CD6-targeted chimeric antigen receptors for the treatment of certain autoimmune disorders

Abstract

In particular, provided herein are CD6-targeted CAR-T cell compositions and methods that can be used to treat autoimmune diseases (e.g., type 1 diabetes).

Description

Background of the Invention

[0002] Type 1 diabetes (T1D) is caused by the loss of functional beta cell clusters due to autoimmune attack on pancreatic beta cells. Functional beta cell clusters are positively influenced by processes that increase the number and size of beta cells, and negatively influenced by processes that reduce cell numbers (i.e., apoptosis, necrosis, and other forms of cell death). Furthermore, the secretory function and capacity of beta cells are important determinants of functional beta cell clusters.

[0003] In patients with type 1 diabetes (T1D), the proliferative and regenerative potential of adult and human islets is low. Therefore, it is important to prevent or delay autoimmune attack and the resulting destruction of β-cells, and to establish methods to promote β-cell cluster expansion, increase β-cell survival, and / or enhance the function of existing / residual β-cells, including engaging in cellular repair mechanisms to restore functional β-cell clusters. However, therapeutic strategies aimed at simultaneously targeting islet-infiltrating lymphocytes and protecting and replenishing functional β-cell clusters are limited. This article provides solutions in this field to these and other problems. Invention Overview

[0005] This article describes a chimeric antigen receptor (CAR) targeting CD6. The CD6 CAR is expressed in regulatory T cells (Tregs) to target the CD6 molecule overexpressed in pro-inflammatory T cells of patients with type 1 diabetes (T1D). This approach contrasts with methods targeting β-cell antigens (which may induce additional damage to the islets of Langerhans). In some cases, the current approach employs a CAR comprising a scFv derived from itolizumab (an immunomodulatory anti-CD6 monoclonal antibody (US 6,572,857)). The CD6 CAR utilizes the CD152 (CTLA-4) cytoplasmic domain (excluding CD3 zeta) to drive inhibitory signaling in the transduced host cells and enhance the immunomodulatory activity of the CAR-Treg. In some cases, CD6 has a relatively low affinity for CD6. This avoids overactivation of adopted cells and prolongs their lifespan. In some cases, the CAR is expressed in the CD6 low / - subgroup of Tregs. Therefore, in some cases, CD6 CARs are expressed in CD4+, CD25hi, CD127 low / -, and CD6 low / - T cells. In some cases, CD6 CARs expressed in Tregs may have better safety compared to CARs expressed in T effector cells (Teffs) because they are less likely to induce adverse cytokine release syndromes. Furthermore, Tregs can produce anti-inflammatory molecules such as IDO, TGF-beta, and IL-10. In some cases, CD6 CARs expressed in Tregs are less susceptible to lymphocyte depletion, leading to prolonged persistence and thus improving the efficacy of adoptive immunotherapy.

[0006] This document provides, in particular, cells, nucleic acids, proteins, methods, and compositions for use in autoimmune diseases. In embodiments, autoimmune diseases are associated with reduced function, viability, or survival of pancreatic islet cells (e.g., β cells). In embodiments, autoimmune diseases include attacks on the subject's pancreatic islet cells (e.g., β cells) by the subject's immune system. This document also provides, in particular, compositions for the treatment of certain autoimmune diseases. In embodiments, this document provides novel CAR-T cells targeting the human CD6 molecule. In embodiments, chimeric antigen receptors (CARs) with different affinity ranges for the CD6 molecule are expressed through genetic engineering in different types of human T cells, including regulatory T cells (Tregs).

[0007] On the one hand, isolated nucleic acids are provided that encode proteins including single-stranded variable fragments (scFv) targeting CD6 and transmembrane domains.

[0008] On the one hand, it provides carriers, including the nucleic acids provided in this paper, including their implementation schemes.

[0009] In one aspect, T lymphocytes, preferably Treg cells, are provided, which include the vectors provided herein, including embodiments thereof.

[0010] On one hand, recombinant proteins are provided, which include a single-stranded variable fragment (scFv) targeting CD6 and a transmembrane domain, including implementation schemes thereof.

[0011] In one aspect, T lymphocytes, preferably Treg cells, are provided, which include the recombinant proteins provided herein, including embodiments thereof.

[0012] In one aspect, a method for treating autoimmune diseases is provided. In an embodiment, the method includes administering an effective amount of T lymphocytes, preferably Treg cells, to a subject in need, as described herein, including embodiments thereof. Attached Figure Description

[0013] Figure 1 The amino acid sequence of the CD6 CAR expressed by pF03496-CD6scFvop(VH_VL)-IgG4(L235E,N297Q)op-CTLA4-Zetaop is shown, with each domain labeled. The mature CAR lacking the signal sequence (MLLLVTSLLLCELPHPAFLLIP; SEQ ID NO:70) is SEQ ID NO:83. The immature sequence is SEQ ID NO:84.

[0014] Figure 2The amino acid sequence of the CD6 CAR expressed by pF03497-CD6scFvop(VL_VH)-IgG4(L235E,N297Q)op-CTLA4-Zetaop is shown, with each domain labeled. The mature CAR lacking the signal sequence (MLLLVTSLLLCELPHPAFLLIP; SEQ ID NO:70) is SEQ ID NO:85. The immature sequence is SEQ ID NO:86.

[0015] Figure 3 The amino acid sequence of the CD6CAR expressed by pF03488-CD6scFv(VH-VL)-IgG4op(L235E,N297Q)-41BB-Zetaop is labeled with each domain. The mature CAR lacking the signal sequence (MLLLVTSLLLCELPHPAFLLIP; SEQ ID NO:70) is SEQ ID NO:87. The immature sequence is SEQ ID NO:88.

[0016] Figure 4 The amino acid sequence of the CD6CAR expressed by pF03491-CD6scFv(VL-VH)-IgG4op(L235E,N297Q)-41BB-Zetaop is labeled with each domain. The mature CAR lacking the signal sequence (MLLLVTSLLLCELPHPAFLLIP; SEQ ID NO:70) is SEQ ID NO:89. The immature sequence is SEQ ID NO:90.

[0017] Figure 5 This is a schematic diagram of Treg preparation. CD25+ cells were isolated from PBMCs. CD4+ cells were then enriched using FACS sorting. + / CD25 高 / CD127 低 / - The resulting cells were highly enriched with Tregs. Optionally, additional steps can be used to enrich Tregs with CD6. 低 / - Subgroup.

[0018] Figure 6This is a graph depicting the proliferation (IC50) of anti-CD6 CAR suppressor effector T cells (Teff) expressed in a host of conventional CD4+CD25hiCD127 low / - T regulatory cells (Tregs) containing either the CD137 (4-1BB) or CD152 (CTLA-4) cytoplasmic domains. Circles represent conventional Treg-MOCK:Teff-MOCK (IC50 = 73603); squares represent conventional Treg-CAR (anti-CD6 / 41BB):Teff-MOCK (IC50 = 43807); and rhombuses represent conventional Treg-CAR (anti-CD6 / CTLA4):Teff-MOCK (IC50 = 14286). Dark single empty squares represent Teff-MOCK in the absence of stimulation, and light single empty squares represent Teff-MOCK in the presence of stimulation (anti-CD3 OKT3 mAb).

[0019] Figure 7 This describes experimental results showing the effects of certain CD6 CARs on Teff proliferation.

[0020] Figure 8 This describes the results of a study examining cytokine expression by Tregs expressing certain CD6 CARs.

[0021] Figure 9 The study described the findings, which showed that Tregs expressing CD6 CARs with the CTLA4 signaling domain can be cultured in the presence of Teff with relatively low levels of the depletion biomarker.

[0022] Figure 10 The amino acid sequence (SEQ ID NO:73) used in the CAR described herein for the substitution of CD6 scFv shows the domains and mutations. Invention Details

[0024] Surprisingly, CARs with low affinity slow, delay, or reduce the depletion of inoculated CAR-T cells, resulting in a longer half-life and improved efficacy of adoptive immunotherapy. In embodiments, the compositions provided herein comprise CAR-T cells that target CD6+ T- and B- lymphocytes in affected organs (e.g., the pancreas in the case of T1D). In embodiments, the CARs provided herein have an affinity for the CD6 molecule (i.e., a protein), for example, a KD of 130 nM or higher. The CAR-T cells provided herein are anticipated to be relevant to the treatment of human autoimmune diseases such as type 1 diabetes, multiple sclerosis, inflammatory bowel disease, or graft-versus-host disease.

[0025] Although various embodiments and aspects of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Many modifications, variations, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention.

[0026] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. See, for example, Singleton et al., *DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed.*, J. Wiley & Sons (New York, NY 1994); Sambrook et al., *MOLECULAR CLONING*, *ALABORATORY MANUAL*, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus, and materials similar to or equivalent to those described herein may be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or parts thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals and monographs, are expressly incorporated herein by reference in their entirety for any purpose.

[0027] As used herein, the term "about" means a range of values ​​that includes the specified value and that will be reasonably considered by those skilled in the art to be reasonably similar to the specified value. In embodiments, the term "about" means within a standard deviation obtained using measurements generally acceptable in the art. In embodiments, "about" means a range extended to + / - 10% of the specified value. In embodiments, "about" means the specified value.

[0028] As used herein, the terms “an” or “a” mean one or more.

[0029] The transitional term "comprising," synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude other unmentioned elements (such as method steps or ingredients). Conversely, the transitional phrase "consisting of," excludes any element not specified in the claim. The transitional phrase "consisting substantially of," limits the scope of the claim to the specified materials or steps "and those that do not substantially affect the essential and novel features of the claimed invention." When the transitional term "comprising" is used to disclose methods and compositions, it should be understood that corresponding methods and compositions having the transitional terms "consisting of" and "consisting substantially of" are also disclosed.

[0030] Where a parameter range is provided, the present invention also provides all integers within that range and their tenths. For example, "0.2-5mg" is disclosed as 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, etc., up to 5.0mg (and including 5.0mg).

[0031] In this specification and claims, phrases such as “at least one” or “one or more” may follow a list of combinations of elements or features. The term “and / or” may also appear in a list of two or more elements or features. Unless implied or significantly contradicted by the context in which the phrase is used, such phrases are intended to mean any element or feature listed alone, or any element or feature described in combination with any other described element or feature. For example, the phrases “at least one of A and B;”, “one or more of A and B;” and “A and / or B” are intended to mean “A alone, B alone, or A and B together”, respectively. A similar interpretation applies to lists containing three or more items. For example, the phrases “at least one of A, B, and C;”, “one or more of A, B, and C;” and “A, B, and / or C” are intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together”, respectively.

[0032] “Nucleic acid” refers to deoxyribonucleotides or ribonucleotides in single-stranded or double-stranded form, their polymers, and their complements. The term “polynucleotide” refers to a linear sequence of nucleotides. The term “nucleotide” generally refers to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified forms thereof. Examples of polynucleotides considered herein include single-stranded and double-stranded DNA, single-stranded and double-stranded RNA (including siRNA), and hybrid molecules having mixtures of single-stranded and double-stranded DNA and RNA. As used herein, “nucleic acid” also refers to nucleic acids having the same basic chemical structure as naturally occurring nucleic acids. Such analogues have modified sugars and / or modified ring substituents but retain the same basic chemical structure as naturally occurring nucleic acids. Nucleic acid mimics are compounds having a structure different from the general chemical structure of nucleic acids but functioning in a manner similar to naturally occurring nucleic acids. Examples of such analogues include, but are not limited to, thiophosphates, aminophosphates, methyl phosphonates, chiral methyl phosphonates, 2-O-methylribonucleotides, and peptide nucleic acids (PNAs).

[0033] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that have been modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., the α-carbon bound to hydrogen, carboxyl, amino, and R groups), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. These analogs have modified R groups (e.g., ortholeucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimics are compounds that have a structure different from the general chemical structure of amino acids but function in a manner similar to naturally occurring amino acids.

[0034] Amino acids can be referred to in this article using their commonly known three-letter symbols or the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Committee. Similarly, nucleotides can be referred to using their generally accepted single-letter codes.

[0035] When the term "isolated" is applied to nucleic acids or proteins, it means that the nucleic acid or protein is essentially free of other cellular components associated with it in its native state. It can be, for example, in a homogeneous state and can be in a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography. Essentially, the main types of proteins present in the formulation have been purified.

[0036] The term "conservatively modified variant" applies to both amino acid and nucleic acid sequences. For a specific nucleic acid sequence, a conservatively modified variant refers to those nucleic acids that encode the same or substantially the same amino acid sequence, or substantially the same sequence if the nucleic acid does not encode an amino acid sequence. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acid sequences encode any given amino acid residue. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Therefore, at each position where the codon specifies alanine, the codon can be changed to any of the corresponding codons without altering the encoded polypeptide. Such nucleic acid variations are "silent variants," a type of conservatively modified variant. Each nucleic acid sequence encoding a polypeptide described herein also describes each possible silent variant of the nucleic acid. Those skilled in the art will recognize that each codon in a nucleic acid (except for AUG, which is typically the only codon for methionine, and TGG, which is typically the only codon for tryptophan) can be modified to produce a functionally identical molecule. Therefore, each silent variant of a nucleic acid encoding a polypeptide is implicit in each of these sequences with respect to the expression product, not with respect to the actual probe sequence.

[0037] Regarding amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions, or additions of single amino acids or small percentages of amino acids in the coding sequence of a nucleic acid, peptide, polypeptide, or protein are “variants of conserved modifications.” In embodiments, the modification results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitutions that provide functionally similar amino acids are well known in the art. Such variants of conserved modifications are, and do not exclude, the polymorphs, interspecific homologues, and alleles of the present invention.

[0038] The following eight groups each contain an amino acid that is conserved to substitute for each other: 1) alanine (A), glycine (G); 2) aspartic acid (D), glutamic acid (E); 3) asparagine (N), glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); 6) phenylalanine (F), tyrosine (Y), tryptophan (W); 7) serine (S), threonine (T); and 8) cysteine ​​(C), methionine (M) (see, for example, Creighton, Proteins (1984)).

[0039] The "position" of an amino acid or nucleotide base is represented by a number that identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5' end). Because deletions, insertions, truncations, fusions, etc., may be considered when determining the optimal alignment, the number of amino acid residues in the test sequence, typically determined solely by counting from the N-terminus, may not be the same as the number of their corresponding positions in the reference sequence. For example, if a variant has a deletion relative to the reference sequence being aligned, the variant will not contain an amino acid corresponding to the deletion site in the reference sequence. If an insertion is present in the aligned reference sequence, the insertion will not correspond to the numbered amino acid position in the reference sequence. In the case of truncation or fusion, there may be amino acid segments in the reference or aligned sequences that do not correspond to any amino acid in the corresponding sequence.

[0040] When used in the context of a given amino acid or polynucleotide sequence number, the terms "reference...number" or "corresponds to" refer to the number of residues in a reference sequence when comparing a given amino acid or polynucleotide sequence to a reference sequence. An amino acid residue in a protein "corresponds to" a given residue when it occupies the same basic structural position in the protein as a given residue. For example, when a selected residue occupies the same basic spatial or other structural relationship as threonine in the light chain at position 40 of the Kabat, the selected residue in the selected antibody (or antigen-binding domain) corresponds to threonine in the light chain at position 40 of the Kabat. In some embodiments, in cases where the selected protein is aligned to the light chain of an antibody (or antigen-binding domain) with maximum homology, the position in the selected protein aligned to threonine 40 is referred to as corresponding to threonine 40. In addition to primary sequence alignment, three-dimensional structural alignment can also be used, for example, where the structure of the selected protein is aligned to the threonine in the light chain at position 40 of the Kabat and the overall structure is compared. In this case, the amino acid that occupies the same basic position as threonine 40 in the structural model is called the residue corresponding to threonine 40.

[0041] The "percentage of sequence identity" is determined by comparing two best-aligned sequences within a comparison window. This comparison window may contain additions or deletions (i.e., vacancies) in the polynucleotide or polypeptide sequence compared to the reference sequence (which does not contain additions or deletions) to ensure optimal alignment. The percentage is calculated as follows: determine the number of positions in both sequences where the same nucleic acid base or amino acid residue appears to generate a matching position number; divide the matching position number by the total number of positions in the comparison window; and then multiply the result by 100 to obtain the percentage of sequence identity.

[0042] In the context of two or more nucleic acid or polypeptide sequences, the term "identical" or "percentage of identity" refers to the identity of two or more identical sequences or subsequences having a specified percentage of identical amino acid residues or nucleotides when compared and aligned against the maximum correspondence using sequence comparison algorithms or by manual alignment and visual inspection (i.e., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity in a specified region, such as the entire polypeptide sequence of the present invention or a specified region of each domain of the polypeptide of the present invention). Such sequences that are at least about 80% identical are referred to as "substantially identical". In some embodiments, the two sequences are 100% identical. In some embodiments, the two sequences are 100% identical over the entire length of one of the sequences (e.g., the shorter of the two sequences in cases where the sequences have different lengths). In various embodiments, identity may refer to the complement of the test sequence. In some embodiments, the identity exists in regions of at least about 10 to about 100, about 20 to about 75, or about 30 to about 50 amino acids or nucleotides in length. In some embodiments, the identity exists in regions of about 10 nucleotides in length, or more preferably in regions of 20 to 50, 100 to 500, or 1000 or more nucleotides in length. In some embodiments, the identity exists in regions of at least about 50 amino acids in length, or more preferably in regions of 100 to 500, 100 to 200, 150 to 200, 175 to 200, 175 to 225, 175 to 250, 200 to 225, or 200 to 250 or more amino acids in length.

[0043] For sequence comparison, a reference sequence is typically used and compared to a test sequence. When using a sequence comparison algorithm, the test and reference sequences are input into the computer, subsequence coordinates are specified if necessary, and the sequence algorithm program parameters are specified. Preferably, default program parameters can be used, or alternative parameters can be specified. The sequence comparison algorithm then calculates the percentage of sequence identity between the test sequence and the reference sequence based on the program parameters.

[0044] A “comparison window” refers to a segment of any one of a plurality of consecutive positions (e.g., at least about 10 to about 100, about 20 to about 75, about 30 to about 50, 100 to 500, 100 to 200, 150 to 200, 175 to 200, 175 to 225, 175 to 250, 200 to 225, 200 to 250), whereby, after optimal alignment of two sequences, the sequences can be compared with a reference sequence of the same number of consecutive positions. In various embodiments, the comparison window is the full length of one or both of the two aligned sequences. In some embodiments, the two sequences being compared comprise different lengths, and the comparison window is the full length of the longer or shorter of the two sequences. In some embodiments involving two sequences of different lengths, the comparison window comprises the full length of the shorter of the two sequences. In some embodiments involving two sequences of different lengths, the comparison window comprises the full length of the longer of the two sequences.

[0045] The methods for sequence alignment used for comparison are well known in the art. Optimal alignments for comparison can be performed, for example, by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search similarity method of Pearson and Lipman (1988) Proc. Nat'l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, for example, Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0046] Examples of algorithms suitable for determining percentage sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. The percentage sequence identity of nucleic acids and proteins can be determined using BLAST and BLAST 2.0 with the parameters described herein. Software for performing BLAST analysis is publicly available from the National Center for Biotechnology Information (NCBI), as is known in the art. Software for performing BLAST analysis is publicly available from the National Center for Biotechnology Information (ncbi.nlm.nih.gov / ). The algorithm involves first identifying high-scoring sequence pairs (HSPs) by recognizing short words of length W in the query sequence that match or satisfy some positive threshold score T when compared to words of the same length in the database sequence. T is called the neighboring word score threshold (Altschul et al., ibid.). These initial neighboring word hits act as seeds to initiate a search for longer HSPs containing them. Word hits extend in both directions along each sequence until the cumulative alignment score can be increased. For nucleotide sequences, the cumulative score is calculated using parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatched residues; always <0). For amino acid sequences, a score matrix is ​​used to calculate the cumulative score. Word hit extension in each direction will stop if the cumulative alignment score decreases by an amount X from its maximum realized value; the cumulative score becomes zero or lower due to the accumulation of one or more negatively scored residues; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. In some implementations, the NCBI BLASTN or BLASTP procedure is used for sequence alignment. In some implementations, the BLASTN or BLASTP procedure uses the default values ​​used by NCBI. In some implementations, the BLASTN program (for nucleotide sequences) uses the following as default values: word length (W) of 28; expected threshold (E) of 10; maximum match in the query range set to 0; match / no-match score of 1, -2; linear void cost; filter using low-complexity regions; and mask used only for the lookup table. In some implementations, the BLASTP program (for amino acid sequences) uses the following as default values: word length (W) of 3; expected threshold (E) of 10; maximum match in the query range set to 0; BLOSUM62 matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1992)); void cost: 11 and extension: 1; and conditional component score matrix adjustment.

[0047] The BLAST algorithm also performs statistical analysis on the similarity between two sequences (see, for example, Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One similarity measure provided by the BLAST algorithm is the minimum sum probability (P(N)), which represents the probability that two nucleotide or amino acid sequences will coincidentally match. For example, if the minimum sum probability in a comparison of the test nucleic acid with a reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001, then the nucleic acid is considered similar to the reference sequence.

[0048] In some implementations, an indication that two nucleic acid sequences or peptides are substantially identical is that the peptide encoded by the first nucleic acid undergoes an immune cross-reaction with an antibody generated against a peptide encoded by the second nucleic acid, as described below. Therefore, the peptide is generally substantially identical to the second peptide, for example, in cases where the two peptides differ only by conserved substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequences.

[0049] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a portion not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of the corresponding naturally occurring amino acids, as well as to both naturally occurring and non-naturally occurring amino acid polymers. A “fusion protein” is a chimeric protein encoding two or more separate protein sequences, which are recombined and expressed as a single part.

[0050] A “marker” or “detectable portion” is a composition that can be detected by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful markers include… 32 P, fluorescent dyes, electron-dense reagents, enzymes (e.g., those commonly used in ELISA), biotin, digoxigenin or haptens, and proteins or other detectable entities (e.g., by incorporating a radiolabel into a peptide or antibody that specifically reacts with the target peptide). Any suitable method known in the art for conjugating antibodies to labels can be employed. For example, the method described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego can be used.

[0051] A “labeled protein or polypeptide” is a labeled protein or polypeptide that is covalently bound to a label via a linker or chemical bond, or non-covalently bound to a label via ions, van der Waals forces, electrostatics, or hydrogen bonds, such that the presence of the labeled protein or polypeptide can be detected by detecting the presence of the label bound to it. Alternatively, the same result can be achieved using a high-affinity interaction method, in which one of a pair of binding partners binds to the other, for example, biotin or streptavidin.

[0052] An "antibody" is a polypeptide containing a framework region derived from an immunoglobulin gene or a fragment thereof, which specifically binds to and recognizes an antigen. Recognized immunoglobulin genes include κ, λ, α, γ, δ, ε, and μ constant region genes, as well as numerous immunoglobulin variable region genes. Light chains are classified as κ or λ. Heavy chains are classified as γ, μ, α, δ, or ε, which, in turn, define the immunoglobulin classes IgG, IgM, IgA, IgD, and IgE, respectively. Typically, the antigen-binding region of an antibody plays a crucial role in determining the specificity and affinity of binding. In some embodiments, the antibody or antibody fragment may be derived from various organisms, including humans, mice, rats, hamsters, camels, etc. The antibodies of this invention may include antibodies that have been modified or mutated at one or more amino acid positions to improve or modulate the desired function of the antibody (e.g., glycosylation, expression, antigen recognition, effector function, antigen binding, specificity, etc.).

[0053] Antibodies are large, complex molecules (approximately 150,000 molecules or about 1,320 amino acids) with complex internal structures. Natural antibody molecules consist of two pairs of identical polypeptide chains, each pair containing one light chain and one heavy chain. Each light and heavy chain is further composed of two regions: a variable (“V”) region involved in binding to the target antigen, and a constant (“C”) region that interacts with other components of the immune system. The variable regions of the light and heavy chains converge in three-dimensional space to form the antigen-binding variable region (e.g., a receptor on a cell surface). Within each light or heavy chain variable region, there are three short segments (averaging 10 amino acids in length) called complementarity-determining regions (“CDRs”). The six CDRs in the antibody variable domain (three from the light chain and three from the heavy chain) fold together in three-dimensional space to form the actual antibody-binding site that docks to the target antigen. The location and length of the CDR have been precisely defined by Kabat, E. et al., Sequences of Proteins of Immunological Interest, Department of Health and Human Services, 1983, 1987. The portion of the variable region not included in the CDR is called the frame (“FR”), which forms the environment of the CDR.

[0054] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer consists of two pairs of identical polypeptide chains, each pair having a "light" chain (approximately 25 kDa) and a "heavy" chain (approximately 50-70 kDa). The N-terminus of each chain defines a variable region of approximately 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains, respectively. The Fc region (i.e., the fragment crystallizable region) is the "base" or "tail" of the immunoglobulin and typically consists of two heavy chains that contribute two or three constant domains depending on the type of antibody. By binding to specific proteins, the Fc region ensures that each antibody produces an appropriate immune response against a given antigen. The Fc region also binds to various cellular receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[0055] The term "antigen" as used in this article refers to a molecule that can bind to an antibody binding site.

[0056] Antibodies exist, for example, as intact immunoglobulins or as numerous well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below a disulfide link in its hinge region to produce F(ab)'2, a dimer of Fab that is itself a light chain linked to VH-CH1 by disulfide bonds. F(ab)'2 can be reduced under mild conditions to disrupt the disulfide link in the hinge region, thereby converting the F(ab)'2 dimer into Fab' monomers. Fab' monomers are essentially antigen-binding moieties with partial hinge regions (see Fundamental Immunology (Pauled., 3d ed. 1993)). While various antibody fragments are defined according to the digestion of intact antibodies, those skilled in the art will understand that such fragments can be synthesized chemically or de novo using recombinant DNA methods. Therefore, the term antibody as used herein also includes antibody fragments generated by modifying the whole antibody, or antibody fragments synthesized de novo using recombinant DNA methods (e.g., single-stranded Fv), or antibody fragments identified using phage display libraries (see, for example, McCafferty et al., Nature 348:552-554 (1990)).

[0057] Single-chain variable fragments (scFvs) are typically fusion proteins of the variable regions of the heavy chain (VH) and light chain (VL) of immunoglobulins, linked by adaptor peptides (e.g., short adaptor peptides of 10 to approximately 25 amino acids). In embodiments, the adaptor is enriched with glycine for flexibility and with serine or threonine for solubility. The adaptor can link the N-terminus of the VH to the C-terminus of the VL, and vice versa.

[0058] An epitope of a mAb is the region of the antigen to which it binds. If each antibody competitively inhibits (blocks) the binding of another antibody to an antigen, then both antibodies bind to the same or overlapping epitopes. That is, as measured in a competitive binding assay, an overdose of one antibody (1x, 5x, 10x, 20x, or 100x) inhibits the binding of another antibody by at least 30%, but preferably 50%, 75%, 90%, or even 99% (see, for example, Junghans et al., Cancer Res. 50:1495, 1990). Alternatively, if substantially all amino acid mutations in the antigen that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody, then the two antibodies have the same epitope. If some amino acid mutations that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody, then the two antibodies have overlapping epitopes.

[0059] To prepare suitable antibodies, many techniques known in the art can be used (see, for example, Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp.77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)). Genes encoding the heavy and light chains of the antibody of interest can be cloned from cells; for example, genes encoding monoclonal antibodies can be cloned from hybridomas and used to produce recombinant monoclonal antibodies. Libraries of genes encoding the heavy and light chains of monoclonal antibodies can also be prepared from hybridomas or plasma cells. Random combinations of heavy and light chain gene products generate a large number of antibodies with different antigen specificities (see, for example, Kuby, Immunology (3rd ed. 1997)). Techniques for generating single-chain antibodies or recombinant antibodies (US Patent 4,946,778, US Patent 4,816,567) can be adapted to generate antibodies against the peptides of the present invention. Similarly, transgenic mice or other organisms, such as other mammals, can be used to express humanized or human antibodies (see, for example, U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology). 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).Alternatively, phage display technology can be used to identify antibodies and heteropolymerized Fab fragments that specifically bind to selected antigens (see, for example, McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., capable of recognizing two different antigens (see, for example, WO 93 / 08829, Traunecker et al., EMBO J.10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). Antibodies can also be heteroconjugates, such as two covalently conjugated antibodies or immunotoxins (see, for example, U.S. Patent Nos. 4,676,980, WO 91 / 00360; WO92 / 200373; and EP 03089).

