Val Cys Leu Arg Leu Pro Gly Gly Ser
Cys Met Ala Val Leu Thr1 5 10
15Val Thr Leu Met Val Leu Ser Ser Pro Leu Ala Leu Ala Gly Asp Thr
20 25 30Arg Pro Arg Phe Leu Glu
Glu Val Lys Phe Glu Cys His Phe Phe Asn 35 40
45Gly Thr Glu Arg Val Arg Leu Leu Glu Arg Arg Val His Asn
Gln Glu 50 55 60Glu Tyr Ala Arg Tyr
Asp Ser Asp Val Gly Glu Tyr Arg Ala Val Thr65 70
75 80Glu Leu Gly Arg Pro Asp Ala Glu Tyr Trp
Asn Ser Gln Lys Asp Leu 85 90
95Leu Glu Arg Arg Arg Ala Ala Val Asp Thr Tyr Cys Arg His Asn Tyr
100 105 110Gly Val Gly Glu Ser
Phe Thr Val Gln Arg Arg Val Gln Pro Lys Val 115
120 125Thr Val Tyr Pro Ser Lys Thr Gln Pro Leu Gln His
His Asn Leu Leu 130 135 140Val Cys Ser
Val Asn Gly Phe Tyr Pro Gly Ser Ile Glu Val Arg Trp145
150 155 160Phe Arg Asn Gly Gln Glu Glu
Lys Thr Gly Val Val Ser Thr Gly Leu 165
170 175Ile Gln Asn Gly Asp Trp Thr Phe Gln Thr Leu Val
Met Leu Glu Thr 180 185 190Val
Pro Gln Ser Gly Glu Val Tyr Thr Cys Gln Val Glu His Pro Ser 195
200 205Val Met Ser Pro Leu Thr Val Glu Trp
Arg Ala Arg Ser Glu Ser Ala 210 215
220Gln Ser Lys Met Leu Ser Gly Val Gly Gly Phe Val Leu Gly Leu Leu225
230 235 240Phe Leu Gly Ala
Gly Leu Phe Ile Tyr Phe Arg Asn Gln Lys Gly His 245
250 255Ser Gly Leu Pro Pro Thr Gly Phe Leu Ser
260 26510250PRTMus musculus 10Arg Ser Arg Ala
Leu Ile Leu Gly Val Leu Ala Leu Thr Thr Met Leu1 5
10 15Ser Leu Cys Gly Gly Glu Asp Tyr Ile Glu
Ala Asp His Val Ala Phe 20 25
30Tyr Gly Ile Ser Val Tyr Gln Ser Pro Gly Asp Ile Gly Gln Tyr Thr
35 40 45Phe Glu Phe Asp Gly Asp Glu Leu
Phe Tyr Val Asp Leu Asp Lys Lys 50 55
60Glu Thr Val Trp Met Leu Pro Glu Phe Gly Gln Leu Thr Ser Phe Asp65
70 75 80Pro Gln Gly Gly Leu
Gln Glu Ile Ala Thr Gly Lys Tyr Asn Leu Glu 85
90 95Ile Leu Ile Lys Asp Ser Asn Phe Thr Pro Ala
Ala Asn Glu Ala Pro 100 105
110Gln Ala Thr Val Phe Pro Lys Ser Pro Val Leu Leu Gly Gln Pro Asn
115 120 125Thr Leu Ile Cys Phe Val Asp
Asn Ile Phe Pro Pro Val Ile Asn Ile 130 135
140Thr Trp Leu Arg Asn Ser Lys Ser Val Thr Asp Gly Val Tyr Glu
Thr145 150 155 160Ser Phe
Leu Val Asn Arg Asp His Ser Phe His Lys Leu Ser Tyr Leu
165 170 175Thr Phe Ile Pro Ser Asp Asp
Asp Ile Tyr Asp Cys Lys Val Glu His 180 185
190Trp Gly Leu Glu Glu Pro Val Leu Lys His Trp Glu Pro Glu
Ile Pro 195 200 205Ala Pro Met Ser
Glu Leu Thr Glu Thr Val Ile Cys Ala Leu Gly Leu 210
215 220Ser Val Gly Leu Val Gly Ile Val Val Gly Thr Ile
Phe Ile Ile Gln225 230 235
240Gly Leu Arg Ser Gly Gly Thr Ser Arg His 245
25011349PRTMus musculus 11Met Ala Gln Arg Thr Leu Phe Leu Leu Leu
Ala Ala Ala Leu Thr Met1 5 10
15Ile Glu Thr Arg Ala Gly Pro His Ser Met Arg Tyr Phe Glu Thr Ala
20 25 30Val Phe Arg Pro Gly Leu
Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr 35 40
45Val Asp Asn Thr Gln Phe Val Ser Phe Asp Ser Asp Ala Glu
Asn Pro 50 55 60Arg Ser Glu Pro Arg
Ala Pro Trp Met Glu Gln Glu Gly Pro Glu Tyr65 70
75 80Trp Glu Arg Glu Thr Gln Ile Ala Lys Asp
Asn Glu Gln Ser Phe Gly 85 90
95Trp Ser Leu Arg Asn Leu Ile His Tyr Tyr Asn Gln Ser Lys Gly Gly
100 105 110Phe His Thr Phe Gln
Arg Leu Ser Gly Cys Asp Met Gly Leu Asp Gly 115
120 125Arg Leu Leu Arg Gly Tyr Leu Gln Phe Ala Tyr Asp
Gly Arg Asp Tyr 130 135 140Ile Thr Leu
Asn Glu Asp Leu Lys Thr Trp Met Ala Ala Asp Leu Val145
150 155 160Ala Leu Ile Thr Arg Arg Lys
Trp Glu Gln Ala Gly Ala Ala Glu Leu 165
170 175Tyr Lys Phe Tyr Leu Glu Gly Glu Cys Val Glu Trp
Leu Arg Arg Tyr 180 185 190Leu
Glu Leu Gly Asn Glu Thr Leu Leu Arg Thr Asp Pro Pro Lys Ala 195
200 205His Val Thr His His Pro Arg Pro Ala
Gly Asp Val Thr Leu Arg Cys 210 215
220Trp Ala Leu Gly Phe Tyr Pro Ala Asp Ile Thr Leu Thr Trp Gln Leu225
230 235 240Asn Gly Glu Glu
Leu Thr Gln Asp Met Glu Leu Val Glu Thr Arg Pro 245
250 255Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala
Ala Val Val Val Pro Leu 260 265
270Gly Lys Glu Gln Asn Tyr Thr Cys His Val Tyr His Glu Gly Leu Pro
275 280 285Glu Pro Leu Thr Leu Arg Trp
Glu Pro Pro Pro Ser Thr Gly Ser Asn 290 295
300Met Val Asn Ile Ala Val Leu Val Val Leu Gly Ala Val Ile Ile
Ile305 310 315 320Glu Ala
Met Val Ala Phe Val Leu Lys Ser Ser Arg Lys Ile Ala Ile
325 330 335Leu Pro Gly Pro Ala Gly Thr
Lys Gly Ser Ser Ala Ser 340 34512350PRTMus
musculus 12Met Ala Pro Cys Thr Leu Leu Leu Leu Leu Ala Ala Ala Leu Ala
Pro1 5 10 15Thr Gln Thr
Arg Ala Ala Arg Ala Ala Ala Arg Gly Pro Val Arg Arg 20
25 30Ser Gly Ser His Arg Ala Pro Pro Pro Gly
Pro His Ser Leu Ser Asp 35 40
45Ala Asp Asn Pro Arg Phe Glu Pro Arg Ala Pro Trp Met Glu Gln Glu 50
55 60Gly Pro Glu Tyr Trp Glu Glu Gln Thr
Gln Arg Ala Lys Ser Asp Glu65 70 75
80Gln Trp Phe Arg Val Ser Leu Arg Thr Ala Gln Arg Tyr Tyr
Asn Gln 85 90 95Ser Lys
Gly Gly Ser His Thr Phe Gln Arg Met Phe Gly Cys Asp Val 100
105 110Gly Ser Asp Trp Arg Leu Leu Arg Gly
Tyr Gln Gln Phe Ala Tyr Asp 115 120
125Gly Arg Asp Tyr Ile Ala Leu Asn Glu Asp Leu Lys Thr Trp Thr Ala
130 135 140Ala Asp Thr Ala Ala Leu Ile
Thr Arg Arg Lys Trp Glu Gln Ala Gly145 150
155 160Asp Ala Glu Tyr Tyr Arg Ala Tyr Leu Glu Gly Glu
Cys Val Glu Trp 165 170
175Leu Arg Arg Tyr Leu Glu Leu Gly Asn Glu Thr Leu Leu Arg Thr Asp
180 185 190Ser Pro Lys Ala His Val
Thr Tyr His Pro Arg Ser Gln Val Asp Val 195 200
205Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Asp Ile
Thr Leu 210 215 220Thr Trp Gln Leu Asn
Gly Glu Asp Leu Thr Gln Asp Met Glu Leu Val225 230
