CA2398877A1 - Nucleic acids, proteins, and antibodies - Google Patents

Abstract

The present invention relates to novel immune/hematopoietic-related polynucleotides and the polypeptides encoded by these polynucleotides herein collectively known as "immune/hematopoietic antigens", and the use of such immune/hematopoietic antigens for detecting immune/hematopoietic-related diseases and/or disorders, particularly the presence of cancer and cancer metastases of cells of hematopoietic origin. More specifically, isolated immune/hematopoietic associated nucleic acid molecules are provided encoding novel immune/hematopoietic associated polypeptides. Novel immune/hematopoietic polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human immune/hematopoietic associated polynucleotides and/or polypeptides. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the immune system or cells and tissues associated with hematopoiesis, including cancers of cells of hematopoietic origin, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further relates to methods and/or compositions for inhibiting the production and function of the polypeptides of the present invention.

Description

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Nucleic Acids, Proteins, and Antibodies [001] This application refers to a "Sequence Listing" that is provided only on electronic media in computer readable form pursuant to Administrative Instructions Section 801(a)(i). The Sequence Listing forms a part of this description pursuant to Rule 5.2 and Administrative Instructions Sections 801 to 806, and is hereby incorporated in its entirety.
[002] The Sequence Listing is provided as an electronic file (PC004PCT
seqList.txt, 76,977,474 bytes in size, created on January 16, 2001) on four identical compact discs (CD-R), labeled "COPY 1," "COPY 2," "COPY 3," and "CRF." The Sequence Listing complies with Annex C of the Administrative Instructions, and may be viewed, for example, on an IBM-PC machine runtung the MS-Windows operating system by using the V viewer software, version 2000 (see World Wide Web URL:
http://www.fileviewer.com).
Field of the Invention [003] The present invention relates to novel immune system and hematopoietic related (herein "immune/hematopoietic") polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "immune/hopoietic antigens," and antibodies that immunospecifically bind these polypeptides, and the use of such immune/hematopoietic polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the immune system, including, but not limited to, the presence of cancer and cancer metastases of cells of hematopitic origin. More specifically, isolated imrr~une/hematopoietic nucleic acid molecules are provided encoding novel immunelhematopoietic polypeptides. Novel immune/hematopoietic polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human immune/hematopoietic polynucleotides, polypeptides, and/or antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to hematopoiesis and the immune system, including cancers of cells of hematopoietic origins, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The invention further relates to methods and/or compositions for inhibiting or promoting the production and/or function of the polypeptides of the invention.
Background of the Invention [004] The immune system is an intricate network composed of cells, tissues and soluble substances that function to protect the body from invasion by foreign substances and pathogens. The major cells of the immune system are white blood cells, including lymphocytes, such as B cells and T cells, and myeloid cells, such as basophils, eosinophils, neutrophils, mast cells, monocytes, macrophages and dendritic cells. The soluble components of the immune system, are molecules (often polypeptides) that are not contained within cells, but rather are found in extracellular fluids such as lymph and blood plasma. Some of the major soluble substances are antibodies, complement proteins, and cytokines.

[005] Cells of the immune system (as well as red blood cells and platelets) are derived from a common precursor stem cell by a process known as hematopoiesis.
During fetal life hematopoiesis occurs in the liver and spleen, but in the adult, hematopoiesis occurs mainly in bone marrow. The stem cells from which all blood cells are derived proliferate and differentiate into the various blood cell lineages, (e.g., lymphocytes (B or T cells), myeloid cells (basophils, eosinophils, neutrophils, mast cells, macrophages), platelets, or red blood cells) in response to signals received from other cells (e.g., stromal cells) in the bone marrow microenvironment and also from cytokines. Many of the cytokines that promote the growth and differentiation of hematopoietic stem cells are known as "colony stimulating factors". For example, interleukin-3 (IL-3, and also known as mufti-colony stimulating factor) and granulocyte macrophage colony stimulationg factor (GM-CSF), which are released by activated macrophages T cells, stimulate the production of macrophages and granulocytes (myelopoiesis). Stem cell factor (SCF, c-kit ligand) is a growth factor for primitive lymphoid and myeloid hematopoietic bone marrow progenitor cells expressing the early cell surface marker CD34. Other hematopoeitic cytokines/growth factors include, but are not limited to macrophage colony stimulating factor (M-CSF) and granulocyte colony stimulating factor (G-CSF). Interleukins-1, 6, and 7 have also been shown to function as hematopoietic growth factors/cytokines.