[0060] Methods for humanizing or primatizing nonhuman antibodies or scFvs are well known in the art (e.g., U.S. Patent Nos. 4,816,567; 5,530,101; 5,859,205; 5,585,089; 5,693,761; 5,693,762; 5,777,085; 6,180,370; 6,210,671; and 6,329,511; WO 87 / 02671; European Patent Application 0173494; Jones et al. (1986) Nature 321:522; and Verhoyen et al. (1988) Science 239:1534). Humanized antibodies are further described, for example, in Winter and Milstein (1991) Nature 349:293. Typically, humanized antibodies contain one or more amino acid residues introduced from a non-human source. These non-human amino acid residues are generally referred to as input residues, and they are usually derived from the input variable domain. Humanization can be performed essentially according to the methods of Winter et al. (see, for example, Morrison et al., PNAS USA, 81:6851-6855 (1984), Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al.) Al., Science 239:1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan, Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3):169-217 (1994)), by replacing the corresponding sequence of human antibody with rodent CDR or CDR sequence. Thus, such humanized antibodies are chimeric antibodies (US Patent No. 4,816,567), in which essentially less than the complete human variable domain has been replaced by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies that have some CDR residues and possibly some FR residues replaced by residues at similar sites in rodent antibodies. For example, a set of polynucleotides comprising a first sequence encoding a humanized immunoglobulin framework region and a second sequence encoding a desired immunoglobulin complementarity-determining region can be generated synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated from various human cells according to well-known procedures.

[0061] "Chimeric antibodies" are antibody molecules in which (a) a constant region or a portion thereof is altered, replaced, or exchanged such that the antigen-binding site (variable region) is linked to a constant region of a different or altered class, effector function, and / or type, or to a completely different molecule that imparts novel properties to the chimeric antibody, such as an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) a variable region or a portion thereof is altered, replaced, or exchanged with a variable region having different or altered antigen specificity. Preferred antibodies used according to the present invention include humanized and / or chimeric monoclonal antibodies.

[0062] As used herein, “therapeutic antibody” refers to any antibody or functional fragment thereof intended to treat cancer, autoimmune diseases, transplant rejection, cardiovascular diseases or other diseases or conditions (as described herein).

[0063] Techniques for conjugating therapeutic agents with antibodies are well-known (see, for example, Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery" in Controlled Drug Delivery (2 ndEd.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review" in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62: 119-58 (1982)). As used herein, the term "antibody-drug conjugate" or "ADC" refers to a therapeutic agent conjugated or otherwise covalently bound to an antibody. As referred to herein, "therapeutic agent" is a composition that can be used to treat or prevent diseases such as autoimmune diseases.

[0064] As used herein, the term "anti-CD6 antibody" refers to an antibody capable of binding to CD6 via an antibody CDR sequence. Therefore, an anti-CD6 antibody comprises an antibody binding site consisting of a CDR that specifically binds to CD6 (e.g., VL-CDR1, VL-CDR2, VL-CDR3, VH-CDR1, VH-CDR2, VH-CDR3).

[0065] As used herein, “CD6,” also known as TP120, includes any recombinant or naturally occurring form of differentiation cluster 6 (CD6), or its variants or homologs that maintain CD6 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to CD6). In all respects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity between the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to the naturally occurring CD6 protein. In some cases, the CD6 protein is substantially identical to the protein identified by UniProt reference number P30203 or a variant or homolog thereof that has substantial identity with it. In some cases, CD6 is the human CD6 protein. In some cases, variants or mutants of the CD6 protein, compared to the naturally occurring CD6 protein, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the CD6 protein, compared to the naturally occurring CD6 protein, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CD6 protein, compared to the naturally occurring CD6 protein, do not include deletions. In some cases, variants or mutants of the CD6 protein, compared to the naturally occurring CD6 protein, do not include insertions. In some cases, variants or mutants of the CD6 protein, compared to the naturally occurring CD6 protein, include substitutions as conserved substitutions. In some cases, CD6 is a protein identified by NCBI sequence reference NP_006716.3, or its equivalent, or a naturally occurring mutant or variant. In some cases, CD6 is a protein identified by NCBI sequence reference NP_001241679.1, or its equivalent, or a naturally occurring mutant or variant. In some cases, CD6 is a protein identified by NCBI sequence reference NP_001241680.1, or its equivalent or a naturally occurring mutant or variant. Non-limiting examples of human CD6 amino acid sequences available under the NCBI sequence reference are as follows:

[0066] NP_006716.3

[0067]

[0068] NP_001241679.1

[0069]

[0070] NP_001241680.1

[0071]

[0072] As used herein, the term "CD28 transmembrane domain" includes any recombinant or naturally occurring form of the transmembrane domain of CD28, or its variants or homologs that maintain the activity of the CD28 transmembrane domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD28 transmembrane domain). In some cases, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to the naturally occurring CD28 transmembrane domain polypeptide. In some cases, the CD28 transmembrane domain is a human CD28 transmembrane domain protein. In some cases, the variants or mutants of the CD28 transmembrane domain protein include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CD28 transmembrane domain protein. In some cases, variants or mutants of the CD28 transmembrane domain protein, compared to naturally occurring CD28 transmembrane domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CD28 transmembrane domain protein, compared to naturally occurring CD28 transmembrane domain proteins, do not include deletions. In some cases, variants or mutants of the CD28 transmembrane domain protein, compared to naturally occurring CD28 transmembrane domain proteins, do not include insertions. In some cases, variants or mutants of the CD28 transmembrane domain protein, compared to naturally occurring CD28 transmembrane domain proteins, include substitutions as conserved substitutions. In some cases, the CD28 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001230006.1, or its equivalents or naturally occurring mutants or variants. In some cases, the CD28 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001230007.1, or its equivalents or naturally occurring mutants or variants. In some cases, the CD28 transmembrane domain comprises all or part of the protein identified by NCBI sequence reference NP_006130.1, or its equivalent or naturally occurring mutant or variant. In some cases, the CD28 transmembrane domain amino acid sequence comprises the sequence RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO:7). In some cases, the CD28 transmembrane domain amino acid sequence is the sequence of SEQ ID NO:7. In some cases, the CD28 transmembrane domain amino acid sequence comprises the sequence RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO:8). In some cases, the CD28 transmembrane domain amino acid sequence is the sequence of SEQ ID NO:8. Non-limiting examples of human CD28 amino acid sequences available under NCBI sequence reference are as follows:

[0073] NP_001230006.1

[0074]

[0075] NP_001230007.1

[0076]

[0077] NP_006130.1

[0078]

[0079] In some cases, the CD28 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001243077.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD28 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001243078.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD28 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_006139.3, or its equivalent or a naturally occurring mutant or variant. In some cases, the variant or mutant of the CD28 transmembrane domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CD28 transmembrane domain nucleic acid sequence. In some cases, the variant or mutant of the CD28 transmembrane domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring CD28 transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD28 transmembrane domain nucleic acid sequence do not include deletions compared to the naturally occurring CD28 transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD28 transmembrane domain nucleic acid sequence do not include insertions compared to the naturally occurring CD28 transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD28 transmembrane domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring CD28 transmembrane domain nucleic acid sequence.

[0080] As used herein, the term "CD4 transmembrane domain" includes any recombinant or naturally occurring form of the transmembrane domain of CD4, or its variants or homologs that maintain CD4 transmembrane domain activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the CD4 transmembrane domain). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to a naturally occurring CD4 transmembrane domain polypeptide. In some cases, the CD4 transmembrane domain amino acid sequence includes the sequence of MALIVLGGVAGLLLFIGLGIFF (SEQ ID NO:23). In some cases, the CD4 transmembrane domain amino acid sequence is the sequence of SEQ ID NO:23. A non-restrictive example of a nucleotide sequence encoding the CD4 transmembrane domain is ATGGCCCTGATTGTGCTGGGGGGCGTCGCCGGCCTCCTGCTTTTCATTG GGCTAGGCATCTTCTTC (SEQ ID NO: 24). In some cases, the CD4 transmembrane domain is a human CD4 transmembrane domain protein. In some cases, variants or mutants of the CD4 transmembrane domain protein, compared to naturally occurring CD4 transmembrane domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the CD4 transmembrane domain protein, compared to naturally occurring CD4 transmembrane domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CD4 transmembrane domain protein, compared to naturally occurring CD4 transmembrane domain proteins, do not include deletions. In some cases, variants or mutants of the CD4 transmembrane domain protein, compared to naturally occurring CD4 transmembrane domain proteins, do not include insertions. In some cases, variants or mutants of CD4 transmembrane domain proteins include substitutions as conserved substitutions compared to naturally occurring CD4 transmembrane domain proteins. In some cases, the CD4 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_000607.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD4 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001181943.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD4 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001181944.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD4 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001181945.1, or its equivalent or a naturally occurring mutant or variant.In some cases, the CD4 transmembrane domain comprises all or part of the protein identified by NCBI sequence reference NP_001181946.1, or its equivalents or naturally occurring mutants or variants. A non-limiting example of a human CD4 amino acid sequence available under the NCBI sequence reference is NP_000607.1.

[0081]

[0082]

[0083] NP_001181943.1

[0084]

[0085] NP_001181944.1

[0086]

[0087] NP_001181945.1

[0088]

[0089] NP_001181946.1

[0090]

[0091] In some cases, the CD4 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_000616.4, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD4 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001195014.2, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD4 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001195015.2, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD4 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001195016.2, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD4 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001195017.2, or its equivalent or a naturally occurring mutant or variant. In some cases, variants or mutants of the CD4 transmembrane domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CD4 transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD4 transmembrane domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring CD4 transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD4 transmembrane domain nucleic acid sequence do not include deletions. In some cases, variants or mutants of the CD4 transmembrane domain nucleic acid sequence do not include insertions. In some cases, variants or mutants of the CD4 transmembrane domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring CD4 transmembrane domain nucleic acid sequence.

[0092] As used herein, the term "CD8 transmembrane domain" includes any recombinant or naturally occurring form of the transmembrane domain of CD8, or variants or homologs thereof that maintain CD8 transmembrane domain activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the CD8 transmembrane domain). In some respects, variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to naturally occurring CD8 transmembrane domain peptides. In some cases, the CD8 transmembrane domain amino acid sequence includes the sequence of IYIWAPLAGTCGVLLLSLVIT (SEQ ID NO:25). In some cases, the CD8 transmembrane domain amino acid sequence is the sequence of SEQ ID NO:25. In some cases, the CD8 transmembrane domain is the CD8A transmembrane domain. In some cases, the CD8 transmembrane domain is the CD8B transmembrane domain. In some cases, the CD8 transmembrane domain is a human CD8 transmembrane domain protein. In some cases, variants or mutants of the CD8 transmembrane domain protein, compared to naturally occurring CD8 transmembrane domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the CD8 transmembrane domain protein, compared to naturally occurring CD8 transmembrane domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CD8 transmembrane domain protein, compared to naturally occurring CD8 transmembrane domain proteins, do not include deletions. In some cases, variants or mutants of the CD8 transmembrane domain protein, compared to naturally occurring CD8 transmembrane domain proteins, do not include insertions. In some cases, variants or mutants of the CD8 transmembrane domain protein, compared to naturally occurring CD8 transmembrane domain proteins, include substitutions as conserved substitutions. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001139345.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001181943.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001181944.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001181945.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_741969.1, or its isotype or naturally occurring mutant or variant.In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001759.3, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference XP_011531466.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_001171571.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_757362.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_742100.1, or its isotype or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_742099.1, or its equivalent or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_004922.1, or its equivalent or naturally occurring mutant or variant. Non-limiting examples of human CD8 amino acid sequences available under NCBI sequence references are as follows:

[0093] NP_001139345.1

[0094]

[0095] NP_741969.1

[0096]

[0097] NP_001759.3

[0098]

[0099] XP_011531466.1

[0100]

[0101] NP_001171571.1

[0102]

[0103] NP_757362.1

[0104]

[0105] NP_742100.1

[0106]

[0107] NP_742099.1

[0108]

[0109] NP_004922.1

[0110]

[0111] In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NR_027353.1, or its equivalent or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001145873.1, or its equivalent or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001768.6, or its equivalent or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_171827.3, or its equivalent or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference XM_011533164.2, or its equivalent or naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001178100.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_004931.4, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_172102.3, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_172101.3, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD8 transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_172213.3, or its equivalent or a naturally occurring mutant or variant. In some cases, variants or mutants of the CD8 transmembrane domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CD8 transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD8 transmembrane domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring CD8 transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD8 transmembrane domain nucleic acid sequence do not include deletions. In some cases, variants or mutants of the CD8 transmembrane domain nucleic acid sequence do not include insertions. In some cases, variants or mutants of the CD8 transmembrane domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring CD8 transmembrane domain nucleic acid sequence.

[0112] As used herein, the term "CD3-zeta transmembrane domain" includes any recombinant or naturally occurring form of the transmembrane domain of CD3-zeta, or its variants or homologs that maintain the activity of the CD3-zeta transmembrane domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD3-zeta transmembrane domain). In some respects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to the naturally occurring CD3-zeta transmembrane domain polypeptide. In some cases, the CD3-zeta transmembrane domain is a human CD3-zeta transmembrane domain protein. In some cases, variants or mutants of the CD3-zeta transmembrane domain protein, compared to naturally occurring CD3-zeta transmembrane domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the CD3-zeta transmembrane domain protein, compared to naturally occurring CD3-zeta transmembrane domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CD3-zeta transmembrane domain protein, compared to naturally occurring CD3-zeta transmembrane domain proteins, do not include deletions. In some cases, variants or mutants of the CD3-zeta transmembrane domain protein, compared to naturally occurring CD3-zeta transmembrane domain proteins, do not include insertions. In some cases, variants or mutants of the CD3-zeta transmembrane domain protein, compared to naturally occurring CD3-zeta transmembrane domain proteins, include substitutions as conserved substitutions. In some cases, the CD3-zeta transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_000725.1, or its equivalent or naturally occurring mutant or variant. In some cases, the CD3-zeta transmembrane domain includes all or part of the protein identified by NCBI sequence reference NP_932170.1, or its equivalent or naturally occurring mutant or variant. Non-limiting examples of human CD3-zeta amino acid sequences available under NCBI sequence references are as follows:

[0113] NP_000725.1

[0114]

[0115] NP_932170.1

[0116]

[0117] In some cases, the CD3-zeta transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_000734.3, or its equivalents or naturally occurring mutants or variants. In some cases, the CD3-zeta transmembrane domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_198053.2, or its equivalents or naturally occurring mutants or variants. In some cases, variants or mutants of the CD3-zeta transmembrane domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CD3-zeta transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD3-zeta transmembrane domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring CD3-zeta transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD3-zeta transmembrane domain nucleic acid sequence do not include deletions compared to the naturally occurring CD3-zeta transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD3-zeta transmembrane domain nucleic acid sequence do not include insertions compared to the naturally occurring CD3-zeta transmembrane domain nucleic acid sequence. In some cases, variants or mutants of the CD3-zeta transmembrane domain nucleic acid sequence include substitutions as conserved alternatives compared to the naturally occurring CD3-zeta transmembrane domain nucleic acid sequence.

[0118] As used herein, the term "CD28 co-stimulatory domain" includes any recombinant or naturally occurring form of the co-stimulatory domain of CD28, or its variants or homologs that maintain CD28 co-stimulatory domain activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the CD28 co-stimulatory domain). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to a naturally occurring CD28 co-stimulatory domain polypeptide. In some cases, the CD28 co-stimulatory domain amino acid sequence includes the sequence RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO:7). In some cases, the CD28 co-stimulatory domain amino acid sequence is the sequence of RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO:8).

[0119] In some cases, the CD28 costimulatory domain is a human CD28 costimulatory domain protein. In some cases, variants or mutants of the CD28 costimulatory domain protein, compared to naturally occurring CD28 costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the CD28 costimulatory domain protein, compared to naturally occurring CD28 costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CD28 costimulatory domain protein, compared to naturally occurring CD28 costimulatory domain proteins, do not include deletions. In some cases, variants or mutants of the CD28 costimulatory domain protein, compared to naturally occurring CD28 costimulatory domain proteins, do not include insertions. In some cases, variants or mutants of the CD28 costimulatory domain protein, compared to naturally occurring CD28 costimulatory domain proteins, include substitutions as conserved substitutions. In some cases, the CD28 co-stimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_001230006.1, or its isotype or a naturally occurring mutant or variant. In some cases, the CD28 co-stimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_001230007.1, or its isotype or a naturally occurring mutant or variant. In some cases, the CD28 co-stimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_006130.1, or its isotype or a naturally occurring mutant or variant. Non-limiting examples of human CD28 amino acid sequences available under NCBI sequence references are as follows:

[0120] NP_001230006.1

[0121]

[0122] NP_001230007.1

[0123]

[0124] NP_006130.1

[0125]

[0126] In some cases, the CD28 co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001243077.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD28 co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001243078.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the CD28 co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_006139.3, or its equivalent or a naturally occurring mutant or variant. In some cases, the variant or mutant of the CD28 co-stimulatory domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CD28 co-stimulatory domain nucleic acid sequence. In some cases, the variant or mutant of the CD28 co-stimulatory domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring CD28 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the CD28 co-stimulatory domain nucleic acid sequence do not include deletions compared to the naturally occurring CD28 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the CD28 co-stimulatory domain nucleic acid sequence do not include insertions compared to the naturally occurring CD28 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the CD28 co-stimulatory domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring CD28 co-stimulatory domain nucleic acid sequence.

[0127] As used herein, the term "4-1BB costimulatory domain" includes any recombinant or naturally occurring form of the 4-1BB costimulatory domain, or its variants or homologs that maintain the activity of the 4-1BB costimulatory domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the 4-1BB costimulatory domain). In some respects, variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to naturally occurring 4-1BB costimulatory domain polypeptides. In some cases, the 4-1BB costimulatory domain is a human 4-1BB costimulatory domain protein. In some cases, variants or mutants of the 4-1BB costimulatory domain protein, compared to naturally occurring 4-1BB costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the 4-1BB costimulatory domain protein, compared to naturally occurring 4-1BB costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the 4-1BB costimulatory domain protein, compared to naturally occurring 4-1BB costimulatory domain proteins, do not include deletions. In some cases, variants or mutants of the 4-1BB costimulatory domain protein, compared to naturally occurring 4-1BB costimulatory domain proteins, do not include insertions. In some cases, variants or mutants of the 4-1BB costimulatory domain protein, compared to naturally occurring 4-1BB costimulatory domain proteins, include substitutions as conserved substitutions. In some cases, the 4-1BB costimulatory domain protein includes the amino acid sequence KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO:14). In some cases, the amino acid sequence of the 4-1BB co-stimulatory domain protein has at least or about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:14. In some cases, the 4-1BB co-stimulatory domain comprises all or part of the protein identified by NCBI Sequence Reference NP_001552.2, or its equivalent or naturally occurring mutant or variant. Non-limiting examples of human 4-1BB amino acid sequences available under NCBI Sequence Reference are as follows:

[0128] NP_001552.2

[0129]

[0130] In some cases, the 4-1BB co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001561.5, or its equivalents or naturally occurring mutants or variants. In some cases, variants or mutants of the 4-1BB co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring 4-1BB co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the 4-1BB co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring 4-1BB co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the 4-1BB co-stimulatory domain nucleic acid sequence do not include deletions compared to the naturally occurring 4-1BB co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the 4-1BB co-stimulatory domain nucleic acid sequence do not include insertions compared to the naturally occurring 4-1BB co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the 4-1BB costimulatory domain nucleic acid sequence include substitutions that are conserved, compared to naturally occurring 4-1BB costimulatory domain nucleic acid sequences.

[0131] As used herein, the term "ICOS co-stimulatory domain" includes any recombinant or naturally occurring form of the co-stimulatory domain of ICOS, or its variants or homologs that maintain the activity of the ICOS co-stimulatory domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the ICOS co-stimulatory domain). In some respects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to a naturally occurring ICOS co-stimulatory domain polypeptide. In some cases, the ICOS co-stimulatory domain amino acid sequence includes the sequence CWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL (SEQ ID NO: 31). In some cases, the ICOS co-stimulatory domain is a human ICOS co-stimulatory domain protein. In some cases, variants or mutants of ICOS co-stimulatory domain proteins, compared to naturally occurring ICOS co-stimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of ICOS co-stimulatory domain proteins, compared to naturally occurring ICOS co-stimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of ICOS co-stimulatory domain proteins, compared to naturally occurring ICOS co-stimulatory domain proteins, do not include deletions. In some cases, variants or mutants of ICOS co-stimulatory domain proteins, compared to naturally occurring ICOS co-stimulatory domain proteins, do not include insertions. In some cases, variants or mutants of ICOS co-stimulatory domain proteins, compared to naturally occurring ICOS co-stimulatory domain proteins, include substitutions as conserved substitutions. In some cases, the ICOS co-stimulatory domain comprises all or part of the protein identified by NCBI Sequence Reference NP_036224.1, or its equivalents or naturally occurring mutants or variants. Non-limiting examples of human ICOS amino acid sequences available under the NCBI Sequence Reference are as follows:

[0132] NP_036224.1

[0133]

[0134] In some cases, the ICOS co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_012092.3, or its equivalents or naturally occurring mutants or variants. In some cases, the variants or mutants of the ICOS co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring ICOS co-stimulatory domain nucleic acid sequence. In some cases, the variants or mutants of the ICOS co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring ICOS co-stimulatory domain nucleic acid sequence. In some cases, the variants or mutants of the ICOS co-stimulatory domain nucleic acid sequence do not include deletions compared to the naturally occurring ICOS co-stimulatory domain nucleic acid sequence. In some cases, the variants or mutants of the ICOS co-stimulatory domain nucleic acid sequence do not include insertions compared to the naturally occurring ICOS co-stimulatory domain nucleic acid sequence. In some cases, the variants or mutants of the ICOS co-stimulatory domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring ICOS co-stimulatory domain nucleic acid sequence.

[0135] As used herein, the term "OX-40 co-stimulatory domain" includes any recombinant or naturally occurring form of the co-stimulatory domain of OX-40, or its variants or homologs that maintain the activity of the OX-40 co-stimulatory domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the OX-40 co-stimulatory domain). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to the naturally occurring OX-40 co-stimulatory domain polypeptide. In some cases, the OX-40 co-stimulatory domain amino acid sequence includes the sequence of ALYLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI (SEQ ID NO:32). In some cases, the OX-40 costimulatory domain is a human OX-40 costimulatory domain protein. In some cases, variants or mutants of the OX-40 costimulatory domain protein, compared to naturally occurring OX-40 costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the OX-40 costimulatory domain protein, compared to naturally occurring OX-40 costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the OX-40 costimulatory domain protein, compared to naturally occurring OX-40 costimulatory domain proteins, do not include deletions. In some cases, variants or mutants of the OX-40 costimulatory domain protein, compared to naturally occurring OX-40 costimulatory domain proteins, do not include insertions. In some cases, variants or mutants of the OX-40 costimulatory domain protein, compared to naturally occurring OX-40 costimulatory domain proteins, include substitutions as conserved substitutions. In some cases, the OX-40 co-stimulatory domain comprises all or part of the protein identified by NCBI sequence reference NP_003318.1, or its equivalents or naturally occurring mutants or variants. A non-restrictive example of a human OX-40 amino acid sequence available under NCBI sequence reference NP_003318.1 is shown below.

[0136]

[0137] In some cases, the OX-40 co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_003327.3, or its equivalents or naturally occurring mutants or variants. In some cases, variants or mutants of the OX-40 co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring OX-40 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the OX-40 co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring OX-40 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the OX-40 co-stimulatory domain nucleic acid sequence do not include deletions compared to the naturally occurring OX-40 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the OX-40 co-stimulatory domain nucleic acid sequence do not include insertions compared to the naturally occurring OX-40 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the OX-40 co-stimulatory domain nucleic acid sequence include substitutions that are conserved, compared to naturally occurring OX-40 co-stimulatory domain nucleic acid sequences.

[0138] As used herein, the term "CTLA-4 co-stimulatory domain" includes any recombinant or naturally occurring form of the co-stimulatory domain of CTLA-4, or its variants or homologs that maintain the activity of the CTLA-4 co-stimulatory domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CTLA-4 co-stimulatory domain). In some respects, variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to naturally occurring CTLA-4 co-stimulatory domain polypeptides. In some cases, the CTLA-4 co-stimulatory domain protein is a human CTLA-4 co-stimulatory domain protein. In some cases, the CTLA-4 co-stimulatory domain includes no more than 5, 4, 3, 2, or 1 deletion. In some cases, the CTLA-4 co-stimulatory domain protein includes no more than 5, 4, 3, 2, or 1 insertions. In some cases, the CTLA-4 co-stimulatory domain protein does not include deletions. In some cases, the CTLA-4 co-stimulatory domain protein does not include insertions. In some cases, the CTLA-4 co-stimulatory domain protein includes substitutions as conserved substitutions. In some cases, the CTLA-4 co-stimulatory domain protein includes the sequence AVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN (SEQ ID NO:17). In some cases, the 4-1BB co-stimulatory domain protein is the sequence SEQ ID NO:17. In some cases, the 4-1BB co-stimulatory domain amino acid sequence has at least or about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:17. In some cases, the CTLA-4 costimulatory domain is a human CTLA-4 costimulatory domain protein. In some cases, variants or mutants of the CTLA-4 costimulatory domain protein, compared to naturally occurring CTLA-4 costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the CTLA-4 costimulatory domain protein, compared to naturally occurring CTLA-4 costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CTLA-4 costimulatory domain protein, compared to naturally occurring CTLA-4 costimulatory domain proteins, do not include deletions. In some cases, variants or mutants of the CTLA-4 costimulatory domain protein, compared to naturally occurring CTLA-4 costimulatory domain proteins, do not include insertions. In some cases, variants or mutants of the CTLA-4 costimulatory domain protein, compared to naturally occurring CTLA-4 costimulatory domain proteins, include substitutions as conserved substitutions.In some cases, the CTLA-4 co-stimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_001032720.1, or its equivalent or naturally occurring mutant or variant. In some cases, the CTLA-4 co-stimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_005205.2, or its equivalent or naturally occurring mutant or variant. Non-limiting examples of human CTLA-4 amino acid sequences available under NCBI sequence references are as follows:

[0139] NP_001032720.1

[0140]

[0141] NP_005205.2

[0142]

[0143] In some cases, the CTLA-4 co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_001037631.3, or its equivalent or a naturally occurring mutant or variant. In some cases, the CTLA-4 co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_005214.5, or its equivalent or a naturally occurring mutant or variant. In some cases, the variant or mutant of the CTLA-4 co-stimulatory domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CTLA-4 co-stimulatory domain nucleic acid sequence. In some cases, the variant or mutant of the CTLA-4 co-stimulatory domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring CTLA-4 co-stimulatory domain nucleic acid sequence. In some cases, the variant or mutant of the CTLA-4 co-stimulatory domain nucleic acid sequence does not include deletions compared to the naturally occurring CTLA-4 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the CTLA-4 co-stimulatory domain nucleic acid sequence do not include insertions compared to the naturally occurring CTLA-4 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the CTLA-4 co-stimulatory domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring CTLA-4 co-stimulatory domain nucleic acid sequence.