235 240Glu Thr Arg Pro Ala Gly Asp Gly Thr Phe
Gln Lys Trp Ala Ala Val 245 250
255Val Val Pro Leu Gly Lys Glu Gln Asn Tyr Thr Cys His Val His His
260 265 270Lys Gly Leu Pro Glu
Pro Leu Thr Leu Arg Trp Lys Leu Pro Pro Pro 275
280 285Thr Val Ser Asn Thr Val Ile Ile Ala Val Leu Val
Val Leu Gly Ala 290 295 300Ala Ile Val
Thr Gly Ala Val Val Ala Phe Val Met Lys Met Arg Arg305
310 315 320Asn Thr Gly Gly Lys Gly Val
Asn Tyr Ala Leu Ala Pro Gly Ser Gln 325
330 335Thr Ser Asp Leu Ser Leu Pro Asp Gly Lys Val Met
Val His 340 345 35013264PRTMus
musculus 13Met Val Trp Leu Pro Arg Val Pro Cys Val Ala Ala Val Ile Leu
Leu1 5 10 15Leu Thr Val
Leu Ser Pro Pro Met Ala Leu Val Arg Asp Ser Arg Pro 20
25 30Trp Phe Leu Glu Tyr Cys Lys Ser Glu Cys
His Phe Tyr Asn Gly Thr 35 40
45Gln Arg Val Arg Leu Leu Glu Arg Tyr Phe Tyr Asn Leu Glu Glu Asn 50
55 60Leu Arg Phe Asp Ser Asp Val Gly Glu
Phe His Ala Val Thr Glu Leu65 70 75
80Gly Arg Pro Asp Ala Glu Asn Trp Asn Ser Gln Pro Glu Phe
Leu Glu 85 90 95Gln Lys
Arg Ala Glu Val Asp Thr Val Cys Arg His Asn Tyr Glu Ile 100
105 110Ser Asp Lys Phe Leu Val Arg Arg Arg
Val Glu Pro Thr Val Thr Val 115 120
125Tyr Pro Thr Lys Thr Gln Pro Leu Glu His His Asn Leu Leu Val Cys
130 135 140Ser Val Ser Asp Phe Tyr Pro
Gly Asn Ile Glu Val Arg Trp Phe Arg145 150
155 160Asn Gly Lys Glu Glu Lys Thr Gly Ile Val Ser Thr
Gly Leu Val Arg 165 170
175Asn Gly Asp Trp Thr Phe Gln Thr Leu Val Met Leu Glu Thr Val Pro
180 185 190Gln Ser Gly Glu Val Tyr
Thr Cys Gln Val Glu His Pro Ser Leu Thr 195 200
205Asp Pro Val Thr Val Glu Trp Lys Ala Gln Ser Thr Ser Ala
Gln Asn 210 215 220Lys Met Leu Ser Gly
Val Gly Gly Phe Val Leu Gly Leu Leu Phe Leu225 230
235 240Gly Ala Gly Leu Phe Ile Tyr Phe Arg Asn
Gln Lys Gly Gln Ser Gly 245 250
255Leu Gln Pro Thr Gly Leu Leu Ser 26014255PRTMus
musculus 14Met Ala Thr Ile Gly Ala Leu Val Leu Arg Phe Phe Phe Ile Ala
Val1 5 10 15Leu Met Ser
Ser Gln Lys Ser Trp Ala Ile Lys Glu Glu His Thr Ile 20
25 30Ile Gln Ala Glu Phe Tyr Leu Leu Pro Asp
Lys Arg Gly Glu Phe Met 35 40
45Phe Asp Phe Asp Gly Asp Glu Ile Phe His Val Asp Ile Glu Lys Ser 50
55 60Glu Thr Ile Trp Arg Leu Glu Glu Phe
Ala Lys Phe Ala Ser Phe Glu65 70 75
80Ala Gln Gly Ala Leu Ala Asn Ile Ala Val Asp Lys Ala Asn
Leu Asp 85 90 95Val Met
Lys Glu Arg Ser Asn Asn Thr Pro Asp Ala Asn Val Ala Pro 100
105 110Glu Val Thr Val Leu Ser Arg Ser Pro
Val Asn Leu Gly Glu Pro Asn 115 120
125Ile Leu Ile Cys Phe Ile Asp Lys Phe Ser Pro Pro Val Val Asn Val
130 135 140Thr Trp Leu Arg Asn Gly Arg
Pro Val Thr Glu Gly Val Ser Glu Thr145 150
155 160Val Phe Leu Pro Arg Asp Asp His Leu Phe Arg Lys
Phe His Tyr Leu 165 170
175Thr Phe Leu Pro Ser Thr Asp Asp Phe Tyr Asp Cys Glu Val Asp His
180 185 190Trp Gly Leu Glu Glu Pro
Leu Arg Lys His Trp Glu Phe Glu Glu Lys 195 200
205Thr Leu Leu Pro Glu Thr Lys Glu Asn Val Val Cys Ala Leu
Gly Leu 210 215 220Phe Val Gly Leu Val
Gly Ile Val Val Gly Ile Ile Leu Ile Met Lys225 230
235 240Gly Ile Lys Lys Arg Asn Val Val Glu Arg
Arg Gln Gly Ala Leu 245 250
25515263PRTMus musculus 15Met Trp Leu Pro Arg Val Pro Cys Val Ala Ala
Val Ile Leu Leu Leu1 5 10
15Thr Val Leu Ser Pro Pro Val Ala Leu Val Arg Asp Ser Arg Pro Trp
20 25 30Phe Leu Glu Tyr Cys Lys Ser
Glu Cys His Phe Tyr Asn Gly Thr Gln 35 40
45Arg Val Arg Leu Leu Val Arg Tyr Phe Tyr Asn Leu Glu Glu Asn
Leu 50 55 60Arg Phe Asp Ser Asp Val
Gly Glu Phe Arg Ala Val Thr Glu Leu Gly65 70
75 80Arg Pro Asp Ala Glu Asn Trp Asn Ser Gln Pro
Glu Phe Leu Glu Gln 85 90
95Lys Arg Ala Glu Val Asp Thr Val Cys Arg His Asn Tyr Glu Ile Phe
100 105 110Asp Asn Phe Leu Val Pro
Arg Arg Val Glu Pro Thr Val Thr Val Tyr 115 120
125Pro Thr Lys Thr Gln Pro Leu Glu His His Asn Leu Leu Val
Cys Ser 130 135 140Val Ser Asp Phe Tyr
Pro Gly Asn Ile Glu Val Arg Trp Phe Arg Asn145 150
155 160Gly Lys Glu Glu Lys Thr Gly Ile Val Ser
Thr Gly Leu Val Arg Asn 165 170
175Gly Asp Trp Thr Phe Gln Thr Leu Val Met Leu Glu Thr Val Pro Gln
180 185 190Ser Gly Glu Val Tyr
Thr Cys Gln Val Glu His Pro Ser Leu Thr Asp 195
200 205Pro Val Thr Val Glu Trp Lys Ala Gln Ser Thr Ser
Ala Gln Asn Lys 210 215 220Met Leu Ser
Gly Val Gly Gly Phe Val Leu Gly Leu Leu Phe Leu Gly225
230 235 240Ala Gly Leu Phe Ile Tyr Phe
Arg Asn Gln Lys Gly Gln Ser Gly Leu 245
250 255Gln Pro Thr Gly Leu Leu Ser
26016142PRTHomo sapiens 16Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln
Leu Arg Asp Ser1 5 10
15Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
20 25 30Thr Asn Val Ser Gln Ser Lys
Asp Ser Asp Val Tyr Ile Thr Asp Lys 35 40
45Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
Val 50 55 60Ala Trp Ser Asn Lys Ser
Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn65 70
75 80Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
Pro Glu Ser Ser Cys 85 90
95Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
100 105 110Phe Gln Asn Leu Ser Val
Ile Gly Phe Arg Ile Leu Leu Leu Lys Val 115 120
125Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135 14017177PRTHomo sapiens 17Glu
Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro1
5 10 15Ser Glu Ala Glu Ile Ser His
Thr Gln Lys Ala Thr Leu Val Cys Leu 20 25
30Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
Val Asn 35 40 45Gly Lys Glu Val
His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys 50 55
60Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
Ser Arg Leu65 70 75
80Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
85 90 95Gln Val Gln Phe Tyr Gly
Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp 100
105 110Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
Ala Trp Gly Arg 115 120 125Ala Asp
Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly Val Leu Ser 130
135 140Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
Ala Thr Leu Tyr Ala145 150 155
160Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
165 170 175Phe18178PRTHomo
sapiens 18Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
Ser1 5 10 15Glu Ala Glu
Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala 20
25 30Thr Gly Phe Tyr Pro Asp His Val Glu Leu
Ser Trp Trp Val Asn Gly 35 40
45Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys Glu 50
55 60Gln Pro Ala Leu Asn Asp Ser Arg Tyr
Cys Leu Ser Ser Arg Leu Arg65 70 75
80Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg
Cys Gln 85 90 95Val Gln
Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg 100
105 110Ala Lys Pro Val Thr Gln Ile Val Ser
Ala Glu Ala Trp Gly Arg Ala 115 120
125Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser Ala
130 135 140Thr Ile Leu Tyr Glu Ile Leu
Leu Gly Lys Ala Thr Leu Tyr Ala Val145 150
155 160Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
Arg Lys Asp Ser 165 170
175Arg Gly19153PRTHomo sapiens 19Ser Gln Pro His Thr Lys Pro Ser Val Phe
Val Met Lys Asn Gly Thr1 5 10
15Asn Val Ala Cys Leu Val Lys Glu Phe Tyr Pro Lys Asp Ile Arg Ile
20 25 30Asn Leu Val Ser Ser Lys
Lys Ile Thr Glu Phe Asp Pro Ala Ile Val 35 40
45Ile Ser Pro Ser Gly Lys Tyr Asn Ala Val Lys Leu Gly Lys
Tyr Glu 50 55 60Asp Ser Asn Ser Val
Thr Cys Ser Val Gln His Asp Asn Lys Thr Val65 70
75 80His Ser Thr Asp Phe Glu Val Lys Thr Asp
Ser Thr Asp His Val Lys 85 90
95Pro Lys Glu Thr Glu Asn Thr Lys Gln Pro Ser Lys Ser Cys His Lys
100 105 110Pro Lys Ala Ile Val
His Thr Glu Lys Val Asn Met Met Ser Leu Thr 115
120 125Val Leu Gly Leu Arg Met Leu Phe Ala Lys Thr Val
Ala Val Asn Phe 130 135 140Leu Leu Thr
Ala Lys Leu Phe Phe Leu145 15020173PRTHomo sapiens 20Asp
Lys Gln Leu Asp Ala Asp Val Ser Pro Lys Pro Thr Ile Phe Leu1
5 10 15Pro Ser Ile Ala Glu Thr Lys
Leu Gln Lys Ala Gly Thr Tyr Leu Cys 20 25
30Leu Leu Glu Lys Phe Phe Pro Asp Val Ile Lys Ile His Trp
Gln Glu 35 40 45Lys Lys Ser Asn
Thr Ile Leu Gly Ser Gln Glu Gly Asn Thr Met Lys 50 55
60Thr Asn Asp Thr Tyr Met Lys Phe Ser Trp Leu Thr Val
Pro Glu Lys65 70 75
80Ser Leu Asp Lys Glu His Arg Cys Ile Val Arg His Glu Asn Asn Lys
85 90 95Asn Gly Val Asp Gln Glu
Ile Ile Phe Pro Pro Ile Lys Thr Asp Val 100
105 110Ile Thr Met Asp Pro Lys Asp Asn Cys Ser Lys Asp
Ala Asn Asp Thr 115 120 125Leu Leu
Leu Gln Leu Thr Asn Thr Ser Ala Tyr Tyr Met Tyr Leu Leu 130
135 140Leu Leu Leu Lys Ser Val Val Tyr Phe Ala Ile
Ile Thr Cys Cys Leu145 150 155
160Leu Arg Arg Thr Ala Phe Cys Cys Asn Gly Glu Lys Ser
165 17021189PRTHomo sapiens 21Asp Lys Gln Leu Asp Ala
Asp Val Ser Pro Lys Pro Thr Ile Phe Leu1 5
10 15Pro Ser Ile Ala Glu Thr Lys Leu Gln Lys Ala Gly
Thr Tyr Leu Cys 20 25 30Leu
Leu Glu Lys Phe Phe Pro Asp Ile Ile Lys Ile His Trp Gln Glu 35
40 45Lys Lys Ser Asn Thr Ile Leu Gly Ser
Gln Glu Gly Asn Thr Met Lys 50 55
60Thr Asn Asp Thr Tyr Met Lys Phe Ser Trp Leu Thr Val Pro Glu Glu65
70 75 80Ser Leu Asp Lys Glu
His Arg Cys Ile Val Arg His Glu Asn Asn Lys 85
90 95Asn Gly Ile Asp Gln Glu Ile Ile Phe Pro Pro
Ile Lys Thr Asp Val 100 105
110Thr Thr Val Asp Pro Lys Asp Ser Tyr Ser Lys Asp Ala Asn Asp Val
115 120 125Ile Thr Met Asp Pro Lys Asp
Asn Trp Ser Lys Asp Ala Asn Asp Thr 130 135
140Leu Leu Leu Gln Leu Thr Asn Thr Ser Ala Tyr Tyr Met Tyr Leu
Leu145 150 155 160Leu Leu
Leu Lys Ser Val Val Tyr Phe Ala Ile Ile Thr Cys Cys Leu
165 170 175Leu Gly Arg Thr Ala Phe Cys
Cys Asn Gly Glu Lys Ser 180 18522138PRTMus
musculus 22Pro Tyr Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
Pro1 5 10 15Arg Ser Gln
Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln 20
25 30Ile Asn Val Pro Lys Thr Met Glu Ser Gly
Thr Phe Ile Thr Asp Lys 35 40
45Thr Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile 50
55 60Ala Trp Ser Asn Gln Thr Ser Phe Thr
Cys Gln Asp Ile Phe Lys Glu65 70 75
80Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
Thr Leu 85 90 95Thr Glu
Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu 100
105 110Ser Val Met Gly Leu Arg Ile Leu Leu
Leu Lys Val Ala Gly Phe Asn 115 120
125Leu Leu Met Thr Leu Arg Leu Trp Ser Ser 130
13523173PRTMus musculus 23Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser
Leu Phe Glu Pro1 5 10
15Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
20 25 30Ala Arg Gly Phe Phe Pro Asp
His Val Glu Leu Ser Trp Trp Val Asn 35 40
45Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr
Lys 50 55 60Glu Ser Asn Tyr Ser Tyr
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala65 70
75 80Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
Cys Gln Val Gln Phe 85 90
95His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
100 105 110Val Thr Gln Asn Ile Ser
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly 115 120
125Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
Ile Leu 130 135 140Tyr Glu Ile Leu Leu