[006] The maturation of lymphocytes has an added layer of complexit<,~ in that each individual T and B cell generates a unique antigen specific receptor - a B
cell receptor (antibody) in the case of B cells or a T cell receptor in the case of T cells . Because it is possible that B and T cells may generate autoreactive antigen receptors, B
and T
cells undergo negative selection processes that eliminate autoreactive lymphocytes from the circulating pool of mature lymphocytes. Defects in negative selection may contribute to the occurrence of autoimmune disease. In addition, T cells undergo a process of positive selection in which T cells are selected for their ability to interact with the major histocompatibility antigens. In the thymus, T cells also differentiate into one of two classes, CD4+ T helper (Th) cells or CD8+ cytotoxic T cells.
The majority of the maturation and selection procees occurs in the bone marrow for B
cells, whereas T cell progenitor cells migrate from the bone marrow to the thymus where they complete their~maturation.

[007] Cells of the immune system circulate throughout the body in both the lymph and the blood. Immune cells will leave the circulatory system and enter the tissues by a process known as diapedesis. Immune cells return to the circulatory system via travel in the lymph. Situated along the lymphatic vessels are lymph nodes, which are small nodular aggregates of lymphoid tissues. The architecture of the lymph node is designed to facilitate acquired immune responses, with antigen presenting cells, B
cells and T cells all in close proximity. Antigen presenting cells (APCs, e.g., dendritic cells, macrophages, B cells) display antigen on their surface in the form of peptides associated MHC class II molecules to T helper cells. T helper cells with T-cell receptors specific for the given antigen become activated if they bind to the peptide MHC complexes and receive co-stimulatory signals (e.g, stimulation of CD28 on the Tcell by B7 molecules on the APC). Activated T helper cells proliferate, secreted cytokines, and can stimulate antigen-specific B cells or T cells to become activated.
Once activated, cytotoxic T cells proliferate and are able to induce apoptosis of cells expressing specific antigen on their surface as a peptide in the context of MHC Class I
molecules. Activated B cells also proliferate and may either enter into germinal center and undergo a process of affinity maturation of their antigen receptor, or differentiate into antibody forming cells (plasma cells) that secrete large quantities of antigen-specific antibody.

[008] Aside from lymphocytes and antigen presenting cells, introduced above, there are several other accessory cells in the immune system including neutrophils, eosinophils, basophils, mast cells, and Natural Killer (NK) cells. NK cells are large granular lymphocytes that have cytotoxic function, especially against cells infected with intracellular pathogens, and may function in the eradication of cancer cells.
Neutrophils are phagocytic cells that play a key role in the inflammatory process.
Activated mast cells release granules containing histamine and other active agents which are effective against large parasites and also contribute to allergic reactions and asthma. Eosinophils bear Fc receptors for IgG and IgE, and participate in the killing of antibody coated parasites.

[009] The immune system can be classified into the acquired and innate immune system. The cells of the innate immune system (e.g., neutrophils, eosinophils, basophils, mast cells) are not antigen specific and their action is not enhanced by repeated exposure to the same antigen. The cells of the acquired immune system (B
and T cells) are antigen specific and repeated exposure of B and T cells to an antigen results in improved immune repsonses (memory responses) produced by these cell types. The cells and products of the acquired immune system can function to focus the action of the innate immune system. For example, eosinophils are not in themselves antigen specific, but as a result of expression of Fc receptors on their surface, their activity can be focused on a specific antigen to which an antibody response has been made by the acquired immune system. For a more extensive review of the immune system, see Fundamental Immunology , 4th edition, ed. William Paul, Lippincott-Raven Pub. (1998).

[010] As illustrated above, an immune response is seldom carried out by a single cell type, but rather requires the coordinated efforts of several cell types. In order to coordinate an immune response, it is necessary that cells of the immune system communicate with each other and with other cells of the body. Communication between cells may be made by cell-cell contact, between membrane bound molecules on each cell, or by the interaction of soluble components of the immune system with cellular receptors. Usually, such receptors are embedded in the plasma membrane, but there also exist a subset of cytoplasmic and nuclear receptors. Communication, or signaling, between cell types may have one or more of a variety of consequences including, activation, proliferation, differentiation, or apoptosis.
Activation and differentiation may result in the expression or secretion of polypeptides, or other molecules, which in turn affect the function of other cells and/or molecules of the immune system.