[0144] As used herein, the term "PD-1 co-stimulatory domain" includes any recombinant or naturally occurring form of the co-stimulatory domain of PD-1, or its variants or homologs that maintain the activity of the PD-1 co-stimulatory domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the PD-1 co-stimulatory domain). In some respects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity in the entire sequence or a portion thereof (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to naturally occurring PD-1 co-stimulatory domain peptides. In some cases, the PD-1 co-stimulatory domain amino acid sequence includes the sequence CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPV PCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWP L (SEQ ID NO: 33). In some cases, the PD-1 co-stimulatory domain is a human PD-1 co-stimulatory domain protein. In some cases, variants or mutants of the PD-1 co-stimulatory domain protein, compared to naturally occurring PD-1 co-stimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the PD-1 co-stimulatory domain protein, compared to naturally occurring PD-1 co-stimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the PD-1 co-stimulatory domain protein, compared to naturally occurring PD-1 co-stimulatory domain proteins, do not include deletions. In some cases, variants or mutants of the PD-1 co-stimulatory domain protein, compared to naturally occurring PD-1 co-stimulatory domain proteins, do not include insertions. In some cases, variants or mutants of PD-1 co-stimulatory domain proteins include substitutions as conserved alternatives compared to naturally occurring PD-1 co-stimulatory domain proteins. In some cases, the PD-1 co-stimulatory domain comprises all or part of the protein identified by NCBI Sequence Reference NP_005009.2, or its equivalents or naturally occurring mutants or variants. Non-limiting examples of human PD-1 amino acid sequences available under the NCBI Sequence Reference are as follows:

[0145] NP_005009.2

[0146]

[0147] In some cases, the PD-1 co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_005018.2, or its equivalents or naturally occurring mutants or variants. In some cases, variants or mutants of the PD-1 co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring PD-1 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the PD-1 co-stimulatory domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring PD-1 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the PD-1 co-stimulatory domain nucleic acid sequence do not include deletions compared to the naturally occurring PD-1 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the PD-1 co-stimulatory domain nucleic acid sequence do not include insertions compared to the naturally occurring PD-1 co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the PD-1 co-stimulatory domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring PD-1 co-stimulatory domain nucleic acid sequence.

[0148] As used herein, the term "GITR co-stimulatory domain" includes any recombinant or naturally occurring form of the co-stimulatory domain of GITR, or its variants or homologs that maintain the activity of the GITR co-stimulatory domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the GITR co-stimulatory domain). In some respects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to the naturally occurring GITR co-stimulatory domain polypeptide. In some cases, the GITR co-stimulatory domain amino acid sequence includes the sequence QLGLHIWQLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGERSAE EKGRLGDLWV (SEQ ID NO: 67). In some cases, the GITR costimulatory domain is a human GITR costimulatory domain protein. In some cases, variants or mutants of the GITR costimulatory domain protein, compared to naturally occurring GITR costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the GITR costimulatory domain protein, compared to naturally occurring GITR costimulatory domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the GITR costimulatory domain protein, compared to naturally occurring GITR costimulatory domain proteins, do not include deletions. In some cases, variants or mutants of the GITR costimulatory domain protein, compared to naturally occurring GITR costimulatory domain proteins, do not include insertions. In some cases, variants or mutants of the GITR costimulatory domain protein, compared to naturally occurring GITR costimulatory domain proteins, include substitutions as conserved substitutions. In some cases, the GITR costimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_004186.1, or its equivalents or naturally occurring mutants or variants. In some cases, the GITR co-stimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_683699.1, or its isotype or naturally occurring mutant or variant. In some cases, the GITR co-stimulatory domain includes all or part of the protein identified by NCBI sequence reference NP_683700.1, or its isotype or naturally occurring mutant or variant. A non-limiting example of a human GITR amino acid sequence available under NCBI sequence reference is as follows: NP_004186.1

[0149]

[0150] NP_683699.1

[0151]

[0152] NP_683700.1

[0153]

[0154] In some cases, the GITR co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_148902.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the GITR co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_004195.2, or its equivalent or a naturally occurring mutant or variant. In some cases, the GITR co-stimulatory domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_148901.1, or its equivalent or a naturally occurring mutant or variant. In some cases, the variant or mutant of the GITR co-stimulatory domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring GITR co-stimulatory domain nucleic acid sequence. In some cases, the variant or mutant of the GITR co-stimulatory domain nucleic acid sequence includes no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring GITR co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the GITR co-stimulatory domain nucleic acid sequence do not include deletions compared to the naturally occurring GITR co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the GITR co-stimulatory domain nucleic acid sequence do not include insertions compared to the naturally occurring GITR co-stimulatory domain nucleic acid sequence. In some cases, variants or mutants of the GITR co-stimulatory domain nucleic acid sequence include substitutions as conserved substitutions compared to the naturally occurring GITR co-stimulatory domain nucleic acid sequence.

[0155] As used herein, the term "CD3ζ intracellular T cell signaling domain" includes any recombinant or naturally occurring form of the CD3ζ intracellular T cell signaling domain, or its variants or homologs that maintain the activity of the CD3ζ intracellular T cell signaling domain (e.g., at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD3ζ intracellular T cell signaling domain). In some respects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity across the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 consecutive amino acid segments) compared to the naturally occurring CD3ζ intracellular T cell signaling domain polypeptide. In some cases, the CD3ζ intracellular T cell signaling domain is a human CD3ζ intracellular T cell signaling domain protein. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain protein, compared to naturally occurring CD3ζ intracellular T cell signaling domain proteins, include no more than 5, 4, 3, 2, or 1 deletions. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain protein, compared to naturally occurring CD3ζ intracellular T cell signaling domain proteins, include no more than 5, 4, 3, 2, or 1 insertions. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain protein, compared to naturally occurring CD3ζ intracellular T cell signaling domain proteins, do not include deletions. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain protein, compared to naturally occurring CD3ζ intracellular T cell signaling domain proteins, do not include insertions. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain protein, compared to naturally occurring CD3ζ intracellular T cell signaling domain proteins, include substitutions as conserved substitutions. In some cases, the CD3ζ intracellular T cell signaling domain comprises all or part of the protein identified by NCBI sequence reference NP_000725.1, or its isotype or a naturally occurring mutant or variant thereof. In some cases, the CD3ζ intracellular T cell signaling domain comprises all or part of the protein identified by NCBI sequence reference NP_932170.1, or its isotype or a naturally occurring mutant or variant thereof. Non-limiting examples of human CD3-zeta amino acid sequences available under NCBI sequence references are identified above. In some cases, the CD3ζ intracellular T cell signaling domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_000734.3, or its isotype or a naturally occurring mutant or variant thereof.In some cases, the CD3ζ intracellular T cell signaling domain is encoded by all or part of the nucleic acid sequence identified by NCBI sequence reference NM_198053.2, or its equivalents or naturally occurring mutants or variants. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 deletions compared to the naturally occurring CD3ζ intracellular T cell signaling domain nucleic acid sequence. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain nucleic acid sequence include no more than 5, 4, 3, 2, or 1 insertions compared to the naturally occurring CD3ζ intracellular T cell signaling domain nucleic acid sequence. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain nucleic acid sequence do not include deletions. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain nucleic acid sequence do not include insertions compared to the naturally occurring CD3ζ intracellular T cell signaling domain nucleic acid sequence. In some cases, variants or mutants of the CD3ζ intracellular T cell signaling domain nucleic acid sequence include substitutions that are conserved, compared to the naturally occurring CD3ζ intracellular T cell signaling domain nucleic acid sequence.

[0156] When referring to proteins or peptides, the phrase "specifically (or selectively) binds to an antibody" or "specifically (or selectively) reacts with…" refers to a binding reaction that typically determines the presence of a protein within a heterogeneous population of proteins and other biological agents. Therefore, under specified immunoassay conditions, the binding of a specified antibody to a particular protein is at least twice the background, and more often, more than 10 to 100 times the background. Specific binding to an antibody under such conditions usually requires selection based on its specificity for the particular protein. For example, polyclonal antibodies can be selected to obtain a subgroup of antibodies that react specifically with the selected antigen without reacting specifically with other proteins. This selection can be achieved by subtracting antibodies that cross-react with other molecules. A variety of immunoassay formats can be used to select antibodies that specifically react with a particular protein. For example, solid-phase ELISA is routinely used to select antibodies that specifically react with a protein (for a description of the immunoassay formats and conditions that can be used to determine specific immunoreactivity, see, for example, Harlow & Lane, Using Antibodies, A Laboratory Manual (1998)).

[0157] A ligand is a reagent, such as a polypeptide or other molecule, that can bind to a receptor.

[0158] When referring to, for example, cells, nucleic acids, proteins, or vectors, the term "recombinant" indicates that the cell, nucleic acid, protein, or vector has been modified by laboratory methods or is the result of laboratory methods. Thus, for example, recombinant proteins include proteins produced by laboratory methods. Recombinant proteins may include amino acid residues not found in the natural (non-recombinant) form of the protein, or may include amino acid residues that have been modified, such as by labeling.

[0159] When used to refer to portions of nucleic acids, the term "heterologous" means that the nucleic acid contains two or more subsequences that are not found in nature to be identical to each other. For example, nucleic acids are often produced by recombination and have two or more sequences from unrelated genes that are arranged to create new functional nucleic acids, such as a promoter from one source and a coding region from another source. Similarly, a heterologous protein means that the protein contains two or more subsequences that are not identical to each other in nature (e.g., a fusion protein).

[0160] As used herein, “cell” means a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a specific dye, the ability to produce progeny, or, in the case of gametes, the ability to bind with a second gamete to produce viable offspring. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian (e.g., human) and insect (e.g., cutworm) cells. It may be useful when cells are naturally non-adherent or have been treated to be non-adherent to a surface (e.g., by trypsin digestion).

[0161] As used herein, the terms “expressed” or “expressed” refer to the transcriptional and / or translational products of that gene. The expression level of a DNA molecule in a cell can be determined based on the amount of the corresponding mRNA present in the cell or the amount of protein encoded by said DNA produced by the cell. The expression level of non-coding nucleic acid molecules (e.g., siRNA) can be detected by standard PCR or Northern blotting methods known in the art. See Sambrook et al., 1989 Molecular Cloning: A Laboratory Manual, 18.1–18.88.

[0162] The terms "plasmid," "vector," or "expression vector" refer to nucleic acid molecules that encode genes and / or regulatory elements necessary for gene expression. Gene expression derived from plasmids can occur in either cis or trans. If a gene is expressed in cis, the gene and regulatory element are encoded by the same plasmid. Trans expression refers to the case where the gene and regulatory element are encoded by separate plasmids.

[0163] The terms “transfection” and “transduction” are used interchangeably and are defined as the process of introducing nucleic acid molecules or proteins into cells. Nucleic acid is introduced into cells using non-viral or viral-based methods. Nucleic acid molecules can be gene sequences encoding complete proteins or functional portions thereof. Non-viral transfection methods include any suitable transfection method that does not use viral DNA or viral particles as a delivery system for introducing nucleic acid molecules into cells. Exemplary non-viral transfection methods include calcium phosphate transfection, liposome transfection, nuclear transfection, acoustic perforation, transfection by heat shock, magnetic transfection, and electroporation. In some embodiments, nucleic acid molecules are introduced into cells using electroporation according to standard procedures well known in the art. For virus-based transfection methods, any useful viral vector can be used in the methods described herein. Examples of viral vectors include, but are not limited to, retroviruses, adenoviruses, lentiviruses, and adeno-associated virus vectors. In some embodiments, nucleic acid molecules are introduced into cells using retroviral vectors according to standard procedures well known in the art. The terms “transfection” and “transduction” also refer to the introduction of proteins into cells from the external environment. Typically, protein transduction or transfection depends on the attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, for example, Ford et al. (2001) Gene Therapy 8:1-4 and Prochiantz (2007) Nat. Methods 4:119-20.

[0164] The expression of a transfected gene can occur transiently or stably in a cell. In transient expression, the transfected gene does not transfer to daughter cells during cell division. Because its expression is limited to the transfected cell, the gene's expression is lost over time. Conversely, stable expression of the transfected gene can occur when it is co-transfected with another gene that confers a selective advantage to the transfected cell. This selective advantage can be resistance to a toxin presented to the cell. The expression of a transfected gene can be further accomplished via transposon-mediated insertion into the host genome. In transposon-mediated insertion, the gene is positioned predictably between two transposon linker sequences, allowing insertion into the host genome and subsequent excision. Stable expression of the transfected gene can be further achieved by infecting cells with a lentiviral vector that integrates into the cell's genome after infection, leading to stable gene expression.

[0165] "Contact" is used in its general sense and refers to the process of bringing at least two different kinds of chemical compounds (e.g., including biomolecules or cells) close enough to react, interact, or physically touch. It should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents, or from an intermediate of one or more added reagents that can be produced in the reaction mixture.

[0166] The term “contact” can include allowing two kinds of reactions, interactions, or physical contact, where the two kinds can be, for example, peptide compounds and antigen binding sites as described herein.

[0167] The term "regulation" or "regulator" is used in its general, common sense and refers to an action that alters or transforms one or more properties. A "regulator" is a composition that increases or decreases the level, function, or physical state of a target molecule. "Regulation" refers to a process that alters or transforms one or more properties. For example, when applied to the effect of a regulator on a biological target, regulation refers to altering the nature or function or quantity of the biological target by increasing or decreasing it.

[0168] As defined herein, the term “inhibition” and similar terms relating to protein-inhibitor (e.g., antagonist) interactions mean a negative effect (e.g., reduction) on the activity or function of a protein relative to the absence of an inhibitor. In some cases, inhibition refers to the reduction of disease or disease symptoms. Therefore, in some cases, inhibition includes at least partial or complete blocking of stimulation, reduction, prevention or delay of activation, or inactivation, desensitization, or downregulation of signal transduction or enzyme activity or the amount of protein. In some cases, the amount of inhibition may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or less compared to a control in the absence of an antagonist. In some cases, inhibition may be 1.5, 2, 3, 4, 5, 10, or more times greater than the expression or activity in the absence of an antagonist.

[0169] Depending on the context, the term "activation," etc., referring to protein-activator (e.g., agonist) interactions, means a positive effect (e.g., an increase) in the activity or function of a protein relative to the absence of an activator (e.g., the compositions described herein). Thus, in some cases, activation includes at least a partial or complete increase in stimulation, an increase or enablement of activation, or an activation, sensitization, or upregulation of the amount of protein reduced in a signal transduction or enzyme activity or disease. The amount of activation can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more compared to a control in the absence of an agonist. In some cases, activation is 1.5, 2, 3, 4, 5, 10, or more times greater than expression or activity in the absence of an agonist.

[0170] As used herein, the term “abnormal” means different from normal. When used to describe enzyme activity, abnormal refers to activity that is greater than or less than the average value of normal or disease-free control samples. Abnormal activity can refer to an amount of activity that causes disease, wherein restoring abnormal activity to a normal or non-disease-related amount (e.g., by using the methods described herein) results in the disease or a reduction in symptoms of one or more diseases.

[0171] Depending on the context, the term "biological sample" or "sample" refers to material obtained from or derived from a subject or patient. In some cases, biological samples include tissue sections, such as biopsy and autopsy samples, as well as frozen sections for histological purposes. Non-limiting examples of samples include bodily fluids, such as blood and blood fractions or products (e.g., serum, plasma, platelets, erythrocytes, etc.), sputum, tissues, cultured cells (e.g., primary cultures, explants, and transformed cells), feces, urine, synovial fluid, joint tissue, synovial tissue, synovial cells, fibroblast-like synovial cells, macrophage-like synovial cells, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc. Biological samples are typically obtained from eukaryotic organisms, such as mammals, such as primates, e.g., chimpanzees or humans; cows; dogs; cats; rodents, e.g., guinea pigs, rats, mice; rabbits; or birds; reptiles; or fish. In some cases, biological samples (e.g., blood) from subjects exhibit abnormal CD6 expression and / or function compared to controls. In some cases, biological samples (e.g., blood) from subjects exhibit abnormal immune cell activity or growth (e.g., an abnormal number of CD6+ immune cells or CD6+ cells with abnormal activity).

[0172] A "control" sample or value refers to a sample used as a reference, typically a known reference, for comparison with the test sample. For example, a test sample may be obtained under test conditions, such as in the presence of the test compound, and compared to a sample under known conditions, such as in the absence of the test compound (negative control) or in the presence of a known compound (positive control). A control may also represent an average value collected from multiple tests or results. Those skilled in the art will recognize that controls can be designed to evaluate any number of parameters. For example, controls can be designed to compare treatment benefits based on pharmacological data (e.g., half-life) or treatment measures (e.g., comparison of side effects). Those skilled in the art will understand which controls are valuable in a given context and are able to analyze data based on comparisons with control values. Controls are also valuable for determining the significance of data. For example, if the value of a given parameter varies greatly in the controls, the variation in the test sample will not be considered significant.

[0173] "Patient" or "subject in need" means a living member of the animal kingdom who has or may have the condition described. In some cases, the subject is a member of a species that includes individuals naturally suffering from the disease. In some cases, the subject is a living organism that has or is susceptible to the disease or symptom, which can be treated by administration of the compositions or pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, dairy cows, deer, and other non-mammalian animals. In some embodiments, the patient is a human.

[0174] The terms "disease" or "symptom" refer to a state or health condition in a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some cases, a disease is an autoimmune disease (e.g., type 1 diabetes, graft-versus-host disease). In other cases,

[0175] As used herein, “autoimmune disease” refers to a disease or condition caused by an alteration in the immune response of a subject’s immune system against substances, tissues, and / or cells normally present in the subject’s body. Autoimmune diseases include, but are not limited to, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, scleroderma, systemic scleroderma, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes mellitus, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjögren’s syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves’ eye disease, inflammatory bowel disease, Addison’s disease, vitiligo, asthma, graft-versus-host disease, and allergic asthma.

[0176] As used in this article, "inflammatory disease" refers to a disease or condition associated with abnormal or altered inflammation. Inflammation is a biological response initiated by the immune system as part of the healing process in response to pathogens, damaged cells or tissues, or irritants. Chronic inflammation can lead to a variety of diseases. Inflammatory diseases include, but are not limited to, atherosclerosis, allergies, asthma, rheumatoid arthritis, transplant rejection, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, and inflammatory myopathy.

[0177] In the context of a substance or its activity or function that is associated with a disease (such as an autoimmune disease), the term “associated” or “related to” means that the disease (in whole or in part) is caused by a substance or its activity or function, or that the symptoms of the disease (in whole or in part) are caused by a substance or its activity or function.

[0178] The term "treatment" refers to any sign of successful treatment or relief of injury, disease, pathology, or symptom, including any objective or subjective parameters such as reduction; relief; lessening of symptoms or making the patient more tolerant of the injury, pathology, or symptom; slowing of the rate of degeneration or decline; reducing the weakening of the final point of degeneration; and improving the patient's physical and mental health. Treatment or relief of symptoms can be based on objective or subjective parameters; including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treatment" and its variations include prevention of injury, pathology, symptom, or disease. In some cases, "treatment" refers to the treatment of autoimmune diseases.

[0179] An "effective amount" is the amount of a compound sufficient to achieve its stated purpose (e.g., to achieve the effect it is applied to, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signal transduction pathways, or reduce symptoms of one or more diseases or symptoms). An example of a "therapeutic effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease; this can also be referred to as a "therapeutic effective amount." "Relief" of one or more symptoms (and its grammatical equivalent) refers to a reduction in the severity or frequency of the symptoms, or the elimination of the symptoms. The exact amount will depend on the purpose of treatment and will be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0180] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of the active agent to a subject and facilitate absorption by the subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments, etc. Such preparations can be sterilized and, if desired, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, humectants, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or aromatic substances, etc., which do not react harmfully with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0181] The term "formulation" is intended to include formulations of active compounds having an encapsulating material as a carrier, provided as capsules, in which the active ingredient, with or without another carrier, is surrounded by the carrier, and thus associated with it. Similarly, this includes capsules and lozenges. Tablets, powders, capsules, pills, capsules, and lozenges can be used as solid dosage forms suitable for oral administration.

[0182] In some cases, the term "administration" includes oral administration to a subject, administration as a suppository, local contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or administration via implanted sustained-release devices such as microosmotic pumps. In some cases, administration can be made via any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, etc.

[0183] Pharmaceutical compositions may include compositions in which an active ingredient (e.g., the compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., an amount that effectively achieves its intended purpose. The actual amount effective for a particular application will depend in particular on the condition being treated. When administered in a manner that treats a disease, such compositions will contain an amount of the active ingredient that effectively achieves the desired results, such as modulating the activity of target molecules and / or reducing, eliminating, or slowing the progression of disease symptoms.

[0184] Recombinant proteins and CAR T cells

[0185] On one hand, this document provides recombinant proteins comprising proteins expressed from isolated nucleic acids provided herein, including embodiments thereof. Thus, on one hand, recombinant proteins, such as chimeric antigen receptors (CARs), are provided, comprising a single-stranded variable fragment (scFv) targeting CD6 and a transmembrane domain. On the other hand, this document provides scFvs targeting CD6 that do not have a transmembrane domain. On the other hand, this document provides cells engineered to express CARs (e.g., cell populations, such as immune effector cell populations), wherein the CAR comprises an antigen-binding domain and a transmembrane domain. In some cases, the antigen-binding domain comprises an antibody fragment or variant targeting CD6. In some cases, the antigen-binding domain is a single-stranded variable fragment (scFv) targeting CD6. In some cases, the CAR further comprises an intracellular signaling domain. In some cases, the cells expressing CARs are T lymphocytes (CAR T cells) or NK cells. In some cases, the cells expressing CARs are T lymphocytes (CAR T cells) or NK cells. In some cases, the cells are CD4+ T cells or CD8+ T cells. In some cases, the T cells are regulatory T cells (Tregs).

[0186] In some cases, the antigen-binding domain may contain the CDR of a monoclonal antibody, the variable region of the monoclonal antibody, and / or its antigen-binding fragment. In some cases, the fragment may be any number of different antigen-binding domains of an antigen-specific antibody. In some cases, the antigen-binding domain contains the CD6-binding fragment of an anti-CD6 antibody. In some cases, the antigen-binding domain contains the CDR of an anti-CD6 antibody. In some cases, the antigen-binding domain contains the VH and VL chains of an anti-CD6 antibody. In some cases, the antigen-binding domain contains an scFv containing the CDR of an anti-CD6 antibody. In some cases, the antigen-binding domain contains an scFv containing the VH and VL chains of an anti-CD6 antibody. In some cases, the anti-CD6 antibody is a monoclonal antibody. In some cases, the monoclonal antibody is a human or humanized monoclonal antibody. In some cases, the monoclonal antibody is an irinotecan antibody. In some cases, the fragment is an antigen-specific scFv encoded by a sequence optimized for expression in human cells using human codons. In some cases, the monoclonal antibody is a chimeric monoclonal antibody. In some cases, the monoclonal antibody is irinotecan. In some cases, the monoclonal antibody is Tl2.l. In some cases, the monoclonal antibody is UMCD6. In some cases, the monoclonal antibody is MEM98. In some cases, the monoclonal antibody is MT605. In some cases, the monoclonal antibody is the antibody described in Gangemi et al. (1989) J Immunol 143(8):2439-47 or U.S. Patent No. 6,572,857, the entire contents of each of which are incorporated herein by reference. In some cases, the fragment is an antigen-specific scFv encoded by a sequence optimized for expression in human cells using human codons. In some cases, the antigen-binding domain includes the following VH sequence or a variant thereof: EVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMSWVRQAPGKRLEWVA TISSGGSYIYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARR DYDLDYFDSWGQGTLVTVSS (SEQ ID NO:35). In some cases, the antigen-binding domain includes the following VL sequence or a variant thereof: DIQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKPGKAPKTLIYYA TSLADGVPSRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGSGTKLEIKRA (SEQ ID NO:34).In some cases, the antigen-binding domain includes the following VH sequence or a variant thereof: EVQLVESGGGL VKPGGSLKLSCAASGFKFSRYAMSWVRQTPEKRLEWVATISSGGSYIYYP DSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYFDSW GQGTTLTVSS (SEQ ID NO:68). In some cases, the antigen-binding domain includes the following VL sequence or a variant thereof: DIKMTQSPSSMYASLGERVTITCKASRDIRSYLTWYQQKPWKSPKTLIYYA TSLADGVPSRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGSGTK LEIKRA (SEQ ID NO:69). In some cases, VL comprises the following sequence or a variant thereof: IQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKPGKAPKTLIYYAT SLADGVPSRFSGSGSGQ (SEQ ID NO:75). In some cases, VL comprises the following sequence or a variant thereof: DIQMTQSPSSLSASVGDRVTITCKASRDIRSY (SEQ ID NO:76). In some cases, VL comprises the following sequence or a variant thereof: LTWYQQKPGKAPKTLIYYATSLADGVPSRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFT (SEQ ID NO:77). In some cases, VL comprises the following sequence or a variant thereof: FGSGTKLEIKRA (SEQ ID NO:78). In some cases, VH comprises the following sequence or a variant thereof: EVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMS (SEQ ID NO:79). In some cases, VH comprises the following sequence or a variant thereof: WVRQAPGKRLEWVATISSGG (SEQ ID NO:80). In some cases, VH comprises the following sequence or a variant thereof: SYIYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLD YFDS (SEQ ID NO:81). In some cases, VH comprises the following sequence or a variant thereof: WGQGTLVTVSS (SEQ ID NO:82). In some cases, variants of the VH or VL sequence provided herein have 5, 4, 3, 2, 1, or 0 deletions compared to the original sequence. In some cases, variants of the VH or VL sequence provided herein have 5, 4, 3, 2, 1, or 0 insertions compared to the original sequence.In some cases, the variants of the VH or VL sequence provided herein have 5, 4, 3, 2, 1, or 0 substitutions compared to the sequence. In embodiments, the variants of the VH or VL sequence provided herein have 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 substitutions compared to the sequence. In some cases, one or more or all of the substitutions are conservative substitutions.

[0187] Table 1. Exemplary sequences of antigen-binding domains and variable regions of the light and heavy chains.

[0188]

[0189]

[0190] In some cases, the arrangement can be multimeric, such as a diabody or a multimer. In some cases, multimers are most likely formed by cross-pairing variable portions of the light and heavy chains into so-called diabolas. In some cases, the hinge portion of the construct can have multiple alternatives, from complete deletion to maintaining the first cysteine ​​residue, to proline instead of serine substitution, to being truncated to the first cysteine ​​residue. In some cases, the Fc portion can be deleted. In some cases, any stable and / or dimerizing protein can achieve this. In some cases, the CAR contains one of the Fc domains, such as the CH2 or CH3 domain from human immunoglobulins. In some cases, the CAR uses the hinge, CH2, and CH3 regions of human immunoglobulins that have been modified to improve dimerization. In some cases, only the hinge portion of the immunoglobulin is used. In some cases, when the antigen-binding domain is expressed, it contains a signal peptide that directs CAR expression to the cell membrane. In some cases, when the signal peptide is on the cell surface, it is not present in the CAR. In some cases, the signal peptide may be the same as or different from the signal peptide of an antibody that has an antigen-binding domain (CDR).

[0191] In some cases, the antigen-binding domain (e.g., scFv as part of a CAR) has a relatively low affinity for CD6 (K). D While still specific for CD6, it still exhibits affinity for CD6 in some cases. -4 M to approximately 1x10 -6 M, approximately 1x10 -8 M to approximately 1x10 -7 M, approximately 1x10 -8 M to approximately 1x10 -6 M, approximately 1x10 -9 M to approximately 1x10 -7 M, approximately 1.5 x 10 -8 M to approximately 1.5 x 10 -7M, or approximately 1x10 -7 M, 2x10 -7 M, 3x10 -7 M, 4x10 -7 M, 5x10 -7 M, 6x10 -7 M, 7x10 -7 M, 8x10 -7 M, 9x10 -7 M, approximately 1x10 -8 M, 2x10 -8 M, 3x10 -8 M, 4x10 -8 M, 5x10 -8 M, 6x10 -8 M, 7x10 -8 M, 8x10 -8 M or 9x10 -8 M. Those skilled in the art can easily detect the K of the antibody. D In a non-limiting example, affinity can be detected, for instance, via yeast surface display. This approach is a genotype-phenotype linkage strategy mediated by the production, secretion, and capture of protein candidates. Candidate proteins can be sorted using a variety of strategies and combinations of selection pressures, including affinity and stability. See, for example, Feldhaus et al. (2003) Flow-cytometric isolation of human antibodies from a nonimmune Saccharomyces cerevisiae esurface display library. Nature biotechnology. 21:163-170; and Zorniak et al. (207) Yeast display biopanning identifies human antibodies targeting glioblastomastem-like cells. Scientific Reports. 7:15840, the entire contents of each of which are incorporated herein by reference.