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser145 150
155 160Thr Leu Val Val Met Ala Met Val Lys Arg
Lys Asn Ser 165 17024173PRTMus musculus
24Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro1
5 10 15Ser Lys Ala Glu Ile Ala
Asn Lys Gln Lys Ala Thr Leu Val Cys Leu 20 25
30Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
Trp Val Asn 35 40 45Gly Lys Glu
Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr Lys 50
55 60Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
Arg Val Ser Ala65 70 75
80Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
85 90 95His Gly Leu Ser Glu Glu
Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro 100
105 110Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
Ala Asp Cys Gly 115 120 125Ile Thr
Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu 130
135 140Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
Ala Val Leu Val Ser145 150 155
160Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn Ser
165 17025167PRTMus musculus 25Asp Lys Arg Leu Asp Ala
Asp Ile Ser Pro Lys Pro Thr Ile Phe Leu1 5
10 15Pro Ser Val Ala Glu Thr Asn Leu His Lys Thr Gly
Thr Tyr Leu Cys 20 25 30Leu
Leu Glu Lys Phe Phe Pro Asp Val Ile Arg Val Tyr Trp Lys Glu 35
40 45Lys Asn Gly Asn Thr Ile Leu Asp Ser
Gln Glu Gly Asp Thr Leu Lys 50 55
60Thr Lys Gly Thr Tyr Met Lys Phe Ser Trp Leu Thr Val Pro Glu Arg65
70 75 80Ala Met Gly Lys Glu
His Ser Cys Ile Val Lys His Glu Asn Asn Lys 85
90 95Gly Gly Ala Asp Gln Glu Ile Phe Phe Pro Ser
Ile Lys Lys Val Ala 100 105
110Thr Thr Cys Trp Gln Asp Lys Asn Asp Val Leu Gln Phe Gln Phe Thr
115 120 125Ser Thr Ser Ala Tyr Tyr Thr
Tyr Leu Leu Leu Leu Leu Lys Ser Val 130 135
140Ile Tyr Leu Ala Ile Ile Ser Phe Ser Leu Leu Arg Arg Thr Ser
Val145 150 155 160Cys Gly
Asn Glu Lys Lys Ser 16526172PRTMus musculus 26Asp Lys Lys
Leu Asp Ala Asp Ile Ser Pro Lys Pro Thr Ile Phe Leu1 5
10 15Pro Ser Val Ala Glu Thr Asn Leu His
Lys Thr Gly Thr Tyr Leu Cys 20 25
30Val Leu Glu Lys Phe Phe Pro Asp Val Ile Arg Val Tyr Trp Lys Glu
35 40 45Lys Lys Gly Asn Thr Ile Leu
Asp Ser Gln Glu Gly Asp Met Leu Lys 50 55
60Thr Asn Asp Thr Tyr Met Lys Phe Ser Trp Leu Thr Val Pro Glu Arg65
70 75 80Ser Met Gly Lys
Glu His Arg Cys Ile Val Lys His Glu Asn Asn Lys 85
90 95Gly Gly Ala Asp Gln Glu Ile Phe Phe Pro
Thr Ile Lys Lys Val Ala 100 105
110Val Ser Thr Lys Pro Thr Thr Cys Trp Gln Asp Lys Asn Asp Val Leu
115 120 125Gln Leu Gln Phe Thr Ile Thr
Ser Ala Tyr Tyr Thr Tyr Leu Leu Leu 130 135
140Leu Leu Lys Ser Val Ile Tyr Leu Ala Ile Ile Ser Phe Ser Leu
Leu145 150 155 160Arg Arg
Thr Ser Val Cys Cys Asn Glu Lys Lys Ser 165
17027169PRTMus musculus 27Pro Ser Asp Lys Arg Leu Asp Ala Asp Ile Ser
Pro Lys Pro Thr Ile1 5 10
15Phe Leu Pro Ser Val Ala Glu Thr Asn Leu His Lys Thr Gly Thr Tyr
20 25 30Leu Cys Ile Leu Glu Lys Phe
Phe Pro Asp Val Ile Arg Val Tyr Trp 35 40
45Lys Asp Lys Asn Gly Asn Thr Ile Leu Asp Ser Gln Glu Gly Asp
Thr 50 55 60Leu Lys Thr Lys Gly Thr
Tyr Met Lys Phe Ser Trp Leu Thr Val Pro65 70
75 80Glu Arg Ser Met Gly Lys Glu His Arg Cys Ile
Val Lys His Glu Asn 85 90
95Asn Lys Gly Gly Ala Asp Gln Glu Ile Phe Phe Pro Ser Ile Lys Lys
100 105 110Val Ala Thr Thr Cys Trp
Gln Asp Lys Asn Asp Val Leu Gln Leu Gln 115 120
125Phe Met Ser Thr Ser Ala Tyr Tyr Thr Tyr Leu Leu Leu Leu
Leu Lys 130 135 140Ser Val Ile Tyr Leu
Ala Ile Ile Ser Phe Ser Leu Leu Arg Arg Thr145 150
155 160Ser Val Cys Cys Asn Glu Lys Arg Ser
16528190PRTMus musculus 28Asp Lys Arg Thr Asp Ser Asp Phe Ser
Pro Lys Pro Thr Ile Phe Leu1 5 10
15Pro Ser Ala Ala Glu Thr Asn Leu His Lys Ala Gly Thr Tyr Leu
Cys 20 25 30Leu Leu Glu Lys
Phe Phe Pro Lys Val Ile Arg Val Tyr Trp Lys Glu 35
40 45Lys Asp Gly Glu Lys Ile Leu Glu Ser Gln Glu Gly
Asn Thr Ile Lys 50 55 60Thr Asn Asp
Arg Tyr Met Lys Phe Ser Trp Leu Thr Val Thr Glu Asp65 70
75 80Ser Met Ala Lys Glu His Ser Cys
Ile Val Lys His Glu Asn Asn Lys 85 90
95Arg Gly Val Asp Gln Glu Ile Leu Phe Pro Pro Ile Gly Lys
Ala Phe 100 105 110Thr Thr Ile
Asn Val Asn Pro Arg Asp Ser Val Leu Arg His Glu Asn 115
120 125Val Asn Asn Ala Thr Asp Leu Glu Asp Cys Met
Lys Gly Arg Lys Asp 130 135 140Met Leu
Gln Leu Gln Val Thr Thr Thr Tyr Ala Phe Tyr Thr Tyr Leu145
150 155 160Ile Leu Phe Phe Lys Ser Met
Val His Leu Ala Phe Val Val Phe Cys 165
170 175Leu Phe Arg Arg Ala Ala Met Ser Cys Asp Asp Gln
Arg Ser 180 185
1902916PRTManduca sexta 29Ala Asn Glu Arg Ala Asp Leu Ile Ala Tyr Leu Lys
Gln Ala Thr Lys1 5 10
1530263PRTArtificial SequenceSynthetic sequence comprising a MHC portion
and a TCR portion 30Met Ala Thr Ile Gly Ala Leu Leu Leu Arg Phe Phe
Phe Ile Ala Val1 5 10
15Leu Met Ser Ser Gln Lys Ser Trp Ala Ile Lys Glu Glu His Thr Ile
20 25 30Ile Gln Ala Glu Phe Tyr Leu
Leu Pro Asp Lys Arg Gly Glu Phe Met 35 40
45Phe Asp Phe Asp Gly Asp Glu Ile Phe His Val Asp Ile Glu Lys
Ser 50 55 60Glu Thr Ile Trp Arg Leu
Glu Glu Phe Ala Lys Phe Ala Ser Phe Glu65 70
75 80Ala Gln Gly Ala Leu Ala Asn Ile Ala Val Asp
Lys Ala Asn Leu Asp 85 90
95Val Met Lys Glu Arg Ser Asn Asn Thr Pro Asp Ala Asn Val Ala Pro
100 105 110Glu Val Thr Val Leu Ser
Arg Ser Pro Val Asn Leu Gly Glu Pro Asn 115 120
125Ile Leu Ile Cys Phe Ile Asp Lys Phe Ser Pro Pro Val Val
Asn Val 130 135 140Thr Trp Phe Arg Asn
Gly Arg Pro Val Thr Glu Gly Val Ser Glu Thr145 150