[011] Signaling molecules of the immune system, including not only cellular receptors and ligands, but also the downstream effectors of the receptors and/or ligands, may be described as immunomodulators. In addition, immunomodulators (also known as biological response modifiers) include microbial or synthetic substances and products of activated cells. The mechanism of action of immunomodulators usually involves a complicated interplay of various regulator and effector systems. Immunomodulators may enhance (immunoprophylaxis, immunostimulation), restore (immunosubstitution, immunorestoration) or suppress (immunosuppression, immunodeviation) immunological functions or activities.
Immunomodulators may be, for example, cytokines, cytokine receptors, inhibitors of DNA synthesis, intacellular receptors, or components of signal transduction pathways, some of which are described in more detail below:
Cytokines and Cytokine Receptors [012] Cytokines are small soluble proteins produced by one cell that alter the behavior or other properties of another cell or itself. Thus, by definition, cytokines are immunomodulatory molecules. Many cytokines have multiple biological effects and are critical to the regulation of the immune response. For a review on cytokines, refer to Chapter 11 of Cellular and Molecularlmmuzzology by Abbas et al. (1991;:

[013] Immune responses of the acquired immune system can be classified into two broad classes of immune responses: humoral (antibody-mediated) immune responses and cell-mediated immune responses (cell-mediated, i.e., cytotoxic T cell, immune response). Both types of responses require activation of CD4+ T helper cells.
Depending on several factors, of which one factor is the cytokine environment, T
helper (Th) cells may differentiate into either Thl cells that promote cell-mediated responses or Th2 cells that promote humoral responses. Thl cells, which produce interferon (IFN)-gamma, interleukin (IL)-2 and tumor necrosis factor (TNF)-beta, evoke cell-mediated immunity and phagocyte-dependent inflammation. Th2 cells, which produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, evoke strong antibody responses (including those of the IgE class) and eosinophil accumulation, but inhibit several functions of phagocytic cells (phagocyte-independent inflammation).
The presence of Th 1 or Th2 T cells can have a dramatic effect on the outcome of infection.
A Thl response during the course of infection by the intracellular bacterium mycobacterium leprae (M. leprae) is protective, whereas a Th2 response is much less so. Patients that make Th2 response to M. leprae develop full-blown lepromatous leprosy which is eventually fatal. The (mis)regulation of Thl and Th2 responses have been implicated in the pathogenesis of several diseases, including several organ-specific autoimmune disorders such as Crohn's disease, sarcoidosis, acute kidney allograft rejection, some unexplained recurrent abortions. For a review on Thl and Th2 subsets, see Romagnani, Anzz. Allergy Asthma Immuzzol. 85:9-18 (2000).

[014] From the preceding example it is apparent that cytokines have play key roles on the class.and effectiveness of the immune response. It is important to note that cytokines have effects on cell of both the innate and acquired immune systems and are produced by both immune and non-immune cells types.

[015] Other cytokines such as interferon-alpha (secreted by leukocytes) and interferon-beta (secreted by fibroblasts and many other cell types) are cytokines that function to target the immune system towards fighting viral infections. The binding of interferon-alpha and -beta to cells results in a cellular signalling cascade which ultimately results in the inhibition of viral replication in infected cells, the upregulation of MHC class I expression on cells, and the activation. of Natural Killer (NK) cells.
Interferons are useful in the diagnosis, treatment and prevention of viral infections and cancers.
Intracellular imnaunomodulators.

[016] Immunomodulatory proteins are not only cytokines or cytokine receptors.
They may also be located intracellularly. For, example they may be intracellular components of a signaling pathway, or even intracellular receptors for certain signaling molecules such as steroids. One example of intracellular immunomodulatory proteins are the immunophilins such as cyclophilin and FK binding protein (FKBP).
These immunophilins are peptidyl-prolyl cis-trans isomerases, though their enzymatic ability may be distinct from their role as immunomodulators. When these molecules are bound by the drugs, Cyclosporin A and FK506, respectively, they in turn inhibit the action of activated calcineurin. Calcineurin is a calcium activated serine/threonine kinase which dephosphorylates the transcription factor Nuclear Factor of Activated T
cells (NF-AT). Upon dephosphorylation, NF-AT enters the nucleus and induces the transcription of several genes including IL-2. In sum, the immunophilin:drug complexes are able to inhibit clonal expansion of T cells by inhibiting IL-2 synthesis.
In addition, FKBP when bound to another drug, rapamycin, can.also inhibit the signaling of IL-2 through the IL-2 receptor. FKBP:rapamycin complexes accomplish the inhibition of IL-2 signaling not by binding to calcineurin, but by binding to and inactivating the protein kinases associated with IL-2 signaling resulting in the same outcome, the inhibition of T cell clonal expansion.