[0192] In some cases, scFv can be designed to have a specific orientation (e.g., V from N to C). H -V L or V L -V H In some cases, V in scFv H and V L V from N end to C endH -V L Orientation. In some cases, V in scFv H and V L V from N end to C end L -V H Orientation. In some cases, the V of the expressed protein... H and V L Some will have slightly different conformations depending on their orientation. In some cases, V H and V L The orientation of a relationship can confer different affinities to ligands (e.g., CD6). In some cases, the difference in affinity between one orientation and another can be an order of magnitude or greater.

[0193] In some cases, scFv's V H and V L Some parts are directly adjacent and connected to each other. Or, V of scFv H and V L They can be separated by a linker (e.g., a flexible linker). In some cases, the linker is a peptide linker. In some cases, the peptide linker is a flexible linker. In some cases, the V of scFv H and V L (In any orientation) fusion can be achieved through flexible linkers of different sizes, such as 18, 19, or 20 amino acids; enabling the V of scFv H and V L The protein folds into its native conformation and retains its antigen-binding properties. In some cases, the linker includes glycine and / or serine residues. In some cases, the linker has the amino acid sequence GSTSGGGSGGGSGGGGSS (SEQ ID NO:36). In some cases, the linker has the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:37). In some cases, the linker is about 18 amino acids long. In some cases, the linker is 18 amino acids long. In some cases, the linker is about 19 amino acids long. In some cases, the linker is 19 amino acids long. In some cases, the linker is about 20 amino acids long. In some cases, the linker is 20 amino acids long. In some cases, the linker sequence is long enough to allow the expressed scFv to fold into its native conformation. In some cases, the linker sequence is long enough to allow the expressed scFv to maintain its antigen-binding properties. Techniques for evaluating protein folding include, but are not limited to, NMR, X-ray crystallography, circular dichroism, fluorescence spectroscopy, double polarization interferometry, and other techniques well known in the art. Techniques for assessing antigen binding behavior include, but are not limited to, surface plasmon resonance (SPR), various ligand binding assays, and other techniques well known in the art.

[0194] In some cases, the recombinant proteins provided herein, including their embodiments, may further include additional components of the CAR. This also includes CARs containing such additional components and cells expressing such CARs.

[0195] In some cases, the recombinant proteins (such as CARs) provided herein (e.g., isolated or expressed on the cell surface), including embodiments thereof, may further include transmembrane domains as described herein, including embodiments thereof, hinge regions as described herein, including embodiments thereof, intracellular signal transduction domains (such as T cell signal transduction domains as described herein), including embodiments thereof, and / or co-stimulatory domains as described herein, including embodiments thereof.

[0196] In some cases, the scFv provided herein can be directly connected (e.g., covalently bonded) to the transmembrane domain, or can be connected (e.g., covalently bonded) to the transmembrane domain via a hinge region.

[0197] As used herein, a “hinge region” is a polypeptide that links an antigen-binding site domain (i.e., scFv) to a transmembrane domain. This document considers any hinge region capable of linking an scFv to a transmembrane domain. In some cases, the hinge region is a polypeptide hinge region. In some cases, the polypeptide hinge region is a flexible hinge region. In some cases, the hinge region includes glycine and / or serine residues. In some cases, the hinge region is or includes an antibody hinge region or a portion thereof. In some cases, the hinge region includes an antibody Fc domain or a portion thereof (e.g., a portion comprising the hinge region). Non-limiting examples of suitable hinge regions considered herein include IgG Fc, human IgG Fc, human IgG1 Fc, IgG4 Fc, and human IgG4 Fc, or a portion thereof (i.e., a portion comprising the hinge region). In some cases, the hinge region is IgG Fc or a portion thereof. In some cases, the hinge region is human IgG Fc or a portion thereof. In some cases, the hinge region is IgG1 Fc or a portion thereof. In some cases, the hinge region is human IgG1 Fc or a portion thereof. In some cases, the hinge region is IgG4 Fc or a portion thereof. In some cases, the hinge region is human IgG4 Fc or a portion thereof. In some cases, the binding site domain is attached to the CAR backbone using an IgG Fc hinge. In some cases, IgG1 or IgG4 human Fc or the portion containing the hinge region includes one or more mutations that reduce or prevent binding to the corresponding Fc receptor. In some cases, IgG1 or IgG4 human Fc or the portion containing the hinge region does not include mutations that reduce or prevent binding to the corresponding Fc receptor. In some cases, the length of a portion of the Fc domain can be 229 amino acids, 129 amino acids, or less.

[0198] In some cases, the hinge region is approximately 229 amino acids long. In some cases, the hinge region is 229 amino acids long. In some cases, the hinge region is approximately 129 amino acids long. In some cases, the hinge region is 129 amino acids long. In some cases, the hinge region is between approximately 129 and approximately 229 amino acids long. In some cases, the hinge region is less than approximately 229 amino acids long. In some cases, the hinge region is less than approximately 129 amino acids long. In some cases, the hinge region is less than 129 amino acids long. In some cases, the hinge region is at least 22 amino acids long. In some cases, the hinge region is 22 amino acids long. In some cases, the hinge region is approximately 25, 50, 75, 100, 125, 150, 175, 200, 225, or 250 amino acids long. In some cases, the hinge region is approximately 25 amino acids long. In some cases, the hinge region is approximately 50 amino acids long. In some cases, the hinge region is approximately 75 amino acids long. In some cases, the hinge region is approximately 100 amino acids long. In some cases, the hinge region is approximately 125 amino acids long. In some cases, the hinge region is approximately 150 amino acids long. In some cases, the hinge region is approximately 175 amino acids long. In some cases, the hinge region is approximately 200 amino acids long. In some cases, the hinge region is approximately 225 amino acids long. In some cases, the hinge region is approximately 250 amino acids long. In some cases, the hinge region is 25 amino acids long. In some cases, the hinge region is 50 amino acids long. In some cases, the hinge region is 75 amino acids long. In some cases, the hinge region is 100 amino acids long. In some cases, the hinge region is 125 amino acids long. In some cases, the hinge region is 150 amino acids long. In some cases, the hinge region is 175 amino acids long. In some cases, the hinge region is 200 amino acids long. In some cases, the hinge region is 225 amino acids long. In some cases, the hinge region is 250 amino acids long.

[0199] In some cases, the length of the hinge region is between approximately 22 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 25 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 50 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 75 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 100 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 125 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 150 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 175 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 200 and approximately 250 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 225 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 200 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 175 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 150 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 125 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 100 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 75 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 50 amino acids. In some cases, the length of the hinge region is between approximately 22 and approximately 25 amino acids.

[0200] In some cases, the hinge region includes an Fc domain. In some cases, the hinge region includes an IgG Fc domain. In some cases, the hinge region is IgG1 Fc or a fragment thereof. In some cases, the hinge region is human IgG1 Fc or a fragment thereof. In some cases, the hinge region is IgG4 Fc or a fragment thereof. In some cases, the hinge region is human IgG4 Fc or a fragment thereof.

[0201] In some cases, the hinge region may be a mutated hinge region. In some cases, a mutated hinge region (e.g., Fc) can be used, for example, to prevent Fc from binding to its homologous Fc receptor. In some cases, the hinge region (e.g., IgG, human IgGFc, IgG1 Fc, human IgG1 Fc, IgG4 Fc, human IgG4 Fc) includes no more than 5, 4, 3, 2, or 1 deletions. In some cases, the hinge region (e.g., IgG, human IgGFc, IgG1 Fc, human IgG1 Fc, IgG4 Fc, human IgG4 Fc) includes no more than 5, 4, 3, 2, or 1 insertions. In some cases, the hinge region (e.g., IgG, human IgG Fc, IgG1 Fc, human IgG1 Fc, IgG4 Fc, human IgG4 Fc) does not include deletions. In some cases, the hinge region (e.g., IgG, human IgGFc, IgG1 Fc, human IgG1 Fc, IgG4 Fc, human IgG4 Fc) does not include insertions. In some cases, the hinge region (e.g., IgG, human IgG Fc, IgG1 Fc, human IgG1 Fc, IgG4 Fc, human IgG4 Fc) includes substitutions as conserved substitutions.

[0202] In some cases, as described herein, a transmembrane domain refers to a polypeptide that forms part of a biological membrane (e.g., spans a biological membrane). In some cases, the transmembrane domains described herein are capable of crossing a biological membrane (e.g., a cell membrane) from one side of the membrane to the other. In some cases, the transmembrane domain spans only a portion of the membrane but is sufficient to anchor an antigen-binding domain to the membrane. In some cases, the transmembrane domain spans from the intracellular side of the cell membrane to the extracellular side. In some cases, the transmembrane domain may include nonpolar hydrophobic residues that anchor the proteins described herein (including embodiments thereof) to a biological membrane (e.g., the cell membrane of a T cell). Any transmembrane domain capable of anchoring the proteins described herein, including embodiments thereof, is contemplated. Non-limiting examples of transmembrane domains include transmembrane domains of CD28, CD8, CD4, or CD3-zeta (CD3ζ).

[0203] In some cases, transmembrane domains include the CD4 transmembrane domain or variants thereof, the CD8 transmembrane domain or variants thereof, the CD28 transmembrane domain or variants thereof, or the CD3ζ transmembrane domain or variants thereof. In some cases, recombinant proteins such as CARs (e.g., cells expressing CARs) contain intracellular co-stimulatory domains and / or intracellular T cell signaling domains.

[0204] In some cases, the transmembrane domain includes the CD4 transmembrane domain or a variant thereof. In some cases, the transmembrane domain includes the CD8 transmembrane domain or a variant thereof. In some cases, the transmembrane domain includes the CD28 transmembrane domain or a variant thereof. In some cases, the transmembrane domain includes the CD3ζ transmembrane domain or a variant thereof.

[0205] In some cases, the transmembrane domain covalently binds to the heavy chain variable region of the scFv. In some cases, the transmembrane domain covalently binds to the light chain variable region of the scFv. In some cases, the transmembrane domain covalently binds to the heavy chain variable region of the scFv via a hinge region. In some cases, the transmembrane domain covalently binds to the light chain variable region of the scFv via a hinge region. In some cases, the recombinant proteins presented herein (such as CARs, e.g., on the cell surface) contain V from the N-terminus to the C-terminus. H V L and transmembrane domains. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L V H and transmembrane domains. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H Connector, V L and transmembrane domains. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L Connector, V H and transmembrane domains. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H Connector, V L Hinge region and transmembrane domain. In some cases, the recombinant proteins presented herein (such as CARs, e.g., on the cell surface) contain V from the N-terminus to the C-terminus. L Connector, V H Hinge region and transmembrane domain. In this paragraph, VH, VL, joint, hinge region, and transmembrane domain refer to those disclosed herein, including their embodiments.

[0206] In some cases, the antigen-binding domain (e.g., scFv) comprises the CDR sequence of the iributyric acid monoclonal antibody. In some cases, the CDR comprises the amino acid sequence shown in SEQ ID NO:28, 29, 30, 31, 32, and 33. In some cases, the CDR is the amino acid sequence shown in SEQ ID NO:28, 29, 30, 31, 32, and 33. In some cases, the CDR specifically binds to CD6. In some cases, the CDR has an amino acid sequence of approximately 1 × 10⁻⁶. -6 Up to 1×10 -8 The affinity between them specifically binds to CD6. In some cases, the CDR is equal to or less than about 1 x 10⁻⁶. -6 Or 1x 10 -7 It has an affinity for and specifically binds to CD6.

[0207] As used herein, "intracellular costimulatory signaling domain," "costimulatory signaling domain," or "intracellular costimulatory domain" includes an amino acid sequence capable of providing costimulatory signaling in response to the binding of an antigen to the antigen-binding domain (including embodiments thereof) of a recombinant protein (e.g., CAR) provided herein. In some cases, signaling by the costimulatory signaling domain leads to the production of cytokines and the proliferation of cells expressing the recombinant protein (e.g., CAR) (e.g., T cells).

[0208] In some cases, the costimulatory domain is an intracellular costimulatory domain of CD28 cells or a variant thereof, an intracellular costimulatory domain of 4-1BB cells or a variant thereof, an intracellular costimulatory signaling domain of ICOS cells or a variant thereof, an intracellular costimulatory signaling domain of OX-40 cells or a variant thereof, an intracellular costimulatory domain of CTLA-4 cells or a variant thereof, an intracellular costimulatory domain of PD-1 cells or a variant thereof, or an intracellular costimulatory domain of GITR cells or a variant thereof. In some cases, the costimulatory domain is an intracellular costimulatory domain of CD28 cells (SEQ ID NO: 7 or 8) or a variant thereof. In some cases, it is an intracellular costimulatory domain of 4-1BB cells (SEQ ID NO: 14) or a variant thereof. In some cases, the costimulatory domain is an intracellular costimulatory signaling domain of ICOS cells or a variant thereof. In some cases, the costimulatory domain is an intracellular costimulatory signaling domain of OX-40 cells or a variant thereof. In some cases, the costimulatory domain is an intracellular costimulatory domain of CTLA-4 cells (SEQ ID NO: 17) or a variant thereof. In some cases, the costimulatory domain is an intracellular costimulatory domain of PD-1 cells or a variant thereof. In some cases, the costimulatory domain is the GITR costimulatory domain or a variant thereof.

[0209] In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H V L Transmembrane domain and co-stimulatory domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L V H Transmembrane domain and co-stimulatory domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H Connector, V L Transmembrane domain and co-stimulatory domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L Connector, V H Transmembrane domain and co-stimulatory domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H Connector, V LHinge region, transmembrane domain, and co-stimulatory domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L Connector, V H The VH, VL, junction, hinge region, transmembrane region, and costimulatory region mentioned in this paragraph refer to those disclosed herein, including their embodiments.

[0210] As described herein, an "intracellular T cell signaling domain" includes an amino acid sequence capable of providing primary signaling in response to the binding of an antigen-binding domain (including embodiments thereof) of a recombinant protein (e.g., CAR) provided herein. In some cases, signaling of the intracellular T cell signaling domain leads to activation of T cells expressing it. In some cases, signaling of the intracellular T cell signaling domain leads to proliferation (cell division) of cells (e.g., T cells) expressing the recombinant protein (e.g., CAR). In some cases, signaling of the intracellular T cell signaling domain leads to T cells expressing proteins characteristic of activated T cells known in the art (e.g., CTLA-4, PD-1, CD28, CD69).

[0211] In some cases, the intracellular T cell signaling domain is the CD3ζ intracellular T cell signaling domain.

[0212] In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H V L It contains a transmembrane domain, a co-stimulatory domain, and an intracellular T cell signaling domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L V H It contains a transmembrane domain, a co-stimulatory domain, and an intracellular T cell signaling domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H Connector, V L It contains a transmembrane domain, a co-stimulatory domain, and an intracellular T cell signaling domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L Connector, V H It contains a transmembrane domain, a co-stimulatory domain, and an intracellular T cell signaling domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. H Connector, V LIt includes a hinge region, transmembrane domain, co-stimulatory domain, and intracellular T cell signaling domain. In some cases, the recombinant proteins presented herein (such as CARs, for example on the cell surface) contain V from the N-terminus to the C-terminus. L Connector, V H The VH, VL, junction, hinge region, transmembrane domain, co-stimulatory domain, and intracellular T cell signaling domain are, in this paragraph, those disclosed herein, including their implementations.

[0213] In some cases, T lymphocytes are regulatory T lymphocytes (Tregs). Effector T cells are a broad category, encompassing various T cell types that actively respond to stimuli (such as co-stimulation). Effector T cells include helper, cytotoxic, regulatory, and potentially other T cell types. Regulatory T cells (formerly known as suppressor T cells) are a subset of T cells that regulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune diseases. Tregs have immunosuppressive effects and typically suppress or downregulate the induction and proliferation of effector T cells. In some cases, effector T lymphocytes are helper T cells. In some cases, effector T lymphocytes are cytotoxic T cells. In some cases, effector T lymphocytes are Tregs.

[0214] In some cases, a Treg is a CD4-positive Treg with high CD25 expression. In some cases, a Treg is a CD4-positive Treg with high CD25 expression and low or negative CD127 expression. In some cases, a Treg is a CD4-positive Treg with high CD25 expression and low or negative CD6 expression. In some cases, a Treg is a CD4-positive Treg with high CD25 expression and low or negative CD127 expression and low or negative CD6 expression. In some cases, a Treg is a CD3-positive Treg with low or negative CD6 expression. In some cases, a Treg is a CD4-positive Treg with low or negative CD6 expression. In some cases, a Treg is a CD8-positive Treg with low CD28 expression. In some cases, a Treg includes CD45RA+ expression. In some cases, a Treg does not include CD45RA+ expression. In some cases, a Treg includes FOXP3 demethylated Tregs. In some cases, a Treg is a Treg that does not include FOXP3 demethylation. In some cases, a Treg can be expanded using any IL-2 and / or rapamycin and / or retinoic acid. In some cases, a Treg can be expanded using IL-2 and / or rapamycin and / or retinoic acid. In some cases, a Treg can be expanded using IL-2. In some cases, a Treg can be expanded using rapamycin. In some cases, a Treg can be expanded using retinoic acid.

[0215] The distinction between "high" and "low" is well known in the field. For example, descriptions of high and low expression of the markers mentioned above, and how to identify and quantify high and low expression, can be found in Putnam, AL, TM Brusko, MR Lee, W. Liu, GLSzot, T. Ghosh, MA Atkinson and JA Bluestone. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58(3):652-662, 2009; Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov. 25;7(315):315ra189;Fuchs,A.,M.Gliwinski,N.Grageda,R.Spiering,AKAbbas,S.Appel,R.Bacchetta,M.Battaglia,D.Berglund,B.Blazar,JABluestone,M.Bornhauser,A.Ten Brinke,TM Brusko,N.Cools,MC Cuturi,E.Geissler,N.Giannoukakis,K.Golab,DAHafler,SMvan Ham,J.Hester,K.Hippen,M.Di Ianni,N.Ilic,J.Isaacs,F.Issa,D.Iwaszkiewicz-Grzes,E.Jaeckel,I.Joosten,D.Klatzmann,H.Koenen,C.van Kooten,O.Korsgren,K.Kretschmer,M.Levings,NMMarek-Trzonkowska,M.Martinez-Llordella,D.Miljkovic,KHGMills,JPMiranda,CAPiccirillo,AL Putnam,T.Ritter,MGRoncarolo,S.Sakaguchi,S.Sanchez-Ramon,B.Sawitzki,L.Sofronic-Milosavljevic,M.Sy kes,Q.Tang,M.Vives-Pi,H.Waldmann,P.Witkowski,KJWood,S.Gregori,CMUHilkens,G.Lombardi,P.Lord,EMMartinez-Caceres andP.Trzonkowski.Minimum Information about T Regulatory Cells:AStep towardReproducibility and Standardization.Front Immunol 8:1844,2017;Duggleby,R.,RDDanby,JAMadrigal and A.Saudemont.Clinical Grade Regulatory CD4(+)TCells(Tregs):Moving Toward Cellular-Based Immunomodulatory Therapies.FrontImmunol 9:252, 2018; the entire contents of each of these articles are incorporated herein by reference in their entirety and for all purposes.

[0216] In some cases, the scFv (e.g., the scFv of CAR) includes the light chain variable region shown in SEQ ID NO:34. In some cases, the scFv includes the heavy chain variable region shown in SEQ ID NO:35. In some cases, the scFv includes the sequence shown in SEQ ID NO:38. In some cases, the scFv includes the sequence shown in SEQ ID NO:39.

[0217] In some cases, the scFv (e.g., the scFv of CAR) is oriented to have a light chain variable region at the N-terminus, followed by a heavy chain variable region. Alternatively, in some cases, the scFv is oriented to have a heavy chain variable region at the N-terminus, followed by a light chain variable region.

[0218] In some cases, the light chain variable region (VL) and heavy chain variable region (VH) of the scFv are separated by a connector. In some cases, the connector contains the sequence shown in SEQ ID NO:36. In some cases, the connector contains the sequence shown in SEQ ID NO:37.

[0219] In some cases, the scFv amino acid sequence includes the sequence shown in SEQ ID NO:38. In some cases, the scFv amino acid sequence includes the sequence shown in SEQ ID NO:39. In some cases, the scFv amino acid sequence includes the sequence shown in SEQ ID NO:40. In some cases, the scFv amino acid sequence includes the sequence shown in SEQ ID NO:41.

[0220] In some cases, the variable region of the light chain is covalently bonded to the transmembrane region via the hinge region. In other cases, the variable region of the heavy chain is covalently bonded to the transmembrane region via the hinge region.

[0221] In some cases, the hinge region is human IgG Fc. In some cases, human IgG Fc is human IgG 4 Fc. In some cases, human IgG Fc is human IgG 1 Fc.

[0222] In some cases, the costimulatory domain is the intracellular costimulatory domain of CD28 cells or a variant thereof, the intracellular costimulatory domain of 4-1BB cells or a variant thereof, the intracellular costimulatory signal transduction domain of ICOS cells or a variant thereof, the intracellular costimulatory signal transduction domain of OX-40 cells or a variant thereof, the intracellular costimulatory signal transduction domain of CTLA-4 cells or a variant thereof, the intracellular costimulatory signal transduction domain of PD-1 cells or a variant thereof, or the intracellular costimulatory signal transduction domain of GITR cells or a variant thereof.

[0223] In some cases, the intracellular T cell signaling domain is the CD3ζ intracellular T cell signaling domain.

[0224] In some cases, scFv contains the CDR sequences shown in SEQ ID NO:28, 29, 30, 31, 32 and 33.

[0225] In one aspect, T lymphocytes are provided, including the recombinant proteins described herein, including embodiments thereof. In some cases, the T lymphocytes are regulatory T lymphocytes (Tregs) as described herein, including embodiments thereof. CAR T cells can be generated using methods well known in the art. For example, T lymphocytes isolated from a subject (e.g., a patient) or a donor (e.g., a healthy subject) can be transduced with nucleic acids encoding CAR. The introduction of nucleic acids encoding CAR can be accomplished by viral or non-viral methods as described above. It should be understood that T lymphocytes obtained from a donor (i.e., allogeneic T lymphocytes) can be genetically edited using gene-editing techniques well known in the art (e.g., CRISPR) to eliminate immunogenic proteins (e.g., natural T cell receptors). After transduction, the T lymphocytes can be activated using, for example, artificial antigen-presenting cells (APCs; e.g., engineered cell lines or antibody-coated magnetic beads). Once activated, the T lymphocytes can be induced to develop into specialized T cell subtypes (e.g., T regulatory cells) by treatment with, for example, a specific mixture of cytokines. Finally, the CAR T cell population can be expanded using techniques well known in the art.

[0226] In some cases, the T lymphocytes comprising the recombinant proteins described herein (including embodiments thereof) are autologous T lymphocytes (i.e., derived from a subject). In some cases, the T lymphocytes comprising the recombinant proteins described herein (including embodiments thereof) are allogeneic T lymphocytes (i.e., T lymphocytes not derived from a subject). In some cases, the allogeneic T lymphocytes have been gene-edited. In some cases, the allogeneic T lymphocytes have been gene-edited to eliminate the expression of native T cell receptor proteins.

[0227] On the one hand, isolated nucleic acids are provided that encode proteins including single-stranded variable fragments (scFv) targeting CD6 and transmembrane domains (e.g., CAR).

[0228] In one aspect, vectors comprising nucleic acids (e.g., isolated nucleic acids) as provided herein (including embodiments thereof) are provided. In some cases, the vector is a composition containing isolated nucleic acids and which can be used to deliver the isolated nucleic acids into the cell. Many vectors are known in the art, including but not limited to linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. In some cases, the vector is a self-replicating plasmid or virus. In some cases, compounds that promote nucleic acid transfer into the cell are used, such as, for example, polylysine compounds, liposomes, etc. Examples of viral transfer vectors include, but are not limited to, adenovirus vectors, adeno-associated virus vectors, retrovirus vectors, lentivirus vectors, etc. In some cases, the vector is a plasmid. In some cases, the vector is extrachromosomal. In some cases, the vector is integrated into the genome of the cell. In some cases, the vector is a viral vector. In some cases, the virus is a lentivirus or an oncogenic retrovirus. In some cases, the virus is a lentivirus. In some cases, the virus is an oncogenic retrovirus. Any suitable virus for delivering a vector comprising nucleic acids (e.g., isolated nucleic acids) provided herein into the cell is considered. In some cases, the vector contains a recombinant polynucleotide containing an expression control sequence operatively linked to the nucleotide sequence to be expressed. The term “lentivirus” refers to a genus within the family Retroviridae. Lentivirals are unique among retroviruses in their ability to infect non-dividing cells; they can deliver large amounts of genetic information into the host cell’s DNA, making them one of the most efficient gene delivery vectors. HIV, SIV, and FIV are examples of lentiviruses. The term “lentiviral vector” refers to a vector derived from at least a portion of a lentiviral genome, particularly including self-inactivated lentiviral vectors as described in Milone et al., Mol. Ther. 17(8):1453-1464 (2009). Other examples of lentiviral vectors that can be used clinically include, for example, those from Oxford BioMedica. Gene delivery technology, LENTIMAX from Lentigen TM Vector systems, etc. Non-clinical types of lentiviral vectors are also available and are known to those skilled in the art.

[0229] On the one hand, T lymphocytes are provided, including the vectors provided herein, including their implementation schemes.

[0230] Treatment

[0231] The compositions provided herein, including embodiments thereof, are considered to be effective treatments for autoimmune diseases. Therefore, in one aspect, a method for treating autoimmune diseases (e.g., type 1 diabetes, graft-versus-host disease, lupus) is provided, comprising administering an effective amount of the T lymphocytes (e.g., CAR-T cells) provided herein, including embodiments thereof, to a subject in need of treatment.

[0232] In some cases, autoimmune diseases are associated with reduced function, viability, or survival of pancreatic islet cells (e.g., beta cells). In some cases, autoimmune diseases are type 1 diabetes. In some cases, autoimmune diseases are graft-versus-host disease. In some cases, autoimmune diseases involve the subject's immune system attacking the subject's pancreatic islet cells (e.g., beta cells).

[0233] In some cases, the T lymphocytes provided herein, including their implementation methods, suppress CD6+ T lymphocytes. In some cases, the T lymphocytes provided herein, including their implementation methods, suppress CD6+ B lymphocytes. Example

[0234] The following examples are intended to further illustrate certain embodiments of this disclosure. These examples are presented to those skilled in the art and are not intended to limit the scope thereof.