155 160Val Phe Leu Pro Arg Asp Asp His Leu Phe
Arg Lys Phe His Tyr Leu 165 170
175Thr Phe Leu Pro Ser Thr Asp Asp Phe Tyr Asp Cys Glu Val Asp His
180 185 190Trp Gly Leu Glu Glu
Pro Leu Arg Lys His Trp Glu Phe Glu Glu Lys 195
200 205Thr Leu Leu Pro Glu Thr Lys Glu Cys Asp Ala Thr
Leu Thr Glu Lys 210 215 220Ser Phe Glu
Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser Val Met225
230 235 240Gly Leu Arg Ile Leu Leu Leu
Lys Val Ala Gly Phe Asn Leu Leu Met 245
250 255Thr Leu Arg Leu Trp Ser Ser
26031315PRTArtificial SequenceSynthetic sequence comprising a MHC portion
and a TCR portion 31Met Val Trp Leu Pro Arg Val Pro Cys Val Ala Ala
Val Ile Leu Leu1 5 10
15Leu Thr Val Leu Ser Pro Pro Val Ala Leu Val Arg Asp Ser Gly Ser
20 25 30Ala Asn Glu Arg Ala Asp Leu
Ile Ala Tyr Leu Lys Gln Ala Thr Lys 35 40
45Glu Phe Arg Ser Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser
Gly 50 55 60Gly Gly Gly Ser Val Asp
Arg Pro Trp Phe Leu Glu Tyr Cys Lys Ser65 70
75 80Glu Cys His Phe Tyr Asn Gly Thr Gln Arg Val
Arg Leu Leu Val Arg 85 90
95Tyr Phe Tyr Asn Leu Glu Glu Asn Leu Arg Phe Asp Ser Asp Val Gly
100 105 110Glu Phe Arg Ala Val Thr
Glu Leu Gly Arg Pro Asp Ala Glu Asn Trp 115 120
125Asn Ser Gln Pro Glu Phe Leu Glu Gln Lys Arg Ala Glu Val
Asp Thr 130 135 140Val Cys Arg His Asn
Tyr Glu Ile Phe Asp Asn Phe Leu Val Pro Arg145 150
155 160Arg Val Glu Pro Thr Val Thr Val Tyr Pro
Thr Lys Thr Gln Pro Leu 165 170
175Glu His His Asn Leu Leu Val Cys Ser Val Ser Asp Phe Tyr Pro Gly
180 185 190Asn Ile Glu Val Arg
Trp Phe Arg Asn Gly Lys Glu Glu Lys Thr Gly 195
200 205Ile Val Ser Thr Gly Leu Val Arg Asn Gly Asp Trp
Thr Phe Gln Thr 210 215 220Leu Val Met
Leu Glu Thr Val Pro Gln Ser Gly Glu Val Tyr Thr Cys225
230 235 240Gln Val Glu His Pro Ser Leu
Thr Asp Pro Val Thr Val Glu Trp Lys 245
250 255Ala Gln Ser Thr Ser Ala Gln Asn Lys Cys Gly Ile
Thr Ser Ala Ser 260 265 270Tyr
His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu 275
280 285Gly Lys Ala Thr Leu Tyr Ala Val Leu
Val Ser Gly Leu Val Leu Met 290 295
300Ala Met Val Lys Lys Lys Asn Ser Ala Ala Ala305 310
31532312PRTArtificial SequenceSynthetic sequence comprising a
MHC portion and a TCR portion 32Met Val Trp Leu Pro Arg Val Pro Cys
Val Ala Ala Val Ile Leu Leu1 5 10
15Leu Thr Val Leu Ser Pro Pro Val Ala Leu Val Arg Asp Ser Gly
Ser 20 25 30Gly Lys Lys Val
Ile Thr Ala Phe Asn Glu Gly Leu Lys Glu Phe Arg 35
40 45Ser Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser
Gly Gly Gly Gly 50 55 60Ser Val Asp
Arg Pro Trp Phe Leu Glu Tyr Cys Lys Ser Glu Cys His65 70
75 80Phe Tyr Asn Gly Thr Gln Arg Val
Arg Leu Leu Val Arg Tyr Phe Tyr 85 90
95Asn Leu Glu Glu Asn Leu Arg Phe Asp Ser Asp Val Gly Glu
Phe Arg 100 105 110Ala Val Thr
Glu Leu Gly Arg Pro Asp Ala Glu Asn Trp Asn Ser Gln 115
120 125Pro Glu Phe Leu Glu Gln Lys Arg Ala Glu Val
Asp Thr Val Cys Arg 130 135 140His Asn
Tyr Glu Ile Phe Asp Asn Phe Leu Val Pro Arg Arg Val Glu145
150 155 160Pro Thr Val Thr Val Tyr Pro
Thr Lys Thr Gln Pro Leu Glu His His 165
170 175Asn Leu Leu Val Cys Ser Val Ser Asp Phe Tyr Pro
Gly Asn Ile Glu 180 185 190Val
Arg Trp Phe Arg Asn Gly Lys Glu Glu Lys Thr Gly Ile Val Ser 195
200 205Thr Gly Leu Val Arg Asn Gly Asp Trp
Thr Phe Gln Thr Leu Val Met 210 215
220Leu Glu Thr Val Pro Gln Ser Gly Glu Val Tyr Thr Cys Gln Val Glu225
230 235 240His Pro Ser Leu
Thr Asp Pro Val Thr Val Glu Trp Lys Ala Gln Ser 245
250 255Thr Ser Ala Gln Asn Lys Cys Gly Ile Thr
Ser Ala Ser Tyr His Gln 260 265
270Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285Thr Leu Tyr Ala Val Leu Val
Ser Gly Leu Val Leu Met Ala Met Val 290 295
300Lys Lys Lys Asn Ser Ala Ala Ala305
31033797PRTArtificial SequenceSynthetic peptide comprising a fusion of
CD80 and Lck 33Met Ala Cys Asn Cys Gln Leu Met Gln Asp Thr Pro Leu Leu
Lys Phe1 5 10 15Pro Cys
Pro Arg Leu Ile Leu Leu Phe Val Leu Leu Ile Arg Leu Ser 20
25 30Gln Val Ser Ser Asp Val Asp Glu Gln
Leu Ser Lys Ser Val Lys Asp 35 40
45Lys Val Leu Leu Pro Cys Arg Tyr Asn Ser Pro His Glu Asp Glu Ser 50
55 60Glu Asp Arg Ile Tyr Trp Gln Lys His
Asp Lys Val Val Leu Ser Val65 70 75
80Ile Ala Gly Lys Leu Lys Val Trp Pro Glu Tyr Lys Asn Arg
Thr Leu 85 90 95Tyr Asp
Asn Thr Thr Tyr Ser Leu Ile Ile Leu Gly Leu Val Leu Ser 100
105 110Asp Arg Gly Thr Tyr Ser Cys Val Val
Gln Lys Lys Glu Arg Gly Thr 115 120
125Tyr Glu Val Lys His Leu Ala Leu Val Lys Leu Ser Ile Lys Ala Asp
130 135 140Phe Ser Thr Pro Asn Ile Thr
Glu Ser Gly Asn Pro Ser Ala Asp Thr145 150
155 160Lys Arg Ile Thr Cys Phe Ala Ser Gly Gly Phe Pro
Lys Pro Arg Phe 165 170
175Ser Trp Leu Glu Asn Gly Arg Glu Leu Pro Gly Ile Asn Thr Thr Ile
180 185 190Ser Gln Asp Pro Glu Ser
Glu Leu Tyr Thr Ile Ser Ser Gln Leu Asp 195 200
205Phe Asn Thr Thr Arg Asn His Thr Ile Lys Cys Leu Ile Lys
Tyr Gly 210 215 220Asp Ala His Val Ser
Glu Asp Phe Thr Trp Glu Lys Pro Pro Glu Asp225 230
235 240Pro Pro Asp Ser Lys Asn Thr Leu Val Leu
Phe Gly Ala Gly Phe Gly 245 250
255Ala Val Ile Thr Val Val Val Ile Val Val Ile Ile Lys Cys Phe Cys
260 265 270Lys His Arg Ser Cys
Phe Arg Arg Asn Glu Ala Ser Arg Glu Thr Asn 275
280 285Asn Ser Leu Thr Phe Gly Pro Glu Glu Ala Leu Ala
Glu Gln Thr Val 290 295 300Phe Leu Thr
Thr Ser His Tyr Pro Ile Val Pro Leu Asp Ser Lys Ile305
310 315 320Ser Leu Pro Ile Arg Asn Gly