[017] Defects in any one or more of the components of the immune system can lead to diseaseor susceptibility to infectious diseases. Two major classes of immune system disorders are autoimmune diseases, and immunodeficiencies. In autoimmunity, the effector mechanisms of the immune system (e.g., antigen specific antibodies and cellular cytotoxicity, e.g., of cytotoxic T cells, or natural killer cells) are misdirected at self rather than foreign antigens resulting is tissue distruction.
Diseases classified as or associated with immunodeficiencies are diseases in which the immune system is unable to mount an effective immune response. A classic example of an immunodeficiecy is X-linked agammaglobulinemia in which an intracellular signalling molecule expressed in B lymphocytes (Bruton's tyrosine kinase) is defective. The loss of function of this kinase prevents B cell maturation, thus patients with X linked agammaglobulinemia do not have mature B cells and are unable to make antibody, and as a result are susceptible to infection.

[018] The discovery of new human immune/hematopoietic polynucleotides, the polypeptides encoded by them, and antibodies that immunospecifically bind these polypeptides, satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, prevention and/or prognosis of disorders of the immune system, including, but not limited to, autoimmune disorders, (e.g., systemic lupus erythematosus, rheumatoid arthritis, idiopathic thrombocytopenic purpura and multiple sclerosis) and immunodeficiencies (e.g., X-linked agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and ataxia telangiectasia). Additionally, immune/hematopoietic molecules would be useful as agents to boost immune responsiveness to pathogens or to suppress immune reactions, for example as is necessary in conjunction with organ transplantation.
Summary of the Invention [019] The present invention relates to novel immune/hematopoietic related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "immune/hematopoietic antigens," and antibodies that immunospecifically bind these polypeptides, and the use of such immune/hematopoietic polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the immune system, including, but not limited to, the presence of cancer and cancer metastases of cells of hematopoietic origin. More specifically, isolated immune/hematopoietic nucleic acid molecules are provided encoding novel immune/hematopoietic polypeptides. Novel immune/hematopoietic polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human immune/hematopoietic polynucleotides, polypeptides, and/or antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the a immune system or hematopoitic cells or tisues, including cancers of cells of hematopoietic origin, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The invention further relates to methods and/or compositions for inhibiting or promoting the production and/or function of the polypeptides of the invention.
Detailed Description Tables [020] Table 1A summarizes some of the polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) and contig nucleotide sequence identifier (SEQ ID NO:X)) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby. The first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA plasmid related to each immune/hematopoietic associated contig sequence disclosed in Table 1A. The second column provides a unique contig identifier, "Contig ID:" for each of the contig sequences disclosed in Table 1A. The third column provides the sequence identifier, "SEQ ID NO:X", for each of the contig polynucleotide sequences disclosed in Table 1A. The fourth column, "ORF (From-To)", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO.:X that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A as SEQ ID NO:Y (column 5). Column 6 lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y). Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4:181-186 (1988)); specifically, the Genetics Computer Group (GCG) implementation of this algorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group (GCG), Madison, Wisc.). This method returns a measure of the probability that a given residue is found on the surface of the protein.
Regions where the antigenic index score is greater than 0.9 over at least 6 amino acids are indicated in Table 1A as "Predicted Epitopes." In particular embodiments, immune/hematopoietic associated polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly. Column 7, "Tissue Distribution" shows the expression profile of tissue, cells, and/or cell line libraries which express the polynucleotides of the invention.
The first number in column 7 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. Expression of these polynucleotides was not observed in the other tissues and/or cell libraries tested.
For those identifier codes in which the first two letters are not "AR", the second number in column 7 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ ID NO:X) was identified in the tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are "AR" designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines.
Probe synthesis was performed in the presence of 33P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after "[array code]:" represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissues) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression. Column ~, "Cytologic Band," provides the chromosomal location of polynucleotides corresponding to SEQ ID NO:X. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Given a presumptive chromosomal location, disease locus association was determined by comparison with the Morbid Map, derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIMTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/). If the putative chromosomal location of the Query overlapped with the chromosomal location of a Morbid Map entry, an OMIM identification number is provided in Table 1A, column 9 labeled "OMIM
Disease References)". A key to the OMIM reference identification numbers is provided in Table 5.