[0235] Example 1: CD6-targeting CAR expressed in TREG

[0236] exist Figures 1 to 4 This paper describes various CARs including scFvs derived from irijuzumab. In addition to scFvs oriented at VL or VH, each includes a spacer derived from a portion of IgG4 with certain mutations, a CD4 transmembrane domain, a CTLA4 or 4-1BB signaling domain, and a CD3 zeta signaling domain. Because yeast surface display technology previously showed that VH-VL scFvs had similar affinity for human CD6 to irijuzumab, while VL-VH scFvs had lower affinity for human CD6 (Garner et al. (2018) Immunology 155:273), CARs were prepared using VH-VL or VL-VH oriented scFvs. Figure 5 It is used to separate Treg and CD6. 低 / -A schematic diagram of the Treg method. Tregs can be isolated using any suitable method (Fuchs et al. (2018) Front Immunol. 8:1844; Duggleby et al. (2018) Front Immunol. 9:252). A comparison of Tregs, Tregs expressing CD6 CAR (CTLA4), and Tregs expressing CD6 CAR (4-1BB) showed that CD6 CARs with the CTLA4 signaling domain are superior in reducing Teff (CD4+) proliferation. Figure 6 Furthermore, CD6CARs with the CTLA4 signaling domain are excellent at reducing target Teff proliferation. Figure 7 Treg cells expressing CD6 induce anti-inflammatory cytokines ( ). Figure 8 ).like Figure 9 As shown, Tregs expressing CD6 CARs with the CTLA4 signaling domain can be cultured in the presence of Teff with relatively low levels of the depletion biomarker.

[0237] Example 2: Expression of CD6-targeted CAR

[0238] CD6-targeting CARs can be expressed in Tregs using lentiviral vectors. Suitable lentiviral vectors are described in WO2016 / 044811. The nucleotide sequence expressing CAR can be compared with the sequence encoding T2A (LEGGGEGRGSLLTCGDVEENPGPR; SEQ ID NO:71) and the sequence encoding a truncated CD19 receptor (MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQL TWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCVPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKR; SEQ ID NO:71) The sequence (NO:73) is within the box. When expressed in this manner, CAR is expressed in coordination with truncated CD19. This facilitates the quantification of CAR expression in cells using readily available CD19 antibodies.

[0239] Figure 10 Depicting alternatives Figure 1-4 The amino acid sequence of the alternative CD6scFv for scFv in any of the constructs described above.

[0240] Informal partial sequence list

[0241] SEQ ID NO:1

[0242] MWLFFFGITGLLTAALSGHPSPAPPDQLNTSSAESELWEPGERLPVRLTNGSSSCSGTVE

[0243] VRLEASWEPACGALWDSRAAEAVCRALGCGGAEAASQLAPPTPELPPPPAAGNTSVA

[0244] ANATLAGAPALLCSGAEWRLCEVVEHACRSDGRRARVTCAENRALRLVDGGGACAG

[0245] RVEMLEHGEWGSVCDDTWDLEDAHVVCRQLGCGWAVQALPGLHFTPGRGPIHRDQ

[0246] VNCSGAEAYLWDCPGLPGQHYCGHKEDAGAVCSEHQSWRLTGGADRCEGQVEVHF

[0247] RGVWNTVCDSEWYPSEAKVLCQSLGCGTAVERPKGLPHSLSGRMYYSCNGEELTLSN

[0248] CSWRFNNSNLCSQSLAARVLCSASRSLHNLSTPEVPASVQTVTIESSVTVKIENKESREL

[0249] MLLIPSIVLGILLLGSLIFIAFILLRIKGKYALPVMVNHQHLPTTIPAGSNSYQPVPITIPKE

[0250] VFMLPIQVQAPPPEDSDSGSDSDYEHYDFSAQPPVALTTFYNSQRHRVTDEEVQQSRF

[0251] QMPPLEEGLEELHASHIPTANPGHCITDPPSLGPQYHPRSNSESSTSGEDYCNSPKSKL

[0252] PPWNPQVFSSERSSFLEQPPNLELAGTQPAFSAGPPADDSSSTSSGEWYQNFQPPPQPPS

[0253] EEQFGCPGSPSPQPDSTDNDDYDDISAA

[0254] SEQ ID NO:2

[0255] MWLFFGITGLLTAALSGHPSPAPPD

[0256] Q

[0257] LNTSSAESELWEPGERLPVRLTNGSSSCSGTVEVRLEASWEPACGALWDSRAAEAVCR

[0258] ALGCGGAEAASQLAPPTPELPPPPAAGNTSVAANATLAGAPALLCSGAEWRLCEVVE

[0259] HACRSDGRRARVTCAENRALRLVDGGGACAGRVEMLEHGEWGSVCDDTWDLEDAH

[0260] VVCRQLGCGWAVQALPGLHFTPGRGPIHRDQVNCSGAEAYLWDCPGLPGQHYCGHK

[0261] EDAGAVCSEHQSWRLTGGADRCEGQVEVHFRGVWNTVCDSEWYPSEAKVLCQSLG

[0262] CGTAVERPKGLPHSLSGRMYYSCNGEELTLSNCSWRFNNSNLCSQSLAARVLCSASRS

[0263] LHNLSTPEVPASVQTVTIESSVTVKIENKESRELMLLIPSIVLGILLLGSLIFIAFILLRIKG

[0264] KYVFMLPIQVQAPPPEDSDSGSDSDYEHYDFSAQPPVALTTFYNSQRHRVTDEEVQQS

[0265] RFQMPPLEEGLEELHASHIPTANPGHCITDPPSLGPQYHPRSNSESSTSSGEDYCNSPKS

[0266] KLPPWNPQVFSSER SSFLEQPPNLELAGTQPAFSGSPSPQPDSTDNDDYDDISAA

[0267] SEQ ID NO:3

[0268] MWLFFGITGLLTAALSGHPSPAPPDQLNTSSAESELWEPGERLPVRLTNGSSSCSGTVE

[0269] VRLEASWEPACGALWDSRAAEAVCRALGCGGAEAASQLAPPTPELPPPPAAGNTSVA

[0270] ANATLAGAPALLCSGAEWRLCEVVEHACRSDGRRARVTCAENRALRLVDGGGACAG

[0271] RVEMLEHGEWGSVCDDTWDLEDAHVVCRQLGCGWAVQALPGLHFTPGRGPIHRDQ

[0272] VNCSGAEAYLWDCPGLPGQHYCGHKEDAGAVCSEHQSWRLTGGADRCEGQVEVHF

[0273] RGVWNTVCDSEWYPSEAKVLCQSLGCGTAVERPKGLPHSLSGRMYYSCNGEELTLSN

[0274] CSWRFNNSNLCSQSLAARVLCSASRSLHNLSTPEVPASVQTVTIESSVTVKIENKESREL

[0275] MLLIPSIVLGILLLGSLIFIAFILLRIKGKYALPVMVNHQHLPTTIPAGSNSYQPVPITIPKE

[0276] DSQRHRVTDEEVQQSRFQMPPLEEGLEELHASHIPTANPGHCITDPPSLGPQYHPRSNS

[0277] ESSTSSGEDYCNSPKSKLPPWNPQVFSSERSSFLEQPPNLELAGTQPAFSGSPSPQPDST

[0278] DNDDYDDISAA

[0279] SEQ ID NO:4

[0280] MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSWKHLCPSPLFPGPSKPFWV

[0281] LVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPR

[0282] DFAAYRS

[0283] SEQ ID NO:5

[0284] MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKG

[0285] LDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIE

[0286] VMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVA

[0287] FIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0288] SEQ ID NO:6

[0289] MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKG

[0290] LDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIE

[0291] VMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVA

[0292] FIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0293] SEQ ID NO:7

[0294] RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0295] SEQ ID NO:8

[0296] RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0297] SEQ ID NO:9

[0298] MNRGVPFRHLLLVLQLALLPAATQGKKVVLGKKGDTVELTCTASQKKSIQFHWKNS

[0299] NQIKILGNQGSFLTKGPSKLNDRADSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKE

[0300] EVQLLVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLE

[0301] LQDSGTWTCTVLQNQKKVEFKIDIVVLAFQKASSIVYKKEGEQVEFSFPLAFTVEKLT

[0302] GSGELWWQAERASSSKSWITFDLKNKEVSVKRVTQDPKLQMGKKLPLHLTLPQALPQ

[0303] YAGSGNLTLALEAKTGKLHQEVNLVVMRATQLQKNLTCEVWGPTSPKLMLSLKLEN

[0304] KEAKVSKREKAVWVLNPEAGMWQCLLSDSGQVLLESNIKVLPTWSTPVQPMALIVLG

[0305] GVAGLLLFIGLGIFFCVRCRHRRRQAERMSQIKRLLSEKKTCQCPHRFQKTCSPI

[0306] SEQ ID NO:10

[0307] MPTPLVHPHLPISSPRVSPFPPPAFQKASSIVYKKEGEQVEFSFPLAFTVEKLTGSGELW

[0308] WQAERASSSKSWITFDLKNKEVSVKRVTQDPKLQMGKKLPLHLTLPQALPQYAGSGN

[0309] LTLALEAKTGKLHQEVNLVVMRATQLQKNLTCEVWGPTSPKLMLSLKLENKEAKVS

[0310] KREKAVWVLNPEAGMWQCLLSDSGQVLLESNIKVLPTWSTPVQPMALIVLGGVAGL

[0311] LLFIGLGIFFCVRCRHRRRQAERMSQIKRLLSEKKTCQCPHRFQKTCSPI

[0312] SEQ ID NO:11

[0313] MGKKLPLHLTLPQALPQYAGSGNLTLALEAKTGKLHQEVNLVVMRATQLQKNLTCE

[0314] VWGPTSPKLMLSLKLENKEAKVSKREKAVWVLNPEAGMWQCLLSDSGQVLLESNIK

[0315] VLPTWSTPVQPMALIVLGGVAGLLLFIGLGIFFCVRCRHRRRQAERMSQIKRLLSEKKT

[0316] CQCPHRFQKTCSPI

[0317] SEQ ID NO:12

[0318] MGKKLPLHLTLPQALPQYAGSGNLTLALEAKTGKLHQEVNLVVMRATQLQKNLTCE

[0319] VWGPTSPKLMLSLKLENKEAKVSKREKAVWVLNPEAGMWQCLLSDSGQVLLESNIK

[0320] VLPTWSTPVQPMALIVLGGVAGLLLFIGLGIFFCVRCRHRRRQAERMSQIKRLLSEKKT

[0321] CQCPHRFQKTCSPI

[0322] SEQ ID NO:13

[0323] MGKKLPLHLTLPQALPQYAGSGNLTLALEAKTGKLHQEVNLVVMRATQLQKNLTCE

[0324] VWGPTSPKLMLSLKLENKEAKVSKREKAVWVLNPEAGMWQCLLSDSGQVLLESNIK

[0325] VLPTWSTPVQPMALIVLGGVAGLLLFIGLGIFFCVRCRHRRRQAERMSQIKRLLSEKKT

[0326] CQCPHRFQKTCSPI

[0327] SEQ ID NO:14

[0328] KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

[0329] SEQ ID NO:15

[0330] MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQ

[0331] RTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKG

[0332] CKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTP

[0333] PAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTT

[0334] QEEDGCSCRFPEEEEGGCEL

[0335] SEQ ID NO:16

[0336] MKSGLWYFFLFCLRIKVLTGEINGSANYEMFIFHNGGVQILCKYPDIVQQFKMQLLKG

[0337] GQILCDLTKTKGSGNTVSIKSLKFCHSQLSNNSVSFFLYNLDHSHANYYFCNLSIFDPPP

[0338] FKVTLTGGYLHIYESQLCCQLKFWLPIGCAAFVVVCILGCILICWLTKKKYSSSVHDPN

[0339] GEYMFMRAVNTAKKSRLTDVTL

[0340] SEQ ID NO:17

[0341] AVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN

[0342] SEQ ID NO:18(VL NA)

[0343] GACATCCAAATGACACAAAGTCCTAGCTCTCTCTCAGCAAGTGTTGGCGACCGTGT

[0344] GACCATCACATGTAAAGCTTCAAGGGATATTCGCAGCTACCTGACTTGGTACCAAC

[0345] AAAAGCCCGGAAAAGCGCCTAAAACGCTTATTTACTATGCCACCAGCCTCGCAGA

[0346] TGGTGTCCCCTCCAGATTTTCTGGATCGGGATCAGGGCAAGATTATAGTCTTACGA

[0347] TATCGAGTCTTGAGTCGGACGATACTGCCACATACTACTGCTTACAGCACGGGGAA

[0348] AGCCCATTCACATTCGGAAGTGGTACGAAACTCGAGATCAAACGGGCA

[0349] SEQ ID NO:19(VH NA)

[0350] GAAGTCCAATTGGTCGAGAGCGGAGGTGGGCTTGTTAAACCAGGAGGCAGTTTAA

[0351] AATTATCATGTGCTGCCTCGGGTTTCAAGTTCTCGCGGTATGCTATGTCCTGGGTAC

[0352] GCCAAGCACCTGGAAAGCGTTTAGAATGGGTGGCCACAATTAGTGGTGGTTC

[0353] ATATATATATTATCCCGACTCCGTCAAAGGAAGGTTCACGATTTCAAGGGACAATG

[0354] TGAAGAACACCCTCTACTTACAGATGAGTAGTCTGCGTTCTGAGGATACCGCTATG

[0355] TACTACTGTGCTCGGAGAGATTACGATCTGGATTATTTCGACAGCTGGGGTCAGGG

[0356] CACACTCGTTACAGTATCCTCG

[0357] SEQ ID NO:20(VH CDR1 NA)

[0358] GTCCAACTTGTTGAATCAGGTGGGGGGCTGGTCAAACCCGGGGGCTCTCTGAAAC

[0359] QUIET

[0360] SEQ ID NO:21(VH CDR2 NA)

[0361] TTCTCTCGGTACGCTATGTCGTGGGTCAGACAAGCGCCCGGCAAA

[0362] SEQ ID NO:22(VH CDR3 NA)

[0363] CGTGATTATGATCTAGACTACTTTGACTCCTGGGGTCAAGGTACGCTCGTGACGGT

[0364] T

[0365] SEQ ID NO:23

[0366] MALIVLGGVAGLLLFIGLGIFF

[0367] SEQ ID NO:24

[0368] ATGGCCCTGATTGTGCTGGGGGGCGTCGCCGGCCTCCTGCTTTTCATTGGGCTAGG

[0369] CATCTTCTTC

[0370] SEQ ID NO:25

[0371] IYIWAPLAGTCGVLLLSLVIT

[0372] SEQ ID NO:26 (Adapter 18NA)

[0373] GGGTCAACGTCGGGCGGGGGTTCCGGTGGAGGAAGTGGAGGTGGTGGAAGTTCT

[0374] SEQ ID NO:27 (Adapter 20NA)

[0375] GGCGGCGGCGGAAGTGGCGGCGGCGGCTCAGGCGGGGGGGGTTCTGGGGGCGGC

[0376] GGTTCA

[0377] SEQ ID NO:28 (VH CDR1 AA)

[0378] VQLVESGGGLVKPGGSLKLS

[0379] SEQ ID NO:29 (VH CDR2 AA)

[0380] FSRYAMSWVRQAPGK

[0381] SEQ ID NO:30 (VH CDR3 AA)

[0382] RDYDLDYFDSWGQGTLVTV

[0383] SEQ ID NO:31 (VL CDR1 AA)

[0384] CWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL

[0385] SEQ ID NO:32

[0386] ALYLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI

[0387] SEQ ID NO:33 ((VL CDR3 AA)

[0388] CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYA

[0389] TIVFPSGMGTSSP ARRGSADGPRSAQPLRPEDGHCSWPL

[0390] SEQ ID NO:34 (VL AA)

[0391] DIQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKPGKAPKTLIYYATSLADGVP

[0392] SRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGSGTKLEIKRA

[0393] SEQ ID NO:35 (VH AA)

[0394] EVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMSWVRQAPGKRLEWVATISSGGSY

[0395] IYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYFDSWGQGTL

[0396] VTVSS

[0397] SEQ ID NO:36 (Linker 18AA)

[0398] GSTSGGGSGGGSGGGGSS

[0399] SEQ ID NO:37 (Linker 20AA)

[0400] GGGGSGGGGSGGGGSGGGGS

[0401] SEQ ID NO:38 (Full scFv (VH-VL) Linker 18)

[0402] EVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMSWVRQAPGKRLEWVATISSGGSY

[0403] IYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYFDSWGQGTL

[0404] VTVSS

[0405] GSTSGGGSGGGSGGGGSSDIQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKP

[0406] GKAPKTLIYYATSLADGVPSRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGS

[0407] GTKLEIKRA

[0408] SEQ ID NO:39 (Full scFv (VH-VL) linker 20)

[0409] EVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMSWVRQAPGKRLEWVATISSGGSY

[0410] IYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYFDSWGQGTL

[0411] VTVSS

[0412] GGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQ

[0413] KPGKAPKTLIYYATSLADGVPSRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTF

[0414] GSGTKLEIKRA

[0415] SEQ ID NO:40 (Full scFv (VL-VH) linker 18AA)

[0416] DIQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKPGKAPKTLIYYATSLADGVP

[0417] SRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGSGTKLEIKRAGSTSGGGSGG

[0418] GSGGGGSSEVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMSWVRQAPGKRLEWV

[0419] ATISSGGSYIYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYF

[0420] DSWGQGTLVTVSS

[0421] SEQ ID NO:41 (Full scFv (VL - VH) linker 20AA)

[0422] DIQMTQSPSSLSASVGDRVTITCKASRDIRSYLTWYQQKPGKAPKTLIYYATSLADGVP

[0423] SRFSGSGSGQDYSLTISSLESDDTATYYCLQHGESPFTFGSGTKLEIKRAGGGGSGGGG

[0424] SGGGGSGGGGSEVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMSWVRQAPGKRL

[0425] EWVATISSGGSYIYYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDL

[0426] DYFDSWGQGTLVTVSS

[0427] SEQ ID NO:42 (Full scFv (VH - VL) linker 18NA)

[0428] GAAGTCCAATTGGTCGAGAGCGGAGGTGGGCTTGTTAAACCAGGAGGCAGTTTAA

[0429] AATTATCATGTGCTGCCTCGGGTTTCAAGTTCTCGCGGTATGCTATGTCCTGGGTAC

[0430] GCCAAGCACCTGGAAAGCGTTTAGAATGGGTGGCCACAATTAGTAGTGGTGGTTC

[0431] ATATATATATTATCCCGACTCCGTCAAAGGAAGGTTCACGATTTCAAGGGACAATG

[0432] TGAAGAACACCCTCTACTTACAGATGAGTAGTCTGCGTTCTGAGGATACCGCTATG

[0433] TACTACTGTGCTCGGAGAGATTACGATCTGGATTATTTCGACAGCTGGGGTCAGGG

[0434] CACACTCGTTACAGTATCCTCGGGGTCAACGTCGGGCGGGGGTTCCGGTGGAGGA

[0435] AGTGGAGGTGGTGGAAGTTCTGACATCCAAATGACACAAAGTCCTAGCTCTCTCTC

[0436] AGCAAGTGTTGGCGACCGTGTGACCATCACATGTAAAGCTTCAAGGGATATTCGC

[0437] AGCTACCTGACTTGGTACCAACAAAAGCCCGGAAAAGCGCCTAAAACGCTTATTT

[0438] ACTATGCCACCAGCCTCGCAGATGGTGTCCCCTCCAGATTTTCTGGATCGGGATCA

[0439] GGGCAAGATTATAGTCTTACGATATCGAGTCTTGAGTCGGACGATACTGCCACATA

[0440] CTACTGCTTACAGCACGGGGAAAGCCCATTCACATTCGGAAGTGGTACGAAACTC

[0441] GAGATCAAACGGGCA

[0442] SEQ ID NO:43(Full scFv (VH-VL) linker 20NA)

[0443] GAAGTCCAATTGGTCGAGAGCGGAGGTGGGCTTGTTAAACCAGGAGGCAGTTTAA

[0444] AATTATCATGTGCTGCCTCGGGTTTCAAGTTCTCGCGGTATGCTATGTCCTGGGTAC

[0445] GCCAAGCACCTGGAAAGCGTTTAGAATGGGTGGCCACAATTAGTAGTGGTGGTTC

[0446] ATATATATATTATCCCGACTCCGTCAAAGGAAGGTTCACGATTTCAAGGGACAATG

[0447] TGAAGAACACCCTCTACTTACAGATGAGTAGTCTGCGTTCTGAGGATACCGCTATG

[0448] TACTACTGTGCTCGGAGAGATTACGATCTGGATTATTTCGACAGCTGGGGTCAGGG

[0449] CACACTCGTTACAGTATCCTCGGGCGGCGGCGGAAGTGGCGGCGGCGGCTCAGGC

[0450] GGGGGGGGTTCTGGGGGCGGCGGTTCAGACATCCAAATGACACAAAGTCCTAGCT

[0451] CTCTCTCAGCAAGTGTTGGCGACCGTGTGACCATCACATGTAAAGCTTCAAGGGAT

[0452] ATTCGCAGCTACCTGACTTGGTACCAACAAAAGCCCGGAAAAGCGCCTAAAACGC

[0453] TTATTTACTATGCCACCAGCCTCGCAGATGGTGTCCCCTCCAGATTTTCTGGATCGG

[0454] GATCAGGGCAAGATTATAGTCTTACGATATCGAGTCTTGAGTCGGACGATACTGCC

[0455] ACATACTACTGCTTACAGCACGGGGAAAGCCCATTCACATTCGGAAGTGGTACGA

[0456] AACTCGAGATCAAACGGGCA

[0457] SEQ ID NO:44 (Full scFv (VL-VH) linker 18NA)

[0458] GACATCCAAATGACACAAAGTCCTAGCTCTCTCTCAGCAAGTGTTGGCGACCGTGT

[0459] GACCATCACATGTAAAGCTTCAAGGGATATTCGCAGCTACCTGACTTGGTACCAAC

[0460] AAAAGCCCGGAAAAGCGCCTAAAACGCTTATTTACTATGCCACCAGCCTCGCAGA

[0461] TGGTGTCCCCTCCAGATTTTCTGGATCGGGATCAGGGCAAGATTATAGTCTTACGA

[0462] TATCGAGTCTTGAGTCGGACGATACTGCCACATACTACTGCTTACAGCACGGGGAA

[0463] AGCCCATTCACATTCGGAAGTGGTACGAAACTCGAGATCAAACGGGCAGGGTCAA

[0464] CGTCGGGCGGGGGTTCCGGTGGAGGAAGTGGAGGTGGTGGAAGTTCTGAAGTCCA

[0465] ATTGGTCGAGAGCGGAGGTGGGCTTGTTAAACCAGGAGGCAGTTTAAAATTATCA

[0466] TGTGCTGCCTCGGGTTTCAAGTTCTCGCGGTATGCTATGTCCTGGGTACGCCAAGC

[0467] ACCTGGAAAGCGTTTAGAATGGGTGGCCACAATTAGTAGTGGTGGTTCATATATAT

[0468] ATTATCCCGACTCCGTCAAAGGAAGGTTCACGATTTCAAGGGACAATGTGAAGAA

[0469] CACCCTCTACTTACAGATGAGTAGTCTGCGTTCTGAGGATACCGCTATGTACTACT

[0470] GTGCTCGGAGAGATTACGATCTGGATTATTTCGACAGCTGGGGTCAGGGCACACTC

[0471] GTTACAGTATCCTCG

[0472] SEQ ID NO:45 (Full scFv (VL-VH) Linker 20NA)

[0473] GACATCCAAATGACACAAAGTCCTAGCTCTCTCTCAGCAAGTGTTGGCGACCGTGT

[0474] GACCATCACATGTAAAGCTTCAAGGGATATTCGCAGCTACCTGACTTGGTACCAAC

[0475] AAAAGCCCGGAAAAGCGCCTAAAACGCTTATTTACTATGCCACCAGCCTCGCAGA

[0476] TGGTGTCCCCTCCAGATTTTCTGGATCGGGATCAGGGCAAGATTATAGTCTTACGA

[0477] TATCGAGTCTTGAGTCGGACGATACTGCCACATACTACTGCTTACAGCACGGGGAA

[0478] AGCCCATTCACATTCGGAAGTGGTACGAAACTCGAGATCAAACGGGCAGGCGGCG

[0479] GCGGAAGTGGCGGCGGCGGCTCAGGCGGGGGGGGTTCTGGGGGCGGCGGTTCAG

[0480] AAGTCCAATTGGTCGAGAGCGGAGGTGGGCTTGTTAAACCAGGAGGCAGTTTAAA

[0481] ATTATCATGTGCTGCCTCGGGTTTCAAGTTCTCGCGGTATGCTATGTCCTGGGTACG

[0482] CCAAGCACCTGGAAAGCGTTTAGAATGGGTGGCCACAATTAGTAGTGGTGGTTCA

[0483] TATATATATTATCCCGACTCCGTCAAAGGAAGGTTCACGATTTCAAGGGACAATGT

[0484] GAAGAACACCCTCTACTTACAGATGAGTAGTCTGCGTTCTGAGGATACCGCTATGT

[0485] ACTACTGTGCTCGGAGAGATTACGATCTGGATTATTTCGACAGCTGGGGTCAGGGC

[0486] ACACTCGTTACAGTATCCTCG

[0487] SEQ ID NO:46

[0488] MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPTSGCSWLF

[0489] QPRGAAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLTLSDFRRENEGYYFCS

[0490] ALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG

[0491] LDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRRVCKCPRPVVKSGDKPSLSARY

[0492] V

[0493] SEQ ID NO:47

[0494] MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPTSGCSWLF

[0495] QPRGAAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLTLSDFRRENEGYYFCS

[0496] ALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAGNRRR

[0497] VCKCPRPVVKSGDKPSLSARYV

[0498] SEQ ID NO:48

[0499] MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPTSGCSWLF

[0500] QPRGAAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLTLSDFRRENEGYYFCS

[0501] ALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG

[0502] LDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRRVCKCPRPVVKSGDKPSLSARY

[0503] V

[0504] SEQ ID NO:49

[0505] MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMRIYWLR

[0506] QRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNLTSVKPEDSGIYF

[0507] CMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVCRLPRPETQKGPLCSPITLGL

[0508] LVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQKFNIVCLKISGFTTCCCFQILQMSREY

[0509] GFGVLLQKDIGQ

[0510] SEQ ID NO:50

[0511] MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMRIYWLR

[0512] QRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNLTSVKPEDSGIYF

[0513] CMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVCRLPRPETQKGLKGKVYQE

[0514] PLSPNACMDTTAILQPHRSCLTHGS

[0515] SEQ ID NO:51

[0516] MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMRIYWLR

[0517] QRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNLTSVKPEDSGIYF

[0518] CMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVCRLPRPETQKGPLCSPITLGL

[0519] LVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQPQGEGISGTFVPQCLHGYYSNTTTSQ

[0520] KLLNPWILKT

[0521] SEQ ID NO:52

[0522] MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMRIYWLR

[0523] QRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNLTSVKPEDSGIYF

[0524] CMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVCRLPRPETQKGRRRRARLR

[0525] FMKQPQGEGISGTFVPQCLHGYYSNTTTSQKLLNPWILKT

[0526] SEQ ID NO:53

[0527] MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMRIYWLR

[0528] QRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNLTSVKPEDSGIYF

[0529] CMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVCRLPRPETQKGPLCSPITLGL

[0530] LVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQLRLHPLEKCSRMDY

[0531] SEQ ID NO:54

[0532] MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMRIYWLR

[0533] QRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNLTSVKPEDSGIYF

[0534] CMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVCRLPRPETQKGPLCSPITLGL

[0535] LVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQFYK

[0536] SEQ ID NO:55

[0537] MKWKALFTAAILQAQLPITEAQSFGLLDPKLCYLLDGILFIYGVILTALFLRVKFSRSAD

[0538] APAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKD

[0539] KMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0540] SEQ ID NO:56

[0541] MKWKALFTAAILQAQLPITEAQSFGLLDPKLCYLLDGILFIYGVILTALFLRVKFSRSAD

[0542] APAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQK

[0543] DKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0544] SEQ ID NO:57

[0545] MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSWKHLCPSPLFPGPSKPFWV

[0546] LVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPR

[0547] DFAAYRS

[0548] SEQ ID NO:58

[0549] MLRLLLALNLFPSIQVTGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFW

[0550] VRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0551] SEQ ID NO:59

[0552] MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKG

[0553] LDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIE

[0554] VMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVA

[0555] FIIFWVRSKSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0556] SEQ ID NO:60