Ser Glu Val Arg Asp Pro Leu Val Thr 325
330 335Tyr Glu Gly Ser Leu Pro Pro Ala Ser Pro Leu Gln
Asp Asn Leu Val 340 345 350Ile
Ala Leu His Ser Tyr Glu Pro Ser His Asp Gly Asp Leu Gly Phe 355
360 365Glu Lys Gly Glu Gln Leu Arg Ile Leu
Glu Gln Ser Gly Glu Trp Trp 370 375
380Lys Ala Gln Ser Leu Thr Thr Gly Gln Glu Gly Phe Ile Pro Phe Asn385
390 395 400Phe Val Ala Lys
Ala Asn Ser Leu Glu Pro Glu Pro Trp Phe Phe Lys 405
410 415Asn Leu Ser Arg Lys Asp Ala Glu Arg Gln
Leu Leu Ala Pro Gly Asn 420 425
430Thr His Gly Ser Phe Leu Ile Arg Glu Ser Glu Ser Thr Ala Gly Ser
435 440 445Phe Ser Leu Ser Val Arg Asp
Phe Asp Gln Asn Gln Gly Glu Val Val 450 455
460Lys His Tyr Lys Ile Arg Asn Leu Asp Asn Gly Gly Phe Tyr Ile
Ser465 470 475 480Pro Arg
Ile Thr Phe Pro Gly Leu His Asp Leu Val Arg His Tyr Thr
485 490 495Asn Ala Ser Asp Gly Leu Cys
Thr Lys Leu Ser Arg Pro Cys Gln Thr 500 505
510Gln Lys Pro Gln Lys Pro Trp Trp Glu Asp Glu Trp Glu Val
Pro Arg 515 520 525Glu Thr Leu Lys
Leu Val Glu Arg Leu Gly Ala Gly Gln Phe Gly Glu 530
535 540Val Trp Met Gly Tyr Tyr Asn Gly His Thr Lys Val
Ala Val Lys Ser545 550 555
560Leu Lys Gln Gly Ser Met Ser Pro Asp Ala Phe Leu Ala Glu Ala Asn
565 570 575Leu Met Lys Gln Leu
Gln His Pro Arg Leu Val Arg Leu Tyr Ala Val 580
585 590Val Thr Gln Glu Pro Ile Tyr Ile Ile Thr Glu Tyr
Met Glu Asn Gly 595 600 605Ser Leu
Val Asp Phe Leu Lys Thr Pro Ser Gly Ile Lys Leu Asn Val 610
615 620Asn Lys Leu Leu Asp Met Ala Ala Gln Ile Ala
Glu Gly Met Ala Phe625 630 635
640Ile Glu Glu Gln Asn Tyr Ile His Arg Asp Leu Arg Ala Ala Asn Ile
645 650 655Leu Val Ser Asp
Thr Leu Ser Cys Lys Ile Ala Asp Phe Gly Leu Ala 660
665 670Arg Leu Ile Glu Asp Asn Glu Tyr Thr Ala Arg
Glu Gly Ala Lys Phe 675 680 685Pro
Ile Lys Trp Thr Ala Pro Glu Ala Ile Asn Tyr Gly Thr Phe Thr 690
695 700Ile Lys Ser Asp Val Trp Ser Phe Gly Ile
Leu Leu Thr Glu Ile Val705 710 715
720Thr His Gly Arg Ile Pro Tyr Pro Gly Met Thr Asn Pro Glu Val
Ile 725 730 735Gln Asn Leu
Glu Arg Gly Tyr Arg Met Val Arg Pro Asp Asn Cys Pro 740
745 750Glu Glu Leu Tyr His Leu Met Met Leu Cys
Trp Lys Glu Arg Pro Glu 755 760
765Asp Arg Pro Thr Phe Asp Tyr Leu Arg Ser Val Leu Asp Asp Phe Phe 770
775 780Thr Ala Thr Glu Gly Gln Tyr Gln
Pro Gln Pro Gly Thr785 790
79534800PRTArtificial SequenceSynthetic peptide comprising a fusion of
CD86 and Lck 34Met Asp Pro Arg Cys Thr Met Gly Leu Ala Ile Leu Ile
Phe Val Thr1 5 10 15Val
Leu Leu Ile Ser Asp Ala Val Ser Val Glu Thr Gln Ala Tyr Phe 20
25 30Asn Gly Thr Ala Tyr Leu Pro Cys
Pro Phe Thr Lys Ala Gln Asn Ile 35 40
45Ser Leu Ser Glu Leu Val Val Phe Trp Gln Asp Gln Gln Lys Leu Val
50 55 60Leu Tyr Glu His Tyr Leu Gly Thr
Glu Lys Leu Asp Ser Val Asn Ala65 70 75
80Lys Tyr Leu Gly Arg Thr Ser Phe Asp Arg Asn Asn Trp
Thr Leu Arg 85 90 95Leu
His Asn Val Gln Ile Lys Asp Met Gly Ser Tyr Asp Cys Phe Ile
100 105 110Gln Lys Lys Pro Pro Thr Gly
Ser Ile Ile Leu Gln Gln Thr Leu Thr 115 120
125Glu Leu Ser Val Ile Ala Asn Phe Ser Glu Pro Glu Ile Lys Leu
Ala 130 135 140Gln Asn Val Thr Gly Asn
Ser Gly Ile Asn Leu Thr Cys Thr Ser Lys145 150
155 160Gln Gly His Pro Lys Pro Lys Lys Met Tyr Phe
Leu Ile Thr Asn Ser 165 170
175Thr Asn Glu Tyr Gly Asp Asn Met Gln Ile Ser Gln Asp Asn Val Thr
180 185 190Glu Leu Phe Ser Ile Ser
Asn Ser Leu Ser Leu Ser Phe Pro Asp Gly 195 200
205Val Trp His Met Thr Val Val Cys Val Leu Glu Thr Glu Ser
Met Lys 210 215 220Ile Ser Ser Lys Pro
Leu Asn Phe Thr Gln Glu Phe Pro Ser Pro Gln225 230
235 240Thr Tyr Trp Lys Glu Ile Thr Ala Ser Val
Thr Val Ala Leu Leu Leu 245 250
255Val Met Leu Leu Ile Ile Val Cys His Lys Lys Pro Asn Gln Pro Ser
260 265 270Arg Pro Ser Asn Thr
Ala Ser Lys Leu Glu Arg Asp Ser Asn Ala Asp 275
280 285Arg Glu Thr Ile Asn Leu Lys Glu Leu Glu Pro Gln
Ile Ala Ser Ala 290 295 300Lys Pro Asn
Ala Glu Cys Thr Ser His Tyr Pro Ile Val Pro Leu Asp305
310 315 320Ser Lys Ile Ser Leu Pro Ile
Arg Asn Gly Ser Glu Val Arg Asp Pro 325
330 335Leu Val Thr Tyr Glu Gly Ser Leu Pro Pro Ala Ser
Pro Leu Gln Asp 340 345 350Asn
Leu Val Ile Ala Leu His Ser Tyr Glu Pro Ser His Asp Gly Asp 355
360 365Leu Gly Phe Glu Lys Gly Glu Gln Leu
Arg Ile Leu Glu Gln Ser Gly 370 375
380Glu Trp Trp Lys Ala Gln Ser Leu Thr Thr Gly Gln Glu Gly Phe Ile385
390 395 400Pro Phe Asn Phe
Val Ala Lys Ala Asn Ser Leu Glu Pro Glu Pro Trp 405
410 415Phe Phe Lys Asn Leu Ser Arg Lys Asp Ala
Glu Arg Gln Leu Leu Ala 420 425
430Pro Gly Asn Thr His Gly Ser Phe Leu Ile Arg Glu Ser Glu Ser Thr
435 440 445Ala Gly Ser Phe Ser Leu Ser
Val Arg Asp Phe Asp Gln Asn Gln Gly 450 455
460Glu Val Val Lys His Tyr Lys Ile Arg Asn Leu Asp Asn Gly Gly
Phe465 470 475 480Tyr Ile
Ser Pro Arg Ile Thr Phe Pro Gly Leu His Asp Leu Val Arg
485 490 495His Tyr Thr Asn Ala Ser Asp
Gly Leu Cys Thr Lys Leu Ser Arg Pro 500 505
510Cys Gln Thr Gln Lys Pro Gln Lys Pro Trp Trp Glu Asp Glu
Trp Glu 515 520 525Val Pro Arg Glu
Thr Leu Lys Leu Val Glu Arg Leu Gly Ala Gly Gln 530
535 540Phe Gly Glu Val Trp Met Gly Tyr Tyr Asn Gly His
Thr Lys Val Ala545 550 555
560Val Lys Ser Leu Lys Gln Gly Ser Met Ser Pro Asp Ala Phe Leu Ala
565 570 575Glu Ala Asn Leu Met
Lys Gln Leu Gln His Pro Arg Leu Val Arg Leu 580
585 590Tyr Ala Val Val Thr Gln Glu Pro Ile Tyr Ile Ile
Thr Glu Tyr Met 595 600 605Glu Asn
Gly Ser Leu Val Asp Phe Leu Lys Thr Pro Ser Gly Ile Lys 610