[021] Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ
ID NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, "SEQ ID NO:X", for each contig sequence. The third column provides a unique contig identifier, "Contig ID:" for each contig sequence. The fourth column, provides a BAC identifier "BAC
ID NO:A" for the BAC clone referenced in the corresponding row of the table.
The fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, "Exon From-To", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).

[022] Table 2 summarizes homology and features of some of the polypeptides of the invention. The first column provides a unique clone identifier, "Clone ID
NO:Z", corresponding to a cDNA disclosed in Table 1 A. The second column provides the unique contig identifier, "Contig ID:" corresponding to contigs in Table 1A
and allowing for correlation with the information in Table 1A. The third column provides the sequence identifier, "SEQ ID NO:X", fox the contig polynucleotide sequences.
The fourth column provides the analysis method by which the homology/identity disclosed in the row was determined. Comparisons were made between polypeptides encoded by the polynucleotides of the invention and either a non-redundant protein database (herein referred to as "NR"), or a database of protein families (herein referred to as "PFAM") as further described below. The fifth column provides a description of PFAM/NR hits having significant matches to a polypeptide of the invention.
Column six provides the accession number of the PFAM/NR hit disclosed in the fifth column.
Column seven, "Score/Percent Identity", provides a quality score or the percent identity, of the hit disclosed in column five. Columns 8 and 9, "NT From" and "NT
To" respectively, delineate the polynucleotides in ~ "SEQ ID NO:X" that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth column. In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by the polynucleotides in SEQ ID NO:X as delineated in columns 8 and 9, or fragments or variants thereof.

[023] Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention. The first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA clone related to immune/hematopoietic associated contig sequences disclosed in Table 1A. The second column provides the sequence identifier, "SEQ ID NO:X", for contig polynucleotide sequences disclosed in Table 1A. The third column provides the unique contig identifier, "Contig ID", for contigs disclosed in Table 1A. The fourth column provides a unique integer 'a' where 'a' is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, represented as "Range of a", and the fifth column provides a unique integer 'b' where 'b' is any integer between 15 and the final nucleotide of SEQ ID NO:X, represented as "Range of b", where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a + 14. For each of the polynucleotides shown as SEQ ID NO:X, the uniquely defined integers can be substituted into the general formula of a-b, and used to describe polynucleotides which may be preferably excluded from the invention. In certain embodiments, preferably excluded from the polynucleotides of the invention (including polynucleotide fragments and variants as described herein and diagnostic andlor therapeutic uses based on these polynucleotides) are at least one, two, three, four, five, ten, or more of the polynucleotide sequences) having the accession numbers) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequences) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC
clone).

[024] Table 4 provides a key to the tissue/cell source identifier code disclosed in Table 1A, column 7. Column 1 provides the key to the tissue/cell source identifier code disclosed in Table 1A, Column 7. Columns 2-5 provide a description of the tissue or cell source. Codes corresponding to diseased tissues are indicated in column 6 with the word "disease". The use of the word "disease" in column 6 is non-limiting.
The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ).
Furthermore, tissues and/or cells lacking the "disease" designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder. In numerous cases where the tissue/cell source is a library, column 7 identifies the vector used to generate the library.

[025] Table 5 provides a key to the OMIMTM reference identification numbers disclosed in Table 1A, column 9. OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIMTM, McICusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, MD) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.govlomim~. Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 8, as determined from the Morbid Map database.

[026] Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application.

(027] Table 7 shows the cDNA libraries sequenced, tissue source description, vector information and ATCC designation numbers relating to these cDNA libraries.

[028] Table ~ provides a physical characterization of clones encompassed by the invention. The first column provides the unique clone identifier, "Clone ID
NO:Z", for certain cDNA clones of the invention, as described in Table 1A. The second column provides the size of the cDNA insert contained in the corresponding cDNA
clone.
Definitions [029] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[030] In the present invention, "isolated" refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered "by the hand of man" from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide. The term "isolated" does not refer to genomic or cDNA libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic DNA
preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide sequences of the present invention.