[0557] MCVGARRLGRGPCAALLLLGLGLSTVTGLHCVGDTYPSNDRCCHECRPGNGMVSRC

[0558] SRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGT

[0559] QPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRDP

[0560] PATQPQETQGPPARPITVQPTEAWPRTSQGPSTRPVEVPGGRAVAAILGLGLVLGLLGP

[0561] LAILLALYLLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI

[0562] SEQ ID NO:61

[0563] MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVC

[0564] EYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSSICTGTSSGNQVNLT

[0565] IQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIAKEKKPSYNRGLCENAPNRAR

[0566] M

[0567] SEQ ID NO:62

[0568] MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVC

[0569] EYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLT

[0570] IQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLF

[0571] FYSFLLTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN

[0572] SEQ ID NO:63

[0573] MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFS

[0574] NTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRAR

[0575] RNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGV

[0576] VGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQW

[0577] REKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL

[0578] SEQ ID NO:64

[0579] MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTR

[0580] CCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCI

[0581] DCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEPLGWLTVVL

[0582] LAVAACVLLLTSAQLGLHIWQLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGER

[0583] SAEEKGRLGDLWV

[0584] SEQ ID NO:65

[0585] MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTR

[0586] CCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCI

[0587] DCASGTFSGGHEGHCKPWTDCCWRCRRRPKTPEAASSPRKSGASDRQRRRGGWETC

[0588] GCEPGRPPGPPTAASPSPGAPQAAGALRSALGRALLPWQQKWVQEGGSDQRPGPCSS

[0589] AAAAGPCRRERETQSWPPSSLAGP DGVGS

[0590] SEQ ID NO:66

[0591] MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTR

[0592] CCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCI

[0593] DCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEPLGWLTVVL

[0594] LAVAACVLLLTSAQLGLHIWQLRKTQLLLEVPPSTEDARSCQFPEEERGERSAEEKGR

[0595] LGDLWV

[0596] SEQ ID NO:67(GITR co-stimulatory domain AA)QLGLHIWQLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGERSAEEKGRLGDLWV

[0597] SEQ ID NO:68(VH AA)

[0598] EVQLVESGGGLVKPGGSLKLSCAASGFKFSRYAMSWVRQTPEKRLEWVATISSGGSYI

[0599] YYPDSVKGRFTISRDNVKNTLYLQMSSLRSEDTAMYYCARRDYDLDYFDSWGQGTT

[0600] LTVSS

[0601] SEQ ID NO:69(VL AA)