615 620Leu Asn Val Asn Lys Leu Leu Asp Met Ala Ala
Gln Ile Ala Glu Gly625 630 635
640Met Ala Phe Ile Glu Glu Gln Asn Tyr Ile His Arg Asp Leu Arg Ala
645 650 655Ala Asn Ile Leu
Val Ser Asp Thr Leu Ser Cys Lys Ile Ala Asp Phe 660
665 670Gly Leu Ala Arg Leu Ile Glu Asp Asn Glu Tyr
Thr Ala Arg Glu Gly 675 680 685Ala
Lys Phe Pro Ile Lys Trp Thr Ala Pro Glu Ala Ile Asn Tyr Gly 690
695 700Thr Phe Thr Ile Lys Ser Asp Val Trp Ser
Phe Gly Ile Leu Leu Thr705 710 715
720Glu Ile Val Thr His Gly Arg Ile Pro Tyr Pro Gly Met Thr Asn
Pro 725 730 735Glu Val Ile
Gln Asn Leu Glu Arg Gly Tyr Arg Met Val Arg Pro Asp 740
745 750Asn Cys Pro Glu Glu Leu Tyr His Leu Met
Met Leu Cys Trp Lys Glu 755 760
765Arg Pro Glu Asp Arg Pro Thr Phe Asp Tyr Leu Arg Ser Val Leu Asp 770
775 780Asp Phe Phe Thr Ala Thr Glu Gly
Gln Tyr Gln Pro Gln Pro Gly Thr785 790
795 80035824DNAArtificial SequenceNucleotide sequence for
synthetic peptide comprising an MHC portion and a TCR portion (see
SEQ ID NO 30) 35aataagcttc tcgagcgcca ccatggccac aattggagcc ctgctgttaa
gatttttctt 60cattgctgtt ctgatgagct cccagaagtc atgggctatc aaagaggaac
acaccatcat 120ccaggcggag ttctatcttt taccagacaa acgtggagag tttatgtttg
actttgacgg 180cgatgagatt ttccatgtag acattgaaaa gtcagagacc atctggagac
ttgaagaatt 240tgcaaagttt gccagctttg aggctcaggg tgcactggct aatatagctg
tggacaaagc 300taacctggat gtcatgaaag agcgttccaa caacactcca gatgccaacg
tggccccaga 360ggtgactgta ctctccagaa gccctgtgaa cctgggagag cccaacatcc
tcatctgttt 420cattgacaag ttctcccctc cagtggtcaa tgtcacctgg ttccggaatg
gacggcctgt 480caccgaaggc gtgtcagaga cagtgtttct cccgagggac gatcacctct
tccgcaaatt 540ccactatctg accttcctgc cctccacaga tgatttctat gactgtgagg
tggatcactg 600gggtttggag gagcctctgc ggaagcactg ggagtttgaa gagaaaaccc
tcctcccaga 660aactaaagag tgtgatgcca cgttgaccga gaaaagcttt gaaacagata
tgaacctaaa 720ctttcaaaac ctgtcagtta tgggactccg aatcctcctg ctgaaagtag
cgggatttaa 780cctgctcatg acgctgaggc tgtggtccag ttgaggatcc gcta
82436988DNAArtificial SequenceNucleotide sequence for
synthetic peptide comprising an MHC portion and a TCR portion (see
SEQ ID NO 31) 36aatctcgagc gccaccatgg tgtggctccc cagagttccc tgtgtggcag
ctgtgatcct 60gttgctgaca gtgctgagcc ctccagtggc tttggtcaga gactccggat
ccgccaacga 120gagggccgac ctgatcgcct acctgaagca ggccaccaag gaattcagat
ccggaggcgg 180aggctccctg gtgcctcggg gctccggagg cggaggctcc gtcgacagac
catggttttt 240ggaatactgt aaatctgagt gtcatttcta caacgggacg cagcgcgtgc
ggcttctggt 300aagatacttc tacaacctgg aggagaacct gcgcttcgac agcgacgtgg
gcgagttccg 360cgcggtgacc gagctggggc ggccagacgc cgagaactgg aacagccagc
cggagttcct 420ggagcaaaag cgggccgagg tggacacggt gtgcagacac aactatgaga
tcttcgataa 480cttccttgtg ccgcggagag ttgagcctac ggtgactgtg taccccacaa
agacgcagcc 540cctggaacac cacaacctcc tggtctgctc tgtgagtgac ttctaccctg
gcaacattga 600agtcagatgg ttccggaatg gcaaggagga gaaaacagga attgtgtcca
cgggcctggt 660ccgaaatgga gactggacct tccagacact ggtgatgctg gagacggttc
ctcagagtgg 720agaggtttac acctgccagg tggagcatcc cagcctgacc gaccctgtca
cggtcgagtg 780gaaagcacag tccacatctg cacagaacaa gtgtggaatc actagtgcat
cctatcatca 840gggggttctg tctgcaacca tcctctatga gatcctactg gggaaggcca
ccctatatgc 900tgtgctggtc agtggcctag tgctgatggc catggtcaag aaaaaaaatt
ccgcggccgc 960atgatgagat ctgagctcca tagaggcg
98837979DNAArtificial SequenceNucleotide sequence for
synthetic peptide comprising an MHC portion and a TCR portion (see
SEQ ID NO 32) 37aatctcgagc gccaccatgg tgtggctccc cagagttccc tgtgtggcag
ctgtgatcct 60gttgctgaca gtgctgagcc ctccagtggc tttggtcaga gactccggat
ccggcaagaa 120ggtgatcacc gccttcaacg agggcctgaa ggaattcaga tccggaggcg
gaggctccct 180ggtgcctcgg ggctccggag gcggaggctc cgtcgacaga ccatggtttt
tggaatactg 240taaatctgag tgtcatttct acaacgggac gcagcgcgtg cggcttctgg
taagatactt 300ctacaacctg gaggagaacc tgcgcttcga cagcgacgtg ggcgagttcc
gcgcggtgac 360cgagctgggg cggccagacg ccgagaactg gaacagccag ccggagttcc
tggagcaaaa 420gcgggccgag gtggacacgg tgtgcagaca caactatgag atcttcgata
acttccttgt 480gccgcggaga gttgagccta cggtgactgt gtaccccaca aagacgcagc
ccctggaaca 540ccacaacctc ctggtctgct ctgtgagtga cttctaccct ggcaacattg
aagtcagatg 600gttccggaat ggcaaggagg agaaaacagg aattgtgtcc acgggcctgg
tccgaaatgg 660agactggacc ttccagacac tggtgatgct ggagacggtt cctcagagtg
gagaggttta 720cacctgccag gtggagcatc ccagcctgac cgaccctgtc acggtcgagt
ggaaagcaca 780gtccacatct gcacagaaca agtgtggaat cactagtgca tcctatcatc
agggggttct 840gtctgcaacc atcctctatg agatcctact ggggaaggcc accctatatg
ctgtgctggt 900cagtggccta gtgctgatgg ccatggtcaa gaaaaaaaat tccgcggccg
catgatgaga 960tctgagctcc atagaggcg
979382433DNAArtificial SequenceNucleotide sequence for
synthetic peptide comprising a fusion of CD80 and Lck (see SEQ ID NO
33) 38acgtctagat acctcgaggc caccatggct tgcaattgtc agttgatgca ggatacacca
60ctcctcaagt ttccatgtcc aaggctcatt cttctctttg tgctgctgat tcgtctttca
120caagtgtctt cagatgttga tgaacaactg tccaagtcag tgaaagataa ggtattgctg
180ccttgccgtt acaactctcc tcatgaagat gagtctgaag accgaatcta ctggcaaaaa
240catgacaaag tggtgctgtc tgtcattgct gggaaactaa aagtgtggcc cgagtataag
300aaccggactt tatatgacaa cactacctac tctcttatca tcctgggcct ggtcctttca
360gaccggggca catacagctg tgtcgttcaa aagaaggaaa gaggaacgta tgaagttaaa
420cacttggctt tagtaaagtt gtccatcaaa gctgacttct ctacccccaa cataactgag
480tctggaaacc catctgcaga cactaaaagg attacctgct ttgcttccgg gggtttccca