[031] As used herein, a "polynucleotide" refers to a molecule having a nucleic acid sequence encoding SEQ ID NO:Y or a fragment or variant thereof, a nucleic acid sequence contained in SEQ ID NO:X (as described in column 3 of Table 1A) or the complement thereof, a cDNA sequence contained in Clone ID NO:Z (as described in column 1 of Table 1A and contained within a library deposited with the ATCC);
a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B or a fragment or variant thereof; or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B
or the complement thereof. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence. Moreover, as used herein, a "polypeptide" refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA).

[032] As used herein, a "immune/hematopoietic antigen" refers collectively to any polynucleotide disclosed herein (e.g., a nucleic acid sequence contained in SEQ ID
NO:X or the complement therof, or cDNA sequence contained in Clone ID NO:Z, or a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B, or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B or the complement thereof and fragments or variants thereof as described herein) or any polypeptide disclosed herein (e.g., an amino acid sequence contained in SEQ ID NO:Y, an amino acid sequence encoded by SEQ ID NO:X, or the complement thereof, an amino acid sequence encoded by the cDNA sequence contained in Clone ID NO:Z, an amino acid sequence encoded by SEQ ID NO:B, or the complement thereof, and fragments or variants thereof as described herein). These immune/hematopoietic antigens have been determined to be predominantly expressed in hematopoietic tissues (e.g., bone marrow, fetal liver, and fetal spleen) or cells and tissues of the immune system (e.g., lymph nodes, spleen, B cells, T cells, monocytes, macrophages, dendritic cells, neutrophils, mast cells, basophils, and eosinophils) including normal or diseased tissues (as shown in Table 1A column 7 and Table 4).

[033] In the present invention, "SEQ ID NO:X" was often generated by overlapping sequences contained in multiple clones (contig analysis). A representative clone containing all or most of the sequence for SEQ ID NO:X is deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library. As shown, for example, in column 1 of Table 1 A, each clone is identified by a cDNA Clone ID
(identifier generally referred to herein as Clone ID NO:Z). Each Clone ID is unique to an individual clone and the Clone ID is all the information needed to retrieve a given clone from the HGS library. Furthermore, certain clones disclosed in this application have been deposited with the ATCC on October 5, 2000, having the ATCC
designation numbers PTA 2574 and PTA 2575; and on January 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2. In addition to the individual cDNA clone deposits, most of the cDNA libraries from which the clones were derived were deposited at the American Type Culture Collection (hereinafter "ATCC"). Table 7 provides a list of the deposited cDNA libraries. One can use the Clone ID NO:Z to determine the library source by reference to Tables 6 and 7.
Table 7 lists the deposited cDNA libraries by name and links each library to an ATCC
Deposit. Library names contain four characters, for example, "HTWE." The name of a cDNA clone (Clone ID NO:Z) isolated from that library begins with the same four characters, for example "HTWEP07". As mentioned below, Table 1A correlates the Clone ID NO:Z names with SEQ ID NO:X. Thus, starting with an SEQ ID NO:X, one can use Tables 1A, 6 and 7 to determine the corresponding Clone ID NO:Z, which library it came from and which ATCC deposit the library is contained in.
Furthermore, it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein. The ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA. The ATCC deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.

[034] In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).

[035) A "polynucleotide" of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, or the complement thereof (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained in Clone ID NO:Z (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA clones deposited with the ATCC, described herein) and/or the polynucleotide sequence delineated in column 6 of Table 1B or the complement thereof. "Stringent hybridization conditions" refers to an overnight incubation at 42 degree C in a solution comprising 50% formamide, Sx SSC (750 mM NaCI, 75 mM
trisodium citrate), 50 mM sodium phosphate (pH 7.6), Sx Denhardt's solution, 10%
dextran sulfate, and 20 ~g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65 degree C.

[036] Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions.
Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency), salt conditions, or temperature. For example, lower stringency conditions include an overnight incubation at 37 degree C in a solution comprising 6X SSPE (20X SSPE = 3M
NaCI;
0.2M NaH2P04; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50 degree C with 1XSSPE, 0.1%
SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X
SSC).

[037] Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.

[038] Of course, a polynucleotide which hybridizes 'only to polyA+ sequences (such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of "polynucleotide," since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone generated using oligo dT as a primer).