[0602] DIKMTQSPSSMYASLGERVTITCKASRDIRSYLTWYQQKPWKSPKTLIYYATSLADGV

[0603] PSRFSGSGSGQDYSL TISSLESDDTATYYCLQHGESPFTFGSGTKLEIKRA sequence list <110> City of Hope Company <120> CD6-targeting chimeric antigen receptor for the treatment of certain autoimmune diseases <130> 40056-0051US1 <140> 17 / 256,788 <141> 2020-12-29 <150> PCT / US2019 / 040185 <151> 2019-07-01 <150> US 62 / 692,609 <151> 2018-06-29 <160> 92 <170> PatentIn version 3.5 <210> 1 <211> 668 <212> PRT <213> Homo sapiens <400> 1 Met Trp Leu Phe Phe Gly Ile Thr Gly Leu Leu Thr Ala Ala Leu Ser 1 5 10 15 Gly His Pro Ser Pro Ala Pro Pro Asp Gln Leu Asn Thr Ser Ser Ala 20 25 30 Glu Ser Glu Leu Trp Glu Pro Gly Glu Arg Leu Pro Val Arg Leu Thr 35 40 45 Asn Gly Ser Ser Ser Cys Ser Gly Thr Val Glu Val Arg Leu Glu Ala 50 55 60 Ser Trp Glu Pro Ala Cys Gly Ala Leu Trp Asp Ser Arg Ala Ala Glu 65 70 75 80 Ala Val Cys Arg Ala Leu Gly Cys Gly Gly Ala Glu Ala Ala Ser Gln 85 90 95 Leu Ala Pro Pro Thr Pro Glu Leu Pro Pro Pro Pro Ala Ala Gly Asn 100 105 110 Thr Ser Val Ala Ala Asn Ala Thr Leu Ala Gly Ala Pro Ala Leu Leu 115 120 125 Cys Ser Gly Ala Glu Trp Arg Leu Cys Glu Val Val Glu His Ala Cys 130 135 140 Arg Ser Asp Gly Arg Arg Ala Arg Val Thr Cys Ala Glu Asn Arg Ala 145 150 155 160 Leu Arg Leu Val Asp Gly Gly Gly Ala Cys Ala Gly Arg Val Glu Met 165 170 175 Leu Glu His Gly Glu Trp Gly Ser Val Cys Asp Asp Thr Trp Asp Leu 180 185 190 Glu Asp Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Trp Ala Val 195 200 205 Gln Ala Leu Pro Gly Leu His Phe Thr Pro Gly Arg Gly Pro Ile His 210 215 220 Arg Asp Gln Val Asn Cys Ser Gly Ala Glu Ala Tyr Leu Trp Asp Cys 225 230 235 240 Pro Gly Leu Pro Gly Gln His Tyr Cys Gly His Lys Glu Asp Ala Gly 245 250 255 Ala Val Cys Ser Glu His Gln Ser Trp Arg Leu Thr Gly Gly Ala Asp 260 265 270 Arg Cys Glu Gly Gln Val Glu Val His Phe Arg Gly Val Trp Asn Thr 275 280 285 Val Cys Asp Ser Glu Trp Tyr Pro Ser Glu Ala Lys Val Leu Cys Gln 290 295 300 Ser Leu Gly Cys Gly Thr Ala Val Glu Arg Pro Lys Gly Leu Pro His 305 310 315 320 Ser Leu Ser Gly Arg Met Tyr Tyr Ser Cys Asn Gly Glu Glu Leu Thr 325 330 335 Leu Ser Asn Cys Ser Trp Arg Phe Asn Asn Ser Asn Leu Cys Ser Gln 340 345 350 Ser Leu Ala Ala Arg Val Leu Cys Ser Ala Ser Arg Ser Leu His Asn 355 360 365 Leu Ser Thr Pro Glu Val Pro Ala Ser Val Gln Thr Val Thr Ile Glu 370 375 380 Ser Ser Val Thr Val Lys Ile Glu Asn Lys Glu Ser Arg Glu Leu Met 385 390 395 400 Leu Leu Ile Pro Ser Ile Val Leu Gly Ile Leu Leu Leu Gly Ser Leu 405 410 415 Ile Phe Ile Ala Phe Ile Leu Leu Arg Ile Lys Gly Lys Tyr Ala Leu 420 425 430 Pro Val Met Val Asn His Gln His Leu Pro Thr Thr Ile Pro Ala Gly 435 440 445 Ser Asn Ser Tyr Gln Pro Val Pro Ile Thr Ile Pro Lys Glu Val Phe 450 455 460 Met Leu Pro Ile Gln Val Gln Ala Pro Pro Pro Glu Asp Ser Asp Ser 465 470 475 480 Gly Ser Asp Ser Asp Tyr Glu His Tyr Asp Phe Ser Ala Gln Pro Pro 485 490 495 Val Ala Leu Thr Thr Phe Tyr Asn Ser Gln Arg His Arg Val Thr Asp 500 505 510 Glu Glu Val Gln Gln Ser Arg Phe Gln Met Pro Pro Leu Glu Glu Gly 515 520 525 Leu Glu Glu Leu His Ala Ser His Ile Pro Thr Ala Asn Pro Gly His 530 535 540 Cys Ile Thr Asp Pro Pro Ser Leu Gly Pro Gln Tyr His Pro Arg Ser 545 550 555 560 Asn Ser Glu Ser Ser Thr Ser Ser Gly Glu Asp Tyr Cys Asn Ser Pro 565 570 575 Lys Ser Lys Leu Pro Pro Trp Asn Pro Gln Val Phe Ser Ser Glu Arg 580 585 590 Ser Ser Phe Leu Glu Gln Pro Pro Asn Leu Glu Leu Ala Gly Thr Gln 595 600 605 Pro Ala Phe Ser Ala Gly Pro Pro Ala Asp Asp Ser Ser Ser Thr Ser 610 615 620 Ser Gly Glu Trp Tyr Gln Asn Phe Gln Pro Pro Pro Gln Pro Pro Ser 625 630 635 640 Glu Glu Gln Phe Gly Cys Pro Gly Ser Pro Ser Pro Gln Pro Asp Ser 645 650 655 Thr Asp Asn Asp Asp Tyr Asp Asp Ile Ser Ala Ala 660 665 <210> 2 <211> 601 <212> PRT <213> Homo sapiens <400> 2 Met Trp Leu Phe Phe Gly Ile Thr Gly Leu Leu Thr Ala Ala Leu Ser 1 5 10 15 Gly His Pro Ser Pro Ala Pro Pro Asp Gln Leu Asn Thr Ser Ser Ala 20 25 30 Glu Ser Glu Leu Trp Glu Pro Gly Glu Arg Leu Pro Val Arg Leu Thr 35 40 45 Asn Gly Ser Ser Ser Cys Ser Gly Thr Val Glu Val Arg Leu Glu Ala 50 55 60 Ser Trp Glu Pro Ala Cys Gly Ala Leu Trp Asp Ser Arg Ala Ala Glu 65 70 75 80 Ala Val Cys Arg Ala Leu Gly Cys Gly Gly Ala Glu Ala Ala Ser Gln 85 90 95 Leu Ala Pro Pro Thr Pro Glu Leu Pro Pro Pro Pro Ala Ala Gly Asn 100 105 110 Thr Ser Val Ala Ala Asn Ala Thr Leu Ala Gly Ala Pro Ala Leu Leu 115 120 125 Cys Ser Gly Ala Glu Trp Arg Leu Cys Glu Val Val Glu His Ala Cys 130 135 140 Arg Ser Asp Gly Arg Arg Ala Arg Val Thr Cys Ala Glu Asn Arg Ala 145 150 155 160 Leu Arg Leu Val Asp Gly Gly Gly Ala Cys Ala Gly Arg Val Glu Met 165 170 175 Leu Glu His Gly Glu Trp Gly Ser Val Cys Asp Asp Thr Trp Asp Leu 180 185 190 Glu Asp Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Trp Ala Val 195 200 205 Gln Ala Leu Pro Gly Leu His Phe Thr Pro Gly Arg Gly Pro Ile His 210 215 220 Arg Asp Gln Val Asn Cys Ser Gly Ala Glu Ala Tyr Leu Trp Asp Cys 225 230 235 240 Pro Gly Leu Pro Gly Gln His Tyr Cys Gly His Lys Glu Asp Ala Gly 245 250 255 Ala Val Cys Ser Glu His Gln Ser Trp Arg Leu Thr Gly Gly Ala Asp 260 265 270 Arg Cys Glu Gly Gln Val Glu Val His Phe Arg Gly Val Trp Asn Thr 275 280 285 Val Cys Asp Ser Glu Trp Tyr Pro Ser Glu Ala Lys Val Leu Cys Gln 290 295 300 Ser Leu Gly Cys Gly Thr Ala Val Glu Arg Pro Lys Gly Leu Pro His 305 310 315 320 Ser Leu Ser Gly Arg Met Tyr Tyr Ser Cys Asn Gly Glu Glu Leu Thr 325 330 335 Leu Ser Asn Cys Ser Trp Arg Phe Asn Asn Ser Asn Leu Cys Ser Gln 340 345 350 Ser Leu Ala Ala Arg Val Leu Cys Ser Ala Ser Arg Ser Leu His Asn 355 360 365 Leu Ser Thr Pro Glu Val Pro Ala Ser Val Gln Thr Val Thr Ile Glu 370 375 380 Ser Ser Val Thr Val Lys Ile Glu Asn Lys Glu Ser Arg Glu Leu Met 385 390 395 400 Leu Leu Ile Pro Ser Ile Val Leu Gly Ile Leu Leu Leu Gly Ser Leu 405 410 415 Ile Phe Ile Ala Phe Ile Leu Leu Arg Ile Lys Gly Lys Tyr Val Phe 420 425 430 Met Leu Pro Ile Gln Val Gln Ala Pro Pro Pro Glu Asp Ser Asp Ser 435 440 445 Gly Ser Asp Ser Asp Tyr Glu His Tyr Asp Phe Ser Ala Gln Pro Pro 450 455 460 Val Ala Leu Thr Thr Phe Tyr Asn Ser Gln Arg His Arg Val Thr Asp 465 470 475 480 Glu Glu Val Gln Gln Ser Arg Phe Gln Met Pro Pro Leu Glu Glu Gly 485 490 495 Leu Glu Glu Leu His Ala Ser His Ile Pro Thr Ala Asn Pro Gly His 500 505 510 Cys Ile Thr Asp Pro Pro Ser Leu Gly Pro Gln Tyr His Pro Arg Ser 515 520 525 Asn Ser Glu Ser Ser Thr Ser Ser Gly Glu Asp Tyr Cys Asn Ser Pro 530 535 540 Lys Ser Lys Leu Pro Pro Trp Asn Pro Gln Val Phe Ser Ser Glu Arg 545 550 555 560 Ser Ser Phe Leu Glu Gln Pro Pro Asn Leu Glu Leu Ala Gly Thr Gln 565 570 575 Pro Ala Phe Ser Gly Ser Pro Ser Pro Gln Pro Asp Ser Thr Asp Asn 580 585 590 Asp Asp Tyr Asp Asp Ile Ser Ala Ala 595 600 <210> 3 <211> 601 <212> PRT <213> Homo sapiens <400> 3 Met Trp Leu Phe Phe Gly Ile Thr Gly Leu Leu Thr Ala Ala Leu Ser 1 5 10 15 Gly His Pro Ser Pro Ala Pro Pro Asp Gln Leu Asn Thr Ser Ser Ala 20 25 30 Glu Ser Glu Leu Trp Glu Pro Gly Glu Arg Leu Pro Val Arg Leu Thr 35 40 45 Asn Gly Ser Ser Ser Cys Ser Gly Thr Val Glu Val Arg Leu Glu Ala 50 55 60 Ser Trp Glu Pro Ala Cys Gly Ala Leu Trp Asp Ser Arg Ala Ala Glu 65 70 75 80 Ala Val Cys Arg Ala Leu Gly Cys Gly Gly Ala Glu Ala Ala Ser Gln 85 90 95 Leu Ala Pro Pro Thr Pro Glu Leu Pro Pro Pro Pro Ala Ala Gly Asn 100 105 110 Thr Ser Val Ala Ala Asn Ala Thr Leu Ala Gly Ala Pro Ala Leu Leu 115 120 125 Cys Ser Gly Ala Glu Trp Arg Leu Cys Glu Val Val Glu His Ala Cys 130 135 140 Arg Ser Asp Gly Arg Arg Ala Arg Val Thr Cys Ala Glu Asn Arg Ala 145 150 155 160 Leu Arg Leu Val Asp Gly Gly Gly Ala Cys Ala Gly Arg Val Glu Met 165 170 175 Leu Glu His Gly Glu Trp Gly Ser Val Cys Asp Asp Thr Trp Asp Leu 180 185 190 Glu Asp Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Trp Ala Val 195 200 205 Gln Ala Leu Pro Gly Leu His Phe Thr Pro Gly Arg Gly Pro Ile His 210 215 220 Arg Asp Gln Val Asn Cys Ser Gly Ala Glu Ala Tyr Leu Trp Asp Cys 225 230 235 240 Pro Gly Leu Pro Gly Gln His Tyr Cys Gly His Lys Glu Asp Ala Gly 245 250 255 Ala Val Cys Ser Glu His Gln Ser Trp Arg Leu Thr Gly Gly Ala Asp 260 265 270 Arg Cys Glu Gly Gln Val Glu Val His Phe Arg Gly Val Trp Asn Thr 275 280 285 Val Cys Asp Ser Glu Trp Tyr Pro Ser Glu Ala Lys Val Leu Cys Gln 290 295 300 Ser Leu Gly Cys Gly Thr Ala Val Glu Arg Pro Lys Gly Leu Pro His 305 310 315 320 Ser Leu Ser Gly Arg Met Tyr Tyr Ser Cys Asn Gly Glu Glu Leu Thr 325 330 335 Leu Ser Asn Cys Ser Trp Arg Phe Asn Asn Ser Asn Leu Cys Ser Gln 340 345 350 Ser Leu Ala Ala Arg Val Leu Cys Ser Ala Ser Arg Ser Leu His Asn 355 360 365 Leu Ser Thr Pro Glu Val Pro Ala Ser Val Gln Thr Val Thr Ile Glu 370 375 380 Ser Ser Val Thr Val Lys Ile Glu Asn Lys Glu Ser Arg Glu Leu Met 385 390 395 400 Leu Leu Ile Pro Ser Ile Val Leu Gly Ile Leu Leu Leu Gly Ser Leu 405 410 415 Ile Phe Ile Ala Phe Ile Leu Leu Arg Ile Lys Gly Lys Tyr Val Phe 420 425 430 Met Leu Pro Ile Gln Val Gln Ala Pro Pro Pro Glu Asp Ser Asp Ser 435 440 445 Gly Ser Asp Ser Asp Tyr Glu His Tyr Asp Phe Ser Ala Gln Pro Pro 450 455 460 Val Ala Leu Thr Thr Phe Tyr Asn Ser Gln Arg His Arg Val Thr Asp 465 470 475 480 Glu Glu Val Gln Gln Ser Arg Phe Gln Met Pro Pro Leu Glu Glu Gly 485 490 495 Leu Glu Glu Leu His Ala Ser His Ile Pro Thr Ala Asn Pro Gly His 500 505 510 Cys Ile Thr Asp Pro Pro Ser Leu Gly Pro Gln Tyr His Pro Arg Ser 515 520 525 Asn Ser Glu Ser Ser Thr Ser Ser Gly Glu Asp Tyr Cys Asn Ser Pro 530 535 540 Lys Ser Lys Leu Pro Pro Trp Asn Pro Gln Val Phe Ser Ser Glu Arg 545 550 555 560 Ser Ser Phe Leu Glu Gln Pro Pro Asn Leu Glu Leu Ala Gly Thr Gln 565 570 575 Pro Ala Phe Ser Gly Ser Pro Ser Pro Gln Pro Asp Ser Thr Asp Asn 580 585 590 Asp Asp Tyr Asp Asp Ile Ser Ala Ala 595 600 <210> 4 <211> 123 <212> PRT <213> Homo sapiens <400> 4 Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val 1 5 10 15 Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr 20 25 30 Asp Asn Ala Val Asn Leu Ser Trp Lys His Leu Cys Pro Ser Pro Leu 35 40 45 Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly 50 55 60 Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe 65 70 75 80 Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn 85 90 95 Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr 100 105 110 Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 115 120 <210> 5 <211> 101 <212> PRT <213> Homo sapiens <400> 5 Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val 1 5 10 15 Thr Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys 20 25 30 Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser 35 40 45 Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg 50 55 60 Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro 65 70 75 80 Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe 85 90 95 Ala Ala Tyr Arg Ser 100 <210> 6 <211> 220 <212> PRT <213> Homo sapiens <400> 6 Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val 1 5 10 15 Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr 20 25 30 Asp Asn Ala Val Asn Leu Ser Cys Lys Tyr Ser Tyr Asn Leu Phe Ser 35 40 45 Arg Glu Phe Arg Ala Ser Leu His Lys Gly Leu Asp Ser Ala Val Glu 50 55 60 Val Cys Val Val Tyr Gly Asn Tyr Ser Gln Gln Leu Gln Val Tyr Ser 65 70 75 80 Lys Thr Gly Phe Asn Cys Asp Gly Lys Leu Gly Asn Glu Ser Val Thr 85 90 95 Phe Tyr Leu Gln Asn Leu Tyr Val Asn Gln Thr Asp Ile Tyr Phe Cys 100 105 110 Lys Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser 115 120 125 Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro 130 135 140 Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly 145 150 155 160 Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile 165 170 175 Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met 180 185 190 Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro 195 200 205 Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 210 215 220 <210> 7 <211> 41 <212> PRT <213> Homo sapiens <400> 7 Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr 1 5 10 15 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 20 25 30 Pro Arg Asp Phe Ala Ala Tyr Arg Ser 35 40 <210> 8 <211> 41 <212> PRT <213> Homo sapiens <400> 8 Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 1 5 10 15 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 20 25 30 Pro Arg Asp Phe Ala Ala Tyr Arg Ser 35 40 <210> 9 <211> 458 <212> PRT <213> Homo sapiens <400> 9 Met Asn Arg Gly Val Pro Phe Arg His Leu Leu Leu Val Leu Gln Leu 1 5 10 15 Ala Leu Leu Pro Ala Ala Thr Gln Gly Lys Lys Val Val Leu Gly Lys 20 25 30 Lys Gly Asp Thr Val Glu Leu Thr Cys Thr Ala Ser Gln Lys Lys Ser 35 40 45 Ile Gln Phe His Trp Lys Asn Ser Asn Gln Ile Lys Ile Leu Gly Asn 50 55 60 Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala 65 70 75 80 Asp Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Phe Pro Leu Ile Ile 85 90 95 Lys Asn Leu Lys Ile Glu Asp Ser Asp Thr Tyr Ile Cys Glu Val Glu 100 105 110 Asp Gln Lys Glu Glu Val Gln Leu Leu Val Phe Gly Leu Thr Ala Asn 115 120 125 Ser Asp Thr His Leu Leu Gln Gly Gln Ser Leu Thr Leu Thr Leu Glu 130 135 140 Ser Pro Pro Gly Ser Ser Pro Ser Val Gln Cys Arg Ser Pro Arg Gly 145 150 155 160 Lys Asn Ile Gln Gly Gly Lys Thr Leu Ser Val Ser Gln Leu Glu Leu 165 170 175 Gln Asp Ser Gly Thr Trp Thr Cys Thr Val Leu Gln Asn Gln Lys Lys 180 185 190 Val Glu Phe Lys Ile Asp Ile Val Val Leu Ala Phe Gln Lys Ala Ser 195 200 205 Ser Ile Val Tyr Lys Lys Glu Gly Glu Gln Val Glu Phe Ser Phe Pro 210 215 220 Leu Ala Phe Thr Val Glu Lys Leu Thr Gly Ser Gly Glu Leu Trp Trp 225 230 235 240 Gln Ala Glu Arg Ala Ser Ser Ser Lys Ser Trp Ile Thr Phe Asp Leu 245 250 255 Lys Asn Lys Glu Val Ser Val Lys Arg Val Thr Gln Asp Pro Lys Leu 260 265 270 Gln Met Gly Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gln Ala Leu 275 280 285 Pro Gln Tyr Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys 290 295 300 Thr Gly Lys Leu His Gln Glu Val Asn Leu Val Val Met Arg Ala Thr 305 310 315 320 Gln Leu Gln Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro 325 330 335 Lys Leu Met Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser 340 345 350 Lys Arg Glu Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp 355 360 365 Gln Cys Leu Leu Ser Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile 370 375 380 Lys Val Leu Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile 385 390 395 400 Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile 405 410 415 Phe Phe Cys Val Arg Cys Arg His Arg Arg Arg Gln Ala Glu Arg Met 420 425 430 Ser Gln Ile Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gln Cys Pro 435 440 445 His Arg Phe Gln Lys Thr Cys Ser Pro Ile 450 455 <210> 10 <211> 279 <212> PRT <213> Homo sapiens <400> 10 Met Pro Thr Pro Leu Val His Pro His Leu Pro Ile Ser Ser Pro Arg 1 5 10 15 Val Ser Pro Phe Pro Pro Pro Ala Phe Gln Lys Ala Ser Ser Ile Val 20 25 30 Tyr Lys Lys Glu Gly Glu Gln Val Glu Phe Ser Phe Pro Leu Ala Phe 35 40 45 Thr Val Glu Lys Leu Thr Gly Ser Gly Glu Leu Trp Trp Gln Ala Glu 50 55 60 Arg Ala Ser Ser Ser Lys Ser Trp Ile Thr Phe Asp Leu Lys Asn Lys 65 70 75 80 Glu Val Ser Val Lys Arg Val Thr Gln Asp Pro Lys Leu Gln Met Gly 85 90 95 Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gln Ala Leu Pro Gln Tyr 100 105 110 Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys Thr Gly Lys 115 120 125 Leu His Gln Glu Val Asn Leu Val Val Met Arg Ala Thr Gln Leu Gln 130 135 140 Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro Lys Leu Met 145 150 155 160 Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser Lys Arg Glu 165 170 175 Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp Gln Cys Leu 180 185 190 Leu Ser Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile Lys Val Leu 195 200 205 Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile Val Leu Gly 210 215 220 Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Cys 225 230 235 240 Val Arg Cys Arg His Arg Arg Arg Gln Ala Glu Arg Met Ser Gln Ile 245 250 255 Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gln Cys Pro His Arg Phe 260 265 270 Gln Lys Thr Cys Ser Pro Ile 275 <210> 11 <211> 185 <212> PRT <213> Homo sapiens <400> 11 Met Gly Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gln Ala Leu Pro 1 5 10 15 Gln Tyr Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys Thr 20 25 30 Gly Lys Leu His Gln Glu Val Asn Leu Val Val Met Arg Ala Thr Gln 35 40 45 Leu Gln Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro Lys 50 55 60 Leu Met Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser Lys 65 70 75 80 Arg Glu Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp Gln 85 90 95 Cys Leu Leu Ser Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile Lys 100 105 110 Val Leu Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile Val 115 120 125 Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe 130 135 140 Phe Cys Val Arg Cys Arg His Arg Arg Arg Gln Ala Glu Arg Met Ser 145 150 155 160 Gln Ile Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gln Cys Pro His 165 170 175 Arg Phe Gln Lys Thr Cys Ser Pro Ile 180 185 <210> 12 <211> 185 <212> PRT <213> Homo sapiens <400> 12 Met Gly Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gln Ala Leu Pro 1 5 10 15 Gln Tyr Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys Thr 20 25 30 Gly Lys Leu His Gln Glu Val Asn Leu Val Val Met Arg Ala Thr Gln 35 40 45 Leu Gln Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro Lys 50 55 60 Leu Met Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser Lys 65 70 75 80 Arg Glu Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp Gln 85 90 95 Cys Leu Leu Ser Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile Lys 100 105 110 Val Leu Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile Val 115 120 125 Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe 130 135 140 Phe Cys Val Arg Cys Arg His Arg Arg Arg Gln Ala Glu Arg Met Ser 145 150 155 160 Gln Ile Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gln Cys Pro His 165 170 175 Arg Phe Gln Lys Thr Cys Ser Pro Ile 180 185 <210> 13 <211> 185 <212> PRT <213> Homo sapiens <400> 13 Met Gly Lys Lys Leu Pro Leu His Leu Thr Leu Pro Gln Ala Leu Pro 1 5 10 15 Gln Tyr Ala Gly Ser Gly Asn Leu Thr Leu Ala Leu Glu Ala Lys Thr 20 25 30 Gly Lys Leu His Gln Glu Val Asn Leu Val Val Met Arg Ala Thr Gln 35 40 45 Leu Gln Lys Asn Leu Thr Cys Glu Val Trp Gly Pro Thr Ser Pro Lys 50 55 60 Leu Met Leu Ser Leu Lys Leu Glu Asn Lys Glu Ala Lys Val Ser Lys 65 70 75 80 Arg Glu Lys Ala Val Trp Val Leu Asn Pro Glu Ala Gly Met Trp Gln 85 90 95 Cys Leu Leu Ser Asp Ser Gly Gln Val Leu Leu Glu Ser Asn Ile Lys 100 105 110 Val Leu Pro Thr Trp Ser Thr Pro Val Gln Pro Met Ala Leu Ile Val 115 120 125 Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe 130 135 140 Phe Cys Val Arg Cys Arg His Arg Arg Arg Gln Ala Glu Arg Met Ser 145 150 155 160 Gln Ile Lys Arg Leu Leu Ser Glu Lys Lys Thr Cys Gln Cys Pro His 165 170 175 Arg Phe Gln Lys Thr Cys Ser Pro Ile 180 185 <210> 14 <211> 42 <212> PRT <213> Homo sapiens <400> 14 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 1 5 10 15 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 20 25 30 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 35 40 <210> 15 <211> 255 <212> PRT <213> Homo sapiens <400> 15 Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu 1 5 10 15 Asn Phe Glu Arg Thr Arg Ser Leu Gln Asp Pro Cys Ser Asn Cys Pro 20 25 30 Ala Gly Thr Phe Cys Asp Asn Asn Arg Asn Gln Ile Cys Ser Pro Cys 35 40 45 Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile 50 55 60 Cys Arg Gln Cys Lys Gly Val Phe Arg Thr Arg Lys Glu Cys Ser Ser 65 70 75 80 Thr Ser Asn Ala Glu Cys Asp Cys Thr Pro Gly Phe His Cys Leu Gly 85 90 95 Ala Gly Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu 100 105 110 Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln 115 120 125 Lys Arg Gly Ile Cys Arg Pro Trp Thr Asn Cys Ser Leu Asp Gly Lys 130 135 140 Ser Val Leu Val Asn Gly Thr Lys Glu Arg Asp Val Val Cys Gly Pro 145 150 155 160 Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Val Thr Pro Pro Ala 165 170 175 Pro Ala Arg Glu Pro Gly His Ser Pro Gln Ile Ile Ser Phe Phe Leu 180 185 190 Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu Leu Phe Phe Leu Thr Leu 195 200 205 Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe 210 215 220 Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly 225 230 235 240 Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 245 250 255 <210> 16 <211> 199 <212> PRT <213> Homo sapiens <400> 16 Met Lys Ser Gly Leu Trp Tyr Phe Phe Leu Phe Cys Leu Arg Ile Lys 1 5 10 15 Val Leu Thr Gly Glu Ile Asn Gly Ser Ala Asn Tyr Glu Met Phe Ile 20 25 30 Phe His Asn Gly Gly Val Gln Ile Leu Cys Lys Tyr Pro Asp Ile Val 35 40 45 Gln Gln Phe Lys Met Gln Leu Leu Lys Gly Gly Gln Ile Leu Cys Asp 50 55 60 Leu Thr Lys Thr Lys Gly Ser Gly Asn Thr Val Ser Ile Lys Ser Leu 65 70 75 80 Lys Phe Cys His Ser Gln Leu Ser Asn Asn Ser Val Ser Phe Phe Leu 85 90 95 Tyr Asn Leu Asp His Ser His Ala Asn Tyr Tyr Phe Cys Asn Leu Ser 100 105 110 Ile Phe Asp Pro Pro Pro Phe Lys Val Thr Leu Thr Gly Gly Tyr Leu 115 120 125 His Ile Tyr Glu Ser Gln Leu Cys Cys Gln Leu Lys Phe Trp Leu Pro 130 135 140 Ile Gly Cys Ala Ala Phe Val Val Val Cys Ile Leu Gly Cys Ile Leu 145 150 155 160 Ile Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro 165 170 175 Asn Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser 180 185 190 Arg Leu Thr Asp Val Thr Leu 195 <210> 17 <211> 41 <212> PRT <213> Homo sapiens <400> 17 Ala Val Ser Leu Ser Lys Met Leu Lys Lys Arg Ser Pro Leu Thr Thr 1 5 10 15 Gly Val Tyr Val Lys Met Pro Pro Thr Glu Pro Glu Cys Glu Lys Gln 20 25 30 Phe Gln Pro Tyr Phe Ile Pro Ile Asn 35 40 <210> 18 <211> 327 <212> DNA <213> Homo sapiens <400> 18 gacatccaaa tgacacaaag tcctagctct ctctcagcaa gtgttggcga ccgtgtgacc 60 atcacatgta aagcttcaag ggatattcgc agctacctga cttggtacca acaaaagccc 120 ggaaaagcgc ctaaaacgct tatttactat gccaccagcc tcgcagatgg tgtcccctcc 180 agattttctg gatcgggatc agggcaagat tatagtctta cgatatcgag tcttgagtcg 240 gacgatactg ccacatacta ctgcttacag cacggggaaa gcccattcac attcggaagt 300 ggtacgaaac tcgagatcaa acgggca 327 <210> 19 <211> 357 <212> DNA <213> Homo sapiens <400> 19 gaagtccaat tggtcgagag cggaggtggg cttgttaaac caggaggcag tttaaaatta 60 tcatgtgctg cctcgggttt caagttctcg cggtatgcta tgtcctgggt acgccaagca 120 cctggaaagc gtttagaatg ggtggccaca attagtagtg gtggttcata tatatattat 180 cccgactccg tcaaaggaag gttcacgatt tcaagggaca atgtgaagaa caccctctac 240 ttacagatga gtagtctgcg ttctgaggat accgctatgt actactgtgc tcggagagat 300 tacgatctgg attatttcga cagctggggt cagggcacac tcgttacagt atcctcg 357 <210> 20 <211> 60 <212> DNA <213> Homo sapiens <400> 20 gtccaacttg ttgaatcagg tggggggctg gtcaaacccg ggggctctct gaaactaagt 60 <210> 21 <211> 45 <212> DNA <213> Homo sapiens <400> 21 ttctctcggt acgctatgtc gtgggtcaga caagcgcccg gcaaa 45 <210> 22 <211> 57 <212> DNA <213> Homo sapiens <400> 22 cgtgattatg atctagacta ctttgactcc tggggtcaag gtacgctcgt gacggtt 57 <210> 23 <211> 22 <212> PRT <213> Homo sapiens <400> 23 Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile 1 5 10 15 Gly Leu Gly Ile Phe Phe 20 <210> 24 <211> 66 <212> DNA <213> Homo sapiens <400> 24 atggccctga ttgtgctggg gggcgtcgcc ggcctcctgc ttttcattgg gctaggcatc 60 ttcttc 66 <210> 25 <211> 21 <212> PRT <213> Homo sapiens <400> 25 Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu 1 5 10 15 Ser Leu Val Ile Thr 20 <210> 26 <211> 54 <212> DNA <213> Homo sapiens <400> 26 gggtcaacgt cgggcggggg ttccggtgga ggaagtggag gtggtggaag ttct 54 <210> 27 <211> 60 <212> DNA <213> Homo sapiens <400> 27 ggcggcggcg gaagtggcgg cggcggctca ggcggggggg gttctggggg cggcggttca 60 <210> 28 <211> 20 <212> PRT <213> Homo sapiens <400> 28 Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser 1 5 10 15 Leu Lys Leu Ser 20 <210> 29 <211> 15 <212> PRT <213> Homo sapiens <400> 29 Phe Ser Arg Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys 1 5 10 15 <210> 30 <211> 19 <212> PRT <213> Homo sapiens <400> 30 Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly Thr Leu 1 5 10 15 Val Thr Val <210> 31 <211> 38 <212> PRT <213> Homo sapiens <400> 31 Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro Asn 1 5 10 15 Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser Arg 20 25 30 Leu Thr Asp Val Thr Leu 35 <210> 32 <211> 42 <212> PRT <213> Homo sapiens <400> 32 Ala Leu Tyr Leu Leu Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His 1 5 10 15 Lys Pro Pro Gly Gly Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln 20 25 30 Ala Asp Ala His Ser Thr Leu Ala Lys Ile 35 40 <210> 33 <211> 97 <212> PRT <213> Homo sapiens <400> 33 Cys Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln 1 5 10 15 Pro Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr 20 25 30 Gly Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val 35 40 45 Pro Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser 50 55 60 Gly Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro 65 70 75 80 Arg Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro 85 90 95 Leu <210> 34 <211> 109 <212> PRT <213> Homo sapiens <400> 34 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala 100 105 <210> 35 <211> 119 <212> PRT <213> Homo sapiens <400> 35 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 36 <211> 18 <212> PRT <213> Homo sapiens <400> 36 Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly 1 5 10 15 Ser Ser <210> 37 <211> 20 <212> PRT <213> Homo sapiens <400> 37 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> 38 <211> 246 <212> PRT <213> Homo sapiens <400> 38 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Lys Ala Ser Arg Asp Ile Arg Ser Tyr Leu Thr Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Thr Leu Ile Tyr Tyr Ala Thr Ser Leu Ala 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr 195 200 205 Ser Leu Thr Ile Ser Ser Leu Glu Ser Asp Asp Thr Ala Thr Tyr Tyr 210 215 220 Cys Leu Gln His Gly Glu Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys 225 230 235 240 Leu Glu Ile Lys Arg Ala 245 <210> 39 <211> 248 <212> PRT <213> Homo sapiens <400> 39 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr Leu Thr Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile Tyr Tyr Ala Thr Ser 180 185 190 Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln 195 200 205 Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser Asp Asp Thr Ala Thr 210 215 220 Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe Thr Phe Gly Ser Gly 225 230 235 240 Thr Lys Leu Glu Ile Lys Arg Ala 245 <210> 40 <211> 246 <212> PRT <213> Homo sapiens <400> 40 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Gly Ser Thr 100 105 110 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Glu 115 120 125 Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser 130 135 140 Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr Ala 145 150 155 160 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala 165 170 175 Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala 210 215 220 Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser 245 <210> 41 <211> 248 <212> PRT <213> Homo sapiens <400> 41 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Gly Gly Gly 100 105 110 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly 130 135 140 Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg 145 150 155 160 Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp 165 170 175 Val Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser 180 185 190 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu 195 200 205 Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr 210 215 220 Cys Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln 225 230 235 240 Gly Thr Leu Val Thr Val Ser Ser 245 <210> 42 <211> 738 <212> DNA <213> Homo sapiens <400> 42 gaagtccaat tggtcgagag cggaggtggg cttgttaaac caggaggcag tttaaaatta 60 tcatgtgctg cctcgggttt caagttctcg cggtatgcta tgtcctgggt acgccaagca 120 cctggaaagc gtttagaatg ggtggccaca attagtagtg gtggttcata tatatattat 180 cccgactccg tcaaaggaag gttcacgatt tcaagggaca atgtgaagaa caccctctac 240 ttacagatga gtagtctgcg ttctgaggat accgctatgt actactgtgc tcggagagat 300 tacgatctgg attatttcga cagctggggt cagggcacac tcgttacagt atcctcgggg 360 tcaacgtcgg gcgggggttc cggtggagga agtggaggtg gtggaagttc tgacatccaa 420 atgacacaaa gtcctagctc tctctcagca agtgttggcg accgtgtgac catcacatgt 480 aaagcttcaa gggatattcg cagctacctg acttggtacc aacaaaagcc cggaaaagcg 540 cctaaaacgc ttatttacta tgccaccagc ctcgcagatg gtgtcccctc cagattttct 600 ggatcgggat cagggcaaga ttatagtctt acgatatcga gtcttgagtc ggacgatact 660 gccacatact actgcttaca gcacggggaa agcccattca cattcggaag tggtacgaaa 720 ctcgagatca aacgggca 738 <210> 43 <211> 744 <212> DNA <213> Homo sapiens <400> 43 gaagtccaat tggtcgagag cggaggtggg cttgttaaac caggaggcag tttaaaatta 60 tcatgtgctg cctcgggttt caagttctcg cggtatgcta tgtcctgggt acgccaagca 120 cctggaaagc gtttagaatg ggtggccaca attagtagtg gtggttcata tatatattat 180 cccgactccg tcaaaggaag gttcacgatt tcaagggaca atgtgaagaa caccctctac 240 ttacagatga gtagtctgcg ttctgaggat accgctatgt actactgtgc tcggagagat 300 tacgatctgg attatttcga cagctggggt cagggcacac tcgttacagt atcctcgggc 360 ggcggcggaa gtggcggcgg cggctcaggc ggggggggtt ctgggggcgg cggttcagac 420 atccaaatga cacaaagtcc tagctctctc tcagcaagtg ttggcgaccg tgtgaccatc 480 acatgtaaag cttcaaggga tattcgcagc tacctgactt ggtaccaaca aaagcccgga 540 aaagcgccta aaacgcttat ttactatgcc accagcctcg cagatggtgt cccctccaga 600 ttttctggat cgggatcagg gcaagattat agtcttacga tatcgagtct tgagtcggac 660 gatactgcca catactactg cttacagcac ggggaaagcc cattcacatt cggaagtggt 720 acgaaactcg agatcaaacg ggca 744 <210> 44 <211> 738 <212> DNA <213> Homo sapiens <400> 44 gacatccaaa tgacacaaag tcctagctct ctctcagcaa gtgttggcga ccgtgtgacc 60 atcacatgta aagcttcaag ggatattcgc agctacctga cttggtacca acaaaagccc 120 ggaaaagcgc ctaaaacgct tatttactat gccaccagcc tcgcagatgg tgtcccctcc 180 agattttctg gatcgggatc agggcaagat tatagtctta cgatatcgag tcttgagtcg 240 gacgatactg ccacatacta ctgcttacag cacggggaaa gcccattcac attcggaagt 300 ggtacgaaac tcgagatcaa acgggcaggg tcaacgtcgg gcgggggttc cggtggagga 360 agtggaggtg gtggaagttc tgaagtccaa ttggtcgaga gcggaggtgg gcttgttaaa 420 ccaggaggca gtttaaaatt atcatgtgct gcctcgggtt tcaagttctc gcggtatgct 480 atgtcctggg tacgccaagc acctggaaag cgtttagaat gggtggccac aattagtagt 540 ggtggttcat atatatatta tcccgactcc gtcaaaggaa ggttcacgat ttcaagggac 600 aatgtgaaga acaccctcta cttacagatg agtagtctgc gttctgagga taccgctatg 660 tactactgtg ctcggagaga ttacgatctg gattatttcg acagctgggg tcagggcaca 720 ctcgttacag tatcctcg 738 <210> 45 <211> 744 <212> DNA <213> Homo sapiens <400> 45 gataccaaa tgacacaag tcctagctct ctctcagcaa gtgttggcga ccgtgtgacc 60 atcacatgta aagcttcaag ggatatcgc agctacctga cttggtacca acaaagcccc 120 ggaaaagcgc ctaaaacgct tattactat gccaccagcc tcgcagatgg tgtcccctcc 180 agattttctg gatcgggatc agggcagat tatagtctta cgatatcgag tcttgagtcg 240 gacgatactg ccacatacta ctgcttacag cacggggaaa gcccattcac attcggaagt 300 ggtacgaac tcgagatcaa acggggcaggc ggcggcggaa gtggcggcgg cggctcaggc 360 ggggggtt ctgggggcgg cggttcagaa gtccaattgg tcgagagcgg aggtggggct 420 gttaaaccag gaggcagttt aaaattatca tgtgctgcct cgggttttcaa gttctcgcgg 480 tatgctatgt cctgggtacg ccaagcacct ggaagcgtt tagaatggt ggccacaatt 540 agtagtggtg gttcatatat atattatccc gactccgtca aaggaaggtt cacgatttca 600 agggacaatg tgagacac ccttactta cagatgagta gtctgcgttc tgaggatacc 660 gctatgtact actgtgctcg gagagattac gatctggatt atttcgacag ctggggtcag 720 ggcacactcg ttacagtatc ctcg 744 <210> 46 <211> 235 <212> PRT <213> Homo sapiens <400> 46 Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Ser Gln Phe Arg Val Ser Pro Leu Asp Arg Thr 20 25 30 Trp Asn Leu Gly Glu Thr Val Glu Leu Lys Cys Gln Val Leu Leu Ser 35 40 45 Asn Pro Thr Ser Gly Cys Ser Trp Leu Phe Gln Pro Arg Gly Ala Ala 50 55 60 Ala Ser Pro Thr Phe Leu Leu Tyr Leu Ser Gln Asn Lys Pro Lys Ala 65 70 75 80 Ala Glu Gly Leu Asp Thr Gln Arg Phe Ser Gly Lys Arg Leu Gly Asp 85 90 95 Thr Phe Val Leu Thr Leu Ser Asp Phe Arg Arg Glu Asn Glu Gly Tyr 100 105 110 Tyr Phe Cys Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe 115 120 125 Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg 130 135 140 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 145 150 155 160 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 165 170 175 Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr 180 185 190 Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His 195 200 205 Arg Asn Arg Arg Arg Val Cys Lys Cys Pro Arg Pro Val Val Lys Ser 210 215 220 Gly Asp Lys Pro Ser Leu Ser Ala Arg Tyr Val 225 230 235 <210> 47 <211> 198 <212> PRT <213> Homo sapiens <400> 47 Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Ser Gln Phe Arg Val Ser Pro Leu Asp Arg Thr 20 25 30 Trp Asn Leu Gly Glu Thr Val Glu Leu Lys Cys Gln Val Leu Leu Ser 35 40 45 Asn Pro Thr Ser Gly Cys Ser Trp Leu Phe Gln Pro Arg Gly Ala Ala 50 55 60 Ala Ser Pro Thr Phe Leu Leu Tyr Leu Ser Gln Asn Lys Pro Lys Ala 65 70 75 80 Ala Glu Gly Leu Asp Thr Gln Arg Phe Ser Gly Lys Arg Leu Gly Asp 85 90 95 Thr Phe Val Leu Thr Leu Ser Asp Phe Arg Arg Glu Asn Glu Gly Tyr 100 105 110 Tyr Phe Cys Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe 115 120 125 Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg 130 135 140 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 145 150 155 160 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Gly Asn Arg Arg Arg 165 170 175 Val Cys Lys Cys Pro Arg Pro Val Val Lys Ser Gly Asp Lys Pro Ser 180 185 190 Leu Ser Ala Arg Tyr Val 195 <210> 48 <211> 235 <212> PRT <213> Homo sapiens <400> 48 Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 1 5 10 15 His Ala Ala Arg Pro Ser Gln Phe Arg Val Ser Pro Leu Asp Arg Thr 20 25 30 Trp Asn Leu Gly Glu Thr Val Glu Leu Lys Cys Gln Val Leu Leu Ser 35 40 45 Asn Pro Thr Ser Gly Cys Ser Trp Leu Phe Gln Pro Arg Gly Ala Ala 50 55 60 Ala Ser Pro Thr Phe Leu Leu Tyr Leu Ser Gln Asn Lys Pro Lys Ala 65 70 75 80 Ala Glu Gly Leu Asp Thr Gln Arg Phe Ser Gly Lys Arg Leu Gly Asp 85 90 95 Thr Phe Val Leu Thr Leu Ser Asp Phe Arg Arg Glu Asn Glu Gly Tyr 100 105 110 Tyr Phe Cys Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe 115 120 125 Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg 130 135 140 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 145 150 155 160 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 165 170 175 Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr 180 185 190 Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His 195 200 205 Arg Asn Arg Arg Arg Val Cys Lys Cys Pro Arg Pro Val Val Lys Ser 210 215 220 Gly Asp Lys Pro Ser Leu Ser Ala Arg Tyr Val 225 230 235 <210> 49 <211> 246 <212> PRT <213> Homo sapiens <400> 49 Met Arg Pro Arg Leu Trp Leu Leu Leu Ala Ala Gln Leu Thr Val Leu 1 5 10 15 His Gly Asn Ser Val Leu Gln Gln Thr Pro Ala Tyr Ile Lys Val Gln 20 25 30 Thr Asn Lys Met Val Met Leu Ser Cys Glu Ala Lys Ile Ser Leu Ser 35 40 45 Asn Met Arg Ile Tyr Trp Leu Arg Gln Arg Gln Ala Pro Ser Ser Asp 50 55 60 Ser His His Glu Phe Leu Ala Leu Trp Asp Ser Ala Lys Gly Thr Ile 65 70 75 80 His Gly Glu Glu Val Glu Gln Glu Lys Ile Ala Val Phe Arg Asp Ala 85 90 95 Ser Arg Phe Ile Leu Asn Leu Thr Ser Val Lys Pro Glu Asp Ser Gly 100 105 110 Ile Tyr Phe Cys Met Ile Val Gly Ser Pro Glu Leu Thr Phe Gly Lys 115 120 125 Gly Thr Gln Leu Ser Val Val Asp Phe Leu Pro Thr Thr Ala Gln Pro 130 135 140 Thr Lys Lys Ser Thr Leu Lys Lys Arg Val Cys Arg Leu Pro Arg Pro 145 150 155 160 Glu Thr Gln Lys Gly Pro Leu Cys Ser Pro Ile Thr Leu Gly Leu Leu 165 170 175 Val Ala Gly Val Leu Val Leu Leu Val Ser Leu Gly Val Ala Ile His 180 185 190 Leu Cys Cys Arg Arg Arg Arg Ala Arg Leu Arg Phe Met Lys Gln Lys 195 200 205 Phe Asn Ile Val Cys Leu Lys Ile Ser Gly Phe Thr Thr Cys Cys Cys 210 215 220 Phe Gln Ile Leu Gln Met Ser Arg Glu Tyr Gly Phe Gly Val Leu Leu 225 230 235 240 Gln Lys Asp Ile Gly Gln 245 <210> 50 <211> 198 <212> PRT <213> Homo sapiens <400> 50 Met Arg Pro Arg Leu Trp Leu Leu Leu Ala Ala Gln Leu Thr Val Leu 1 5 10 15 His Gly Asn Ser Val Leu Gln Gln Thr Pro Ala Tyr Ile Lys Val Gln 20 25 30 Thr Asn Lys Met Val Met Leu Ser Cys Glu Ala Lys Ile Ser Leu Ser 35 40 45 Asn Met Arg Ile Tyr Trp Leu Arg Gln Arg Gln Ala Pro Ser Ser Asp 50 55 60 Ser His His Glu Phe Leu Ala Leu Trp Asp Ser Ala Lys Gly Thr Ile 65 70 75 80 His Gly Glu Glu Val Glu Gln Glu Lys Ile Ala Val Phe Arg Asp Ala 85 90 95 Ser Arg Phe Ile Leu Asn Leu Thr Ser Val Lys Pro Glu Asp Ser Gly 100 105 110 Ile Tyr Phe Cys Met Ile Val Gly Ser Pro Glu Leu Thr Phe Gly Lys 115 120 125 Gly Thr Gln Leu Ser Val Val Asp Phe Leu Pro Thr Thr Ala Gln Pro 130 135 140 Thr Lys Lys Ser Thr Leu Lys Lys Arg Val Cys Arg Leu Pro Arg Pro 145 150 155 160 Glu Thr Gln Lys Gly Leu Lys Gly Lys Val Tyr Gln Glu Pro Leu Ser 165 170 175 Pro Asn Ala Cys Met Asp Thr Thr Ala Ile Leu Gln Pro His Arg Ser 180 185 190 Cys Leu Thr His Gly Ser 195 <210> 51 <211> 243 <212> PRT <213> Homo sapiens <400> 51 Met Arg Pro Arg Leu Trp Leu Leu Leu Ala Ala Gln Leu Thr Val Leu 1 5 10 15 His Gly Asn Ser Val Leu Gln Gln Thr Pro Ala Tyr Ile Lys Val Gln 20 25 30 Thr Asn Lys Met Val Met Leu Ser Cys Glu Ala Lys Ile Ser Leu Ser 35 40 45 Asn Met Arg Ile Tyr Trp Leu Arg Gln Arg Gln Ala Pro Ser Ser Asp 50 55 60 Ser His His Glu Phe Leu Ala Leu Trp Asp Ser Ala Lys Gly Thr Ile 65 70 75 80 His Gly Glu Glu Val Glu Gln Glu Lys Ile Ala Val Phe Arg Asp Ala 85 90 95 Ser Arg Phe Ile Leu Asn Leu Thr Ser Val Lys Pro Glu Asp Ser Gly 100 105 110 Ile Tyr Phe Cys Met Ile Val Gly Ser Pro Glu Leu Thr Phe Gly Lys 115 120 125 Gly Thr Gln Leu Ser Val Val Asp Phe Leu Pro Thr Thr Ala Gln Pro 130 135 140 Thr Lys Lys Ser Thr Leu Lys Lys Arg Val Cys Arg Leu Pro Arg Pro 145 150 155 160 Glu Thr Gln Lys Gly Pro Leu Cys Ser Pro Ile Thr Leu Gly Leu Leu 165 170 175 Val Ala Gly Val Leu Val Leu Leu Val Ser Leu Gly Val Ala Ile His 180 185 190 Leu Cys Cys Arg Arg Arg Arg Ala Arg Leu Arg Phe Met Lys Gln Pro 195 200 205 Gln Gly Glu Gly Ile Ser Gly Thr Phe Val Pro Gln Cys Leu His Gly 210 215 220 Tyr Tyr Ser Asn Thr Thr Thr Ser Gln Lys Leu Leu Asn Pro Trp Ile 225 230 235 240 Leu Lys Thr <210> 52 <211> 213 <212> PRT <213> Homo sapiens <400> 52 Met Arg Pro Arg Leu Trp Leu Leu Leu Ala Ala Gln Leu Thr Val Leu 1 5 10 15 His Gly Asn Ser Val Leu Gln Gln Thr Pro Ala Tyr Ile Lys Val Gln 20 25 30 Thr Asn Lys Met Val Met Leu Ser Cys Glu Ala Lys Ile Ser Leu Ser 35 40 45 Asn Met Arg Ile Tyr Trp Leu Arg Gln Arg Gln Ala Pro Ser Ser Asp 50 55 60 Ser His His Glu Phe Leu Ala Leu Trp Asp Ser Ala Lys Gly Thr Ile 65 70 75 80 His Gly Glu Glu Val Glu Gln Glu Lys Ile Ala Val Phe Arg Asp Ala 85 90 95 Ser Arg Phe Ile Leu Asn Leu Thr Ser Val Lys Pro Glu Asp Ser Gly 100 105 110 Ile Tyr Phe Cys Met Ile Val Gly Ser Pro Glu Leu Thr Phe Gly Lys 115 120 125 Gly Thr Gln Leu Ser Val Val Asp Phe Leu Pro Thr Thr Ala Gln Pro 130 135 140 Thr Lys Lys Ser Thr Leu Lys Lys Arg Val Cys Arg Leu Pro Arg Pro 145 150 155 160 Glu Thr Gln Lys Gly Arg Arg Arg Arg Ala Arg Leu Arg Phe Met Lys 165 170 175 Gln Pro Gln Gly Glu Gly Ile Ser Gly Thr Phe Val Pro Gln Cys Leu 180 185 190 His Gly Tyr Tyr Ser Asn Thr Thr Thr Ser Gln Lys Leu Leu Asn Pro 195 200 205 Trp Ile Leu Lys Thr 210 <210> 53 <211> 221 <212> PRT <213> Homo sapiens <400> 53 Met Arg Pro Arg Leu Trp Leu Leu Leu Ala Ala Gln Leu Thr Val Leu 1 5 10 15 His Gly Asn Ser Val Leu Gln Gln Thr Pro Ala Tyr Ile Lys Val Gln 20 25 30 Thr Asn Lys Met Val Met Leu Ser Cys Glu Ala Lys Ile Ser Leu Ser 35 40 45 Asn Met Arg Ile Tyr Trp Leu Arg Gln Arg Gln Ala Pro Ser Ser Asp 50 55 60 Ser His His Glu Phe Leu Ala Leu Trp Asp Ser Ala Lys Gly Thr Ile 65 70 75 80 His Gly Glu Glu Val Glu Gln Glu Lys Ile Ala Val Phe Arg Asp Ala 85 90 95 Ser Arg Phe Ile Leu Asn Leu Thr Ser Val Lys Pro Glu Asp Ser Gly 100 105 110 Ile Tyr Phe Cys Met Ile Val Gly Ser Pro Glu Leu Thr Phe Gly Lys 115 120 125 Gly Thr Gln Leu Ser Val Val Asp Phe Leu Pro Thr Thr Ala Gln Pro 130 135 140 Thr Lys Lys Ser Thr Leu Lys Lys Arg Val Cys Arg Leu Pro Arg Pro 145 150 155 160 Glu Thr Gln Lys Gly Pro Leu Cys Ser Pro Ile Thr Leu Gly Leu Leu 165 170 175 Val Ala Gly Val Leu Val Leu Leu Val Ser Leu Gly Val Ala Ile His 180 185 190 Leu Cys Cys Arg Arg Arg Arg Ala Arg Leu Arg Phe Met Lys Gln Leu 195 200 205 Arg Leu His Pro Leu Glu Lys Cys Ser Arg Met Asp Tyr 210 215 220 <210> 54 <211> 210 <212> PRT <213> Homo sapiens <400> 54 Met Arg Pro Arg Leu Trp Leu Leu Leu Ala Ala Gln Leu Thr Val Leu 1 5 10 15 His Gly Asn Ser Val Leu Gln Gln Thr Pro Ala Tyr Ile Lys Val Gln 20 25 30 Thr Asn Lys Met Val Met Leu Ser Cys Glu Ala Lys Ile Ser Leu Ser 35 40 45 Asn Met Arg Ile Tyr Trp Leu Arg Gln Arg Gln Ala Pro Ser Ser Asp 50 55 60 Ser His His Glu Phe Leu Ala Leu Trp Asp Ser Ala Lys Gly Thr Ile 65 70 75 80 His Gly Glu Glu Val Glu Gln Glu Lys Ile Ala Val Phe Arg Asp Ala 85 90 95 Ser Arg Phe Ile Leu Asn Leu Thr Ser Val Lys Pro Glu Asp Ser Gly 100 105 110 Ile Tyr Phe Cys Met Ile Val Gly Ser Pro Glu Leu Thr Phe Gly Lys 115 120 125 Gly Thr Gln Leu Ser Val Val Asp Phe Leu Pro Thr Thr Ala Gln Pro 130 135 140 Thr Lys Lys Ser Thr Leu Lys Lys Arg Val Cys Arg Leu Pro Arg Pro 145 150 155 160 Glu Thr Gln Lys Gly Pro Leu Cys Ser Pro Ile Thr Leu Gly Leu Leu 165 170 175 Val Ala Gly Val Leu Val Leu Leu Val Ser Leu Gly Val Ala Ile His 180 185 190 Leu Cys Cys Arg Arg Arg Arg Ala Arg Leu Arg Phe Met Lys Gln Phe 195 200 205 Tyr Lys 210 <210> 55 <211> 163 <212> PRT <213> Homo sapiens <400> 55 Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu 1 5 10 15 Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys 20 25 30 Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala 35 40 45 Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 50 55 60 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 65 70 75 80 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 85 90 95 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 100 105 110 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 115 120 125 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 130 135 140 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 145 150 155 160 Pro Pro Arg <210> 56 <211> 164 <212> PRT <213> Homo sapiens <400> 56 Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu 1 5 10 15 Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys 20 25 30 Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala 35 40 45 Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 50 55 60 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 65 70 75 80 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 85 90 95 Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 100 105 110 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 115 120 125 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 130 135 140 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 145 150 155 160 Leu Pro Pro Arg <210> 57 <211> 123 <212> PRT <213> Homo sapiens <400> 57 Met Leu Arg Leu Leu Leu Ala Leu Asn Leu Phe Pro Ser Ile Gln Val 1 5 10 15 Thr Gly Asn Lys Ile Leu Val Lys Gln Ser Pro Met Leu Val Ala Tyr 20 25 30 Asp Asn Ala Val Asn Leu Ser Trp Lys His Leu Cys Pro Ser Pro Leu 35 40 45 Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly 50 55 60 Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe 65 70 75 80 Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn 85 90 95 Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr 100 105 110 Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 115 120 <210> 58 <211> 101 <212> PRT <213> Homo sapiens <400> 58 Methionine, Leucine, Arginine, Leucine, Leucine, Leucine, Alanine, Leucine, Asparagine, Leucine, Phenylalanine, Proline, Serine, Isoleucine, Glutamine, Valine 1 5 10 15 Threonine, Glycine, Lysine, Histidine, Leucine, Cysteine, Proline, Serine, Proline, Leucine, Phenylalanine, Proline, Glycine, Proline, Serine, Lysine 20 25 30 Proline, Phenylalanine, Tryptophan, Valine, Leucine, Valine, Valine, Valine, Glycine, Glycine, Valine, Leucine, Alanine, Cysteine, Tyrosine, Serine 35 40 45 Leucine, Leucine, Valine, Threonine, Valine, Alanine, Phenylalanine, Isoleucine, Isoleucine, Phenylalanine, Tryptophan, Valine, Arginine, Serine, Lysine, Arginine 50 55 60 Serine, Arginine, Leucine, Leucine, Histidine, Serine, Aspartic acid, Tyrosine, Methionine, Asparagine, Methionine, Threonine, Proline, Arginine, Arginine, Proline 65 70 75 80 Glycine, Proline, Threonine, Arginine, Lysine, Histidine, Tyrosine, Glutamine, Proline, Tyrosine, Alanine, Proline, Proline, Arginine, Aspartic acid, Phenylalanine 85 90 95 Alanine, Alanine, Tyrosine, Arginine, Serine 100 <210> 59 <211> 220 <212> PRT <213> Homo sapiens <400> 59 Methionine, Leucine, Arginine, Leucine, Leucine, Leucine, Alanine, Leucine, Asparagine, Leucine, Phenylalanine, Proline, Serine, Isoleucine, Glutamine, Valine 1 5 10 15 Threonine, Glycine, Asparagine, Lysine, Isoleucine, Leucine, Valine, Lysine, Glutamine, Serine, Proline, Methionine, Leucine, Valine, Alanine, Tyrosine 20 25 30 Asp Asn Ala Val Asn Leu Ser Cys Lys Tyr Ser Tyr Asn Leu Phe Ser 35 40 45 Arg Glu Phe Arg Ala Ser Leu His Lys Gly Leu Asp Ser Ala Val Glu 50 55 60 Val Cys Val Val Tyr Gly Asn Tyr Ser Gln Gln Leu Gln Val Tyr Ser 65 70 75 80 Lys Thr Gly Phe Asn Cys Asp Gly Lys Leu Gly Asn Glu Ser Val Thr 85 90 95 Phe Tyr Leu Gln Asn Leu Tyr Val Asn Gln Thr Asp Ile Tyr Phe Cys 100 105 110 Lys Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser 115 120 125 Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro 130 135 140 Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly 145 150 155 160 Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile 165 170 175 Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met 180 185 190 Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro 195 200 205 Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 210 215 220 <210> 60 <211> 277 <212> PRT <213> Homo sapiens <400> 60 Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu 1 5 10 15 Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val 20 25 30 Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro 35 40 45 Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys 50 55 60 Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro 65 70 75 80 Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys 85 90 95 Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly 100 105 110 Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys 115 120 125 Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp 130 135 140 Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn 145 150 155 160 Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro 165 170 175 Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr 180 185 190 Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu 195 200 205 Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val 210 215 220 Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu 225 230 235 240 Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly 245 250 255 Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser 260 265 270 Thr Leu Ala Lys Ile 275 <210> 61 <211> 174 <212> PRT <213> Homo sapiens <400> 61 Met Ala Cys Leu Gly Phe Gln Arg His Lys Ala Gln Leu Asn Leu Ala 1 5 10 15 Thr Arg Thr Trp Pro Cys Thr Leu Leu Phe Phe Leu Leu Phe Ile Pro 20 25 30 Val Phe Cys Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala 35 40 45 Ser Ser Arg Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly 50 55 60 Lys Ala Thr Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln 65 70 75 80 Val Thr Glu Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr 85 90 95 Phe Leu Asp Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val 100 105 110 Asn Leu Thr Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile 115 120 125 Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly 130 135 140 Asn Gly Thr Gln Ile Tyr Val Ile Ala Lys Glu Lys Lys Pro Ser Tyr 145 150 155 160 Asn Arg Gly Leu Cys Glu Asn Ala Pro Asn Arg Ala Arg Met 165 170 <210> 62 <211> 223 <212> PRT <213> Homo sapiens <400> 62 Met Ala Cys Leu Gly Phe Gln Arg His Lys Ala Gln Leu Asn Leu Ala 1 5 10 15 Thr Arg Thr Trp Pro Cys Thr Leu Leu Phe Phe Leu Leu Phe Ile Pro 20 25 30 Val Phe Cys Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala 35 40 45 Ser Ser Arg Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly 50 55 60 Lys Ala Thr Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln 65 70 75 80 Val Thr Glu Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr 85 90 95 Phe Leu Asp Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val 100 105 110 Asn Leu Thr Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile 115 120 125 Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly 130 135 140 Asn Gly Thr Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser 145 150 155 160 Asp Phe Leu Leu Trp Ile Leu Ala Ala Val Ser Ser Gly Leu Phe Phe 165 170 175 Tyr Ser Phe Leu Leu Thr Ala Val Ser Leu Ser Lys Met Leu Lys Lys 180 185 190 Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu 195 200 205 Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn 210 215 220 <210> 63 <211> 288 <212> PRT <213> Homo sapiens <400> 63 Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln 1 5 10 15 Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp 20 25 30 Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp 35 40 45 Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val 50 55 60 Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala 65 70 75 80 Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg 85 90 95 Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg 100 105 110 Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu 115 120 125 Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val 130 135 140 Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro 145 150 155 160 Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly 165 170 175 Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys 180 185 190 Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro 195 200 205 Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly 210 215 220 Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro 225 230 235 240 Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly 245 250 255 Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg 260 265 270 Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu 275 280 285 <210> 64 <211> 241 <212> PRT <213> Homo sapiens <400> 64 Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu 1 5 10 15 Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro 20 25 30 Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg 35 40 45 Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu 50 55 60 Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His 65 70 75 80 Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro 85 90 95 Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys 100 105 110 Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys 115 120 125 Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro 130 135 140 Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala 145 150 155 160 Glu Pro Leu Gly Trp Leu Thr Val Val Leu Leu Ala Val Ala Ala Cys 165 170 175 Val Leu Leu Leu Thr Ser Ala Gln Leu Gly Leu His Ile Trp Gln Leu 180 185 190 Arg Ser Gln Cys Met Trp Pro Arg Glu Thr Gln Leu Leu Leu Glu Val 195 200 205 Pro Pro Ser Thr Glu Asp Ala Arg Ser Cys Gln Phe Pro Glu Glu Glu 210 215 220 Arg Gly Glu Arg Ser Ala Glu Glu Lys Gly Arg Leu Gly Asp Leu Trp 225 230 235 240 Val <210> 65 <211> 255 <212> PRT <213> Homo sapiens <400> 65 Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu 1 5 10 15 Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro 20 25 30 Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg 35 40 45 Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu 50 55 60 Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His 65 70 75 80 Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro 85 90 95 Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys 100 105 110 Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys 115 120 125 Lys Pro Trp Thr Asp Cys Cys Trp Arg Cys Arg Arg Arg Pro Lys Thr 130 135 140 Pro Glu Ala Ala Ser Ser Pro Arg Lys Ser Gly Ala Ser Asp Arg Gln 145 150 155 160 Arg Arg Arg Gly Gly Trp Glu Thr Cys Gly Cys Glu Pro Gly Arg Pro 165 170 175 Pro Gly Pro Pro Thr Ala Ala Ser Pro Ser Pro Gly Ala Pro Gln Ala 180 185 190 Ala Gly Ala Leu Arg Ser Ala Leu Gly Arg Ala Leu Leu Pro Trp Gln 195 200 205 Gln Lys Trp Val Gln Glu Gly Gly Ser Asp Gln Arg Pro Gly Pro Cys 210 215 220 Ser Ser Ala Ala Ala Ala Gly Pro Cys Arg Arg Glu Arg Glu Thr Gln 225 230 235 240 Ser Trp Pro Pro Ser Ser Leu Ala Gly Pro Asp Gly Val Gly Ser 245 250 255 <210> 66 <211> 234 <212> PRT <213> Homo sapiens <400> 66 Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu 1 5 10 15 Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro 20 25 30 Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg 35 40 45 Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu 50 55 60 Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His 65 70 75 80 Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro 85 90 95 Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys 100 105 110 Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys 115 120 125 Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro 130 135 140 Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala 145 150 155 160 Glu Pro Leu Gly Trp Leu Thr Val Val Leu Leu Ala Val Ala Ala Cys 165 170 175 Val Leu Leu Leu Thr Ser Ala Gln Leu Gly Leu His Ile Trp Gln Leu 180 185 190 Arg Lys Thr Gln Leu Leu Leu Glu Val Pro Pro Ser Thr Glu Asp Ala 195 200 205 Arg Ser Cys Gln Phe Pro Glu Glu Glu Arg Gly Glu Arg Ser Ala Glu 210 215 220 Glu Lys Gly Arg Leu Gly Asp Leu Trp Val 225 230 <210> 67 <211> 57 <212> PRT <213> Homo sapiens <400> 67 Gln Leu Gly Leu His Ile Trp Gln Leu Arg Ser Gln Cys Met Trp Pro 1 5 10 15 Arg Glu Thr Gln Leu Leu Leu Glu Val Pro Pro Ser Thr Glu Asp Ala 20 25 30 Arg Ser Cys Gln Phe Pro Glu Glu Glu Arg Gly Glu Arg Ser Ala Glu 35 40 45 Glu Lys Gly Arg Leu Gly Asp Leu Trp 50 55 <210> 68 <211> 118 <212> PRT <213> Homo sapiens <400> 68 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser 115 <210> 69 <211> 109 <212> PRT <213> Homo sapiens <400> 69 Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Trp Lys Ser Pro Lys Thr Leu Ile 35 40 45 Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala 100 105 <210> 70 <211> 22 <212> PRT <213> Homo sapiens <400> 70 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 Ala Phe Leu Leu Ile Pro 20 <210> 71 <211> 24 <212> PRT <213> Homo sapiens <400> 71 Leu Glu Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp 1 5 10 15 Val Glu Glu Asn Pro Gly Pro Arg 20 <210> 72 <400> 72 000 <210> 73 <211> 323 <212> PRT <213> Homo sapiens <400> 73 Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met 1 5 10 15 Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp 20 25 30 Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln 35 40 45 Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu 50 55 60 Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile 65 70 75 80 Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu 85 90 95 Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr 100 105 110 Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp 115 120 125 Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro 130 135 140 Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala 145 150 155 160 Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Val Pro Pro 165 170 175 Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro 180 185 190 Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser 195 200 205 Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser 210 215 220 Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp 225 230 235 240 Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala 245 250 255 Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu 260 265 270 Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly 275 280 285 Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu 290 295 300 Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg 305 310 315 320 Arg Lys Arg <210> 74 <400> 74 000 <210> 75 <211> 68 <212> PRT <213> Homo sapiens <400> 75 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 1 5 10 15 Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr Leu 20 25 30 Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile Tyr 35 40 45 Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Gln 65 <210> 76 <211> 32 <212> PRT <213> Homo sapiens <400> 76 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr 20 25 30 <210> 77 <211> 65 <212> PRT <213> Homo sapiens <400> 77 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 1 5 10 15 Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 20 25 30 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 35 40 45 Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe 50 55 60 Thr 65 <210> 78 <211> 12 <212> PRT <213> Homo sapiens <400> 78 Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala 1 5 10 <210> 79 <211> 35 <212> PRT <213> Homo sapiens <400> 79 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr 20 25 30 Ala Met Ser 35 <210> 80 <211> 20 <212> PRT <213> Homo sapiens <400> 80 Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala Thr Ile 1 5 10 15 Ser Ser Gly Gly 20 <210> 81 <211> 53 <212> PRT <213> Homo sapiens <400> 81 Ser Tyr Ile Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 1 5 10 15 Arg Asp Asn Val Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg 20 25 30 Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg Arg Asp Tyr Asp Leu 35 40 45 Asp Tyr Phe Asp Ser 50 <210> 82 <211> 11 <212> PRT <213> Homo sapiens <400> 82 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 83 <211> 653 <212> PRT <213> Homo sapiens <400> 83 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Lys Ala Ser Arg Asp Ile Arg Ser Tyr Leu Thr Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Thr Leu Ile Tyr Tyr Ala Thr Ser Leu Ala 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr 195 200 205 Ser Leu Thr Ile Ser Ser Leu Glu Ser Asp Asp Thr Ala Thr Tyr Tyr 210 215 220 Cys Leu Gln His Gly Glu Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys 225 230 235 240 Leu Glu Ile Lys Arg Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val 465 470 475 480 Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe 485 490 495 Phe Ala Val Ser Leu Ser Lys Met Leu Lys Lys Arg Ser Pro Leu Thr 500 505 510 Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu Pro Glu Cys Glu Lys 515 520 525 Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn Gly Gly Gly Arg Val Lys 530 535 540 Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln 545 550 555 560 Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu 565 570 575 Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg 580 585 590 Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met 595 600 605 Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly 610 615 620 Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp 625 630 635 640 Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 645 650 <210> 84 <211> 675 <212> PRT <213> Homo sapiens <400> 84 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Lys Phe Ser Arg Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly 50 55 60 Lys Arg Leu Glu Trp Val Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Val Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp 100 105 110 Thr Ala Met Tyr Tyr Cys Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe 115 120 125 Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr 130 135 140 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp 145 150 155 160 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 165 170 175 Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr Leu 180 185 190 Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile Tyr 195 200 205 Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser 210 215 220 Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser Asp 225 230 235 240 Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe Thr 245 250 255 Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Glu Ser Lys Tyr 260 265 270 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro 275 280 285 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 290 295 300 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 305 310 315 320 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 325 330 335 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val 340 345 350 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 355 360 365 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 370 375 380 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 385 390 395 400 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 405 410 415 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 420 425 430 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 435 440 445 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 450 455 460 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 465 470 475 480 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 485 490 495 Lys Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe 500 505 510 Ile Gly Leu Gly Ile Phe Phe Ala Val Ser Leu Ser Lys Met Leu Lys 515 520 525 Lys Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr 530 535 540 Glu Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn 545 550 555 560 Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 565 570 575 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 580 585 590 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 595 600 605 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 610 615 620 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 625 630 635 640 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 645 650 655 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 660 665 670 Pro Pro Arg 675 <210> 85 <211> 653 <212> PRT <213> Homo sapiens <400> 85 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 498>Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Gly Ser Thr 100 105 110 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Glu 115 120 125 Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser 130 135 140 Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr Ala 145 150 155 160 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala 165 170 175 Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala 210 215 220 Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val 465 470 475 480 Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe 485 490 495 Phe Ala Val Ser Leu Ser Lys Met Leu Lys Lys Arg Ser Pro Leu Thr 500 505 510 Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu Pro Glu Cys Glu Lys 515 520 525 Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn Gly Gly Gly Arg Val Lys 530 535 540 Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln 545 550 555 560 Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu 565 570 575 Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg 580 585 590 Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met 595 600 605 Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly 610 615 620 Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp 625 630 635 640 Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 645 650 <210> 86 <211> 675 <212> PRT <213> Homo sapiens <400> 86 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser 35 40 45 Arg Asp Ile Arg Ser Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Thr Leu Ile Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr 85 90 95 Ile Ser Ser Leu Glu Ser Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 His Gly Glu Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Ala Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu 145 150 155 160 Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe 165 170 175 Lys Phe Ser Arg Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys 180 185 190 Arg Leu Glu Trp Val Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr 195 200 205 Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val 210 215 220 Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr 225 230 235 240 Ala Met Tyr Tyr Cys Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp 245 250 255 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Ser Lys Tyr 260 265 270 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro 275 280 285 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 290 295 300 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 305 310 315 320 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 325 330 335 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val 340 345 350 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 355 360 365 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 370 375 380 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 385 390 395 400 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 405 410 415 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 420 425 430 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 435 440 445 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 450 455 460 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 465 470 475 480 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 485 490 495 Lys Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe 500 505 510 Ile Gly Leu Gly Ile Phe Phe Ala Val Ser Leu Ser Lys Met Leu Lys 515 520 525 Lys Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr 530 535 540 Glu Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn 545 550 555 560 Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 565 570 575 Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 580 585 590 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 595 600 605 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 610 615 620 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 625 630 635 640 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 645 650 655 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 660 665 670 Pro Pro Arg 675 <210> 87 <211> 654 <212> PRT <213> Homo sapiens <400> 87 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Gly Gly Ser Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Lys Ala Ser Arg Asp Ile Arg Ser Tyr Leu Thr Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Thr Leu Ile Tyr Tyr Ala Thr Ser Leu Ala 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr 195 200 205 Ser Leu Thr Ile Ser Ser Leu Glu Ser Asp Asp Thr Ala Thr Tyr Tyr 210 215 220 Cys Leu Gln His Gly Glu Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys 225 230 235 240 Leu Glu Ile Lys Arg Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val 465 470 475 480 Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe 485 490 495 Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe 500 505 510 Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg 515 520 525 Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val 530 535 540 Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn 545 550 555 560 Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val 565 570 575 Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg 580 585 590 Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 595 600 605 Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 610 615 620 Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 625 630 635 640 Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 645 650 <210> 88 <211> 676 <212> PRT <213> Homo sapiens <400> 88 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 Ala Phe Leu Leu Ile Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Lys Phe Ser Arg Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly 50 55 60 Lys Arg Leu Glu Trp Val Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Val Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp 100 105 110 Thr Ala Met Tyr Tyr Cys Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe 115 120 125 Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr 130 135 140 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp 145 150 155 160 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 165 170 175 Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr Leu 180 185 190 Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile Tyr 195 200 205 Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser 210 215 220 Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser Asp 225 230 235 240 Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe Thr 245 250 255 Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Glu Ser Lys Tyr 260 265 270 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro 275 280 285 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 290 295 300 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 305 310 315 320 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 325 330 335 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val 340 345 350 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 355 360 365 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 370 375 380 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 385 390 395 400 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 405 410 415 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 420 425 430 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 435 440 445 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 450 455 460 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 465 470 475 480 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 485 490 495 Lys Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe 500 505 510 Ile Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr 515 520 525 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 530 535 540 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 545 550 555 560 Leu Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 565 570 575 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 580 585 590 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 595 600 605 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 610 615 620 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 625 630 635 640 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 645 650 655 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 660 665 670 Leu Pro Pro Arg 675 <210> 89 <211> 654 <212> PRT <213> Homo sapiens <400> 89 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Ile Arg Ser Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Gly Glu Ser Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Gly Ser Thr 100 105 110 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Glu 115 120 125 Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser 130 135 140 Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ser Arg Tyr Ala 145 150 155 160 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala 165 170 175 Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala 210 215 220 Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp Ser Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met Ala Leu Ile Val 465 470 475 480 Leu Gly Gly Val Ala Gly Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe 485 490 495 Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe 500 505 510 Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg 515 520 525 Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Gly Gly Gly Arg Val 530 535 540 Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn 545 550 555 560 Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val 565 570 575 Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg 580 585 590 Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 595 600 605 Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 610 615 620 Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 625 630 635 640 Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 645 650 <210> 90 <211> 676 <212> PRT <213> Homo sapiens <400> 90 Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro 1 5 10 15 Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser 35 40 45 Arg Asp Ile Arg Ser Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Thr Leu Ile Tyr Tyr Ala Thr Ser Leu Ala Asp Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr 85 90 95 Ile Ser Ser Leu Glu Ser Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 His Gly Glu Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Ala Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu 145 150 155 160 Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe 165 170 175 Lys Phe Ser Arg Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys 180 185 190 Arg Leu Glu Trp Val Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr 195 200 205 Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val 210 215 220 Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr 225 230 235 240 Ala Met Tyr Tyr Cys Ala Arg Arg Asp Tyr Asp Leu Asp Tyr Phe Asp 245 250 255 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Ser Lys Tyr 260 265 270 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro 275 280 285 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 290 295 300 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 305 310 315 320 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 325 330 335 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val 340 345 350 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 355 360 365 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 370 375 380 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 385 390 395 400 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 405 410 415 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 420 425 430 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 435 440 445 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 450 455 460 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 465 470 475 480 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 485 490 495 Lys Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu Leu Phe 500 505 510 Ile Gly Leu Gly Ile Phe Phe Lys Arg Gly Arg Lys Lys Leu Leu Tyr 515 520 525 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 530 535 540 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 545 550 555 560 Leu Gly Gly Gly Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 565 570 575 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 580 585 590 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 595 600 605 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 610 615 620 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 625 630 635 640 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 645 650 655 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 660 665 670 Leu Pro Pro Arg 675 <210> 91 <211> 229 <212> PRT <213> Homo sapiens <400> 91 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 1 5 10 15 Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 20 25 30 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 35 40 45 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 50 55 60 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser 65 70 75 80 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 85 90 95 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 100 105 110 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 115 120 125 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 130 135 140 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 145 150 155 160 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 165 170 175 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 180 185 190 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 195 200 205 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 210 215 220 Leu Ser Leu Gly Lys 225 <210> 92 <211> 112 <212> PRT <213> Homo sapiens <400> 92 Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 1 5 10 15 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 20 25 30 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 35 40 45 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 50 55 60 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 65 70 75 80 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 85 90 95 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 100 105 110