540aagcctcgct tctcttggtt ggaaaatgga agagaattac ctggcatcaa tacgacaatt
600tcccaggatc ctgaatctga attgtacacc attagtagcc aactagattt caatacgact
660cgcaaccaca ccattaagtg tctcattaaa tatggagatg ctcacgtgtc agaggacttc
720acctgggaaa aacccccaga agaccctcct gatagcaaga acacacttgt gctctttggg
780gcaggattcg gcgcagtaat aacagtcgtc gtcatcgttg tcatcatcaa atgcttctgt
840aagcacagaa gctgtttcag aagaaatgag gcaagcagag aaacaaacaa cagccttacc
900ttcgggcctg aagaagcatt agctgaacag accgtcttcc ttaccactag tcactatccc
960atagtcccac tggacagcaa gatctcgctg cccatccgga atggctctga agtgcgggac
1020ccactggtca cctatgaggg atctctccca ccagcatccc cgctgcaaga caacctggtt
1080atcgccctgc acagttatga gccctcccat gatggagact tgggctttga gaagggtgaa
1140cagctccgaa tcctggagca gagcggtgag tggtggaagg ctcagtccct gacgactggc
1200caagaaggct tcattccctt caacttcgtg gcgaaagcaa acagcctgga gcctgaacct
1260tggttcttca agaatctgag ccgtaaggac gccgagcggc agcttttggc gcccgggaac
1320acgcatggat ccttcctgat ccgggaaagc gaaagcactg cggggtcctt ttccctgtcg
1380gtcagagact tcgaccagaa ccagggagaa gtggtgaaac attacaagat ccgtaaccta
1440gacaacggtg gcttctacat ctcccctcgt atcacttttc ccggattgca cgatctagtc
1500cgccattaca ccaacgcctc tgatgggctg tgcacaaagt tgagccgtcc ttgccagacc
1560cagaagcccc agaaaccatg gtgggaggac gaatgggaag ttcccaggga aacactgaag
1620ttggtggagc ggctgggagc tggccagttc ggggaagtgt ggatggggta ctacaacgga
1680cacacgaagg tggcggtgaa gagtctgaaa caagggagca tgtcccccga cgccttcctg
1740gctgaggcta acctcatgaa gcagctgcag cacccgcggc tagtccggct ttatgcagtg
1800gtcacccagg aacccatcta catcatcacg gaatacatgg agaacgggag cctagtagat
1860tttctcaaga ctccctcggg catcaagttg aatgtcaaca aacttttgga catggcagcc
1920cagattgcag agggcatggc gttcatcgaa gaacagaatt acatccatcg ggacctgcgc
1980gccgccaaca tcctggtgtc tgacacgctg agctgcaaga ttgcagactt tggcctggcg
2040cgcctcattg aggacaatga gtacacggcc cgggaggggg ccaaatttcc cattaagtgg
2100acagcaccag aagccattaa ctatgggacc ttcaccatca agtcagacgt gtggtccttc
2160gggatcttgc ttacagagat cgtcacccac ggtcgaatcc cttacccagg aatgaccaac
2220cctgaagtca ttcagaacct ggagagaggc taccgcatgg tgagacctga caactgtccg
2280gaagagctgt accacctcat gatgctgtgc tggaaggagc gcccagagga ccggcccacg
2340tttgactacc ttcggagtgt tctggatgac ttcttcacag ccacagaggg ccagtaccag
2400ccccagcctg gtacctagtg agaattctac atg
2433392442DNAArtificial SequenceNucleotide sequence for synthetic peptide
comprising a fusion of CD86 and Lck (see SEQ ID NO 34) 39tactctagat
acctcgaggc caccatggac cccagatgca ccatgggctt ggcaatcctt 60atctttgtga
cagtcttgct gatctcagat gctgtttccg tggagacgca agcttatttc 120aatgggactg
catatctgcc gtgcccattt acaaaggctc aaaacataag cctgagtgag 180ctggtagtat
tttggcagga ccagcaaaag ttggttctgt acgagcacta tttgggcaca 240gagaaacttg
atagtgtgaa tgccaagtac ctgggccgca cgagctttga caggaacaac 300tggactctac
gacttcacaa tgttcagatc aaggacatgg gctcgtatga ttgttttata 360caaaaaaagc
cacccacagg atcaattatc ctccaacaga cattaacaga actgtcagtg 420atcgccaact
tcagtgaacc tgaaataaaa ctggctcaga atgtaacagg aaattctggc 480ataaatttga
cctgcacgtc taagcaaggt cacccgaaac ctaagaagat gtattttctg 540ataactaatt
caactaatga gtatggtgat aacatgcaga tatcacaaga taatgtcaca 600gaactgttca
gtatctccaa cagcctctct ctttcattcc cggatggtgt gtggcatatg 660accgttgtgt
gtgttctgga aacggagtca atgaagattt cctccaaacc tctcaatttc 720actcaagagt
ttccatctcc tcaaacgtat tggaaggaga ttacagcttc agttactgtg 780gccctcctcc
ttgtgatgct gctcatcatt gtatgtcaca agaagccgaa tcagcctagc 840aggcccagca
acacagcctc taagttagag cgggatagta acgctgacag agagactatc 900aacctgaagg
aacttgaacc ccaaattgct tcagcaaaac caaatgcaga gtgtactagt 960cactatccca
tagtcccact ggacagcaag atctcgctgc ccatccggaa tggctctgaa 1020gtgcgggacc
cactggtcac ctatgaggga tctctcccac cagcatcccc gctgcaagac 1080aacctggtta
tcgccctgca cagttatgag ccctcccatg atggagactt gggctttgag 1140aagggtgaac
agctccgaat cctggagcag agcggtgagt ggtggaaggc tcagtccctg 1200acgactggcc
aagaaggctt cattcccttc aacttcgtgg cgaaagcaaa cagcctggag 1260cctgaacctt
ggttcttcaa gaatctgagc cgtaaggacg ccgagcggca gcttttggcg 1320cccgggaaca
cgcatggatc cttcctgatc cgggaaagcg aaagcactgc ggggtccttt 1380tccctgtcgg
tcagagactt cgaccagaac cagggagaag tggtgaaaca ttacaagatc 1440cgtaacctag
acaacggtgg cttctacatc tcccctcgta tcacttttcc cggattgcac 1500gatctagtcc
gccattacac caacgcctct gatgggctgt gcacaaagtt gagccgtcct 1560tgccagaccc
agaagcccca gaaaccatgg tgggaggacg aatgggaagt tcccagggaa 1620acactgaagt
tggtggagcg gctgggagct ggccagttcg gggaagtgtg gatggggtac 1680tacaacggac
acacgaaggt ggcggtgaag agtctgaaac aagggagcat gtcccccgac 1740gccttcctgg
ctgaggctaa cctcatgaag cagctgcagc acccgcggct agtccggctt 1800tatgcagtgg
tcacccagga acccatctac atcatcacgg aatacatgga gaacgggagc 1860ctagtagatt
ttctcaagac tccctcgggc atcaagttga atgtcaacaa acttttggac 1920atggcagccc
agattgcaga gggcatggcg ttcatcgaag aacagaatta catccatcgg 1980gacctgcgcg
ccgccaacat cctggtgtct gacacgctga gctgcaagat tgcagacttt 2040ggcctggcgc
gcctcattga ggacaatgag tacacggccc gggagggggc caaatttccc 2100attaagtgga
cagcaccaga agccattaac tatgggacct tcaccatcaa gtcagacgtg 2160tggtccttcg
ggatcttgct tacagagatc gtcacccacg gtcgaatccc ttacccagga 2220atgaccaacc
ctgaagtcat tcagaacctg gagagaggct accgcatggt gagacctgac 2280aactgtccgg
aagagctgta ccacctcatg atgctgtgct ggaaggagcg cccagaggac 2340cggcccacgt
ttgactacct tcggagtgtt ctggatgact tcttcacagc cacagagggc 2400cagtaccagc
cccagcctgg tacctagtga gaattctaca tg 2442
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