Claims

1. An isolated nucleic acid encoding a chimeric antigen receptor (CAR), the CAR comprising: a single-chain variable fragment (scFv) targeting CD6, consisting of an amino acid sequence selected from SEQ ID NO: 38, 39, 40 and 41, a spacer consisting of the amino acid sequence of SEQ ID NO: 91; a transmembrane domain selected from the group consisting of a CD4 transmembrane domain consisting of the amino acid sequence of SEQ ID NO: 23, a CD8 transmembrane domain consisting of the amino acid sequence of SEQ ID NO: 25, and a CD28 transmembrane domain consisting of the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8; a CTLA4 costimulatory domain consisting of the amino acid sequence of SEQ ID NO: 17; and The CD3 zeta signaling domain consists of the amino acid sequence of SEQ ID NO:

92.

2. The isolated nucleic acid of claim 1, wherein the CAR consists of the amino acid sequence of any one of SEQ ID Nos: 83-86.

3. The isolated nucleic acid of claim 1 , wherein the CAR comprises: A single-chain variable fragment targeting CD6, consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 38, 39, 40 and 41; a spacer consisting of the amino acid sequence of SEQ ID NO: 91; a transmembrane domain consisting of the amino acid sequence of SEQ ID NO: 23; a CTLA4 costimulatory domain consisting of the amino acid sequence of SEQ ID NO: 17; and The CD3 zeta signaling domain consists of the amino acid sequence of SEQ ID NO:

92.

4. The isolated nucleic acid of claim 1, wherein the CAR comprises: A single-chain variable fragment targeting CD6, consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 38, 39, 40 and 41; a spacer consisting of the amino acid sequence of SEQ ID NO: 91; a transmembrane domain consisting of the amino acid sequence of SEQ ID NO: 25; a CTLA4 costimulatory domain consisting of the amino acid sequence of SEQ ID NO: 17; and The CD3 zeta signaling domain consists of the amino acid sequence of SEQ ID NO:

92.

5. The isolated nucleic acid of claim 1, wherein the CAR comprises: A single-chain variable fragment targeting CD6, consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 38, 39, 40 and 41; a spacer consisting of the amino acid sequence of SEQ ID NO: 91; a transmembrane domain consisting of the amino acid sequence of SEQ ID NO: 7; a CTLA4 costimulatory domain consisting of the amino acid sequence of SEQ ID NO: 17; and The CD3 zeta signaling domain consists of the amino acid sequence of SEQ ID NO:

92.

6. The isolated nucleic acid of claim 1, wherein the CAR comprises: A single-chain variable fragment targeting CD6, consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 38, 39, 40 and 41; a spacer consisting of the amino acid sequence of SEQ ID NO: 91; a transmembrane domain consisting of the amino acid sequence of SEQ ID NO: 8; a CTLA4 costimulatory domain consisting of the amino acid sequence of SEQ ID NO: 17; and The CD3 zeta signaling domain consists of the amino acid sequence of SEQ ID NO:

92.

7. A vector comprising the nucleic acid according to any one of claims 1 to 6.

8. The vector of claim 7, wherein the vector is a viral vector.

9. T lymphocytes comprising the vector of claim 7.

10. The T lymphocyte of claim 9, wherein the T lymphocyte is a regulatory T cell.

11. A population of T lymphocytes expressing a chimeric antigen receptor (CAR), wherein the CAR comprises an amino acid sequence selected from SEQ ID NOs: 83-86.

12. The T lymphocyte population of claim 11, wherein the CAR consists of the amino acid sequence of any one of SEQ ID No: 83-86.

13. The T lymphocyte population of claim 11 or 12, wherein the T lymphocyte population comprises regulatory T cells.

14. The T lymphocyte population of claim 13, wherein at least 70%, 80% or 90% of the cells in the population are CD4 + / CD25 高 / CD127 低 / - , and at least 70%, 80% or 90% of the cells in the population are CD6 低 / - .

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