[039] The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA
that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, the polynucleotide can be composed of triple-sfiranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA
and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms.

[040] The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids.
The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
(See, for instance, PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993);
POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C.
Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth.
Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992).) [041] "SEQ ID NO:X" refers to a polynucleotide sequence described, for example, in Tables 1A or 2, while "SEQ ID NO:Y" refers to a polypeptide sequence described in column 5 of Table 1A. SEQ ID NO:X is identified by an integer specified in column 3 of Table 1A. The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID NO:X. "Clone ID NO:Z" refers to a cDNA clone described in column 1 of Table 1A.

[042] "A polypeptide having biological activity" refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).

[043] Table 1A summarizes some of the immune/hematopoietic associated polynucleotides encompassed by the invention (including contig sequences (SEQ
ID
NO:X) and clones (Clone ID NO:Z) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.
Polynucleotides and Polyuentides c ' ~, OAw a do .b U

7.~'. .. yD N v0 O

w eC ~ ~ co "' N ~ N

O ~ ~, O O O .. M O ~ O TJ
~ :
~
~

0 o a aNV~~,~
x~a a ~ ~

~ N
,d O ,:.; ~D 00 N M ~ .-i p~ .--i -n ~ p ,-; ~ ,~ ~ ..-i V.j .-~

L .a V1 '_' ~ t~ ~ O O 01 O 0 ~ 0 ~ O
e,.., ~
y ~
~

. O 0 0 ~ O 1 ~ ~ 'ct l Ov .a o d x o x o , 0 0 0 0 0 r ~ o x ~ x o ,_ ..~ ~ ~ o ~ 0 ~~ M~x~xNx~x~x~a~x~x x a x x x ~

, N ~ .-n N~ N
~ 00 . .
Vi L --~ Q
i -~
;
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. ..
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M M ~j .
p .-..-n ~ .~ d' O "" M . . \O V1 V1 O O ~ ~ O .~ ~p ~:rj 0 N [v O O O Ol~ Ch V1 .
47 M l0 M V7 ~
~

N O O O OM v0 N M
O O V7 0 N O M O ~ O p O 0 et ~t ~
O N O

~O

x O O O OO N O O
.. ~, N y0 x O a pp C/~ ~ a ~ ~n ~t 0 ~ O
x0 O O O
O
O OO

" x x x0 xx0 xO x o ~
M

W , ~' N.-~ V1 ~ N o0 -.N.r ~ .
, , 00 O~

'C7 m v~ p4. m0 M
~ ~ O
~

y N ~ v~y W .r a d~c7d~ ~ v ~' , , :

a o 0 00 0 0 ce _o .. O ~ O~ ~O
i O M
~

N N ..~N M l~ ~ N
~ ,~

_~ ~~ _~
_~ t=m~.

E-i C7 HC7 t7 d w C7 vwn M

01O~ 01 O~O~ O~ Q~

EI 00\O O OO 0 --n M '-"0 O
N M N

i y 'd- ~ M
O ~ ~ ~o~ ,r, ~~ M

M ~ N NM M .-n '-' "'~ M

~7 O "' N M ~ V1~O l~ 00 Wz bD ~O N N o0 v1I~ .W p : ~

~ O~.r ~O MI~
+ M ~OM l~ 00d' 0~0 M

M ~O 00 .~
V. d.

V ~ ~ ~ ~' ~M ~ ' o o o o , , , o N

I~ 00 O\M M
x ~ ~ ~a a x ~ ~ ~

o d d ~ ~ d x x x xx x x U

o N O

N

O
O

~
O

~. M

N

a' a' M

h cf. d- ~n , O ' . . . , ..-~O J ~ b O
~ h ' o p .-r ~ .-n.-~ rrr"
x T.. ~
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~ ~ o ~x~~~ ~ ~ ~ ~ ~ M
~ a~

_ O .r .--wy. . N ., " O .-,W O .--.
M ' M .-a 00 '._' N
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y0 M O x ~ ~ ~ ~ N x x x ~
p ~

Tj-i O N
o O M
p~

~ 'oo E' ~ ~xo'~'o~,,oa ~ a , ~ ~ d , . , ~
~
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v, N-~; N .-iN N a i i ~ N N ~' '-' '-' r . ., .. .-,r- .- .-r.-aN N<l',-n-nN N
., ' ' ~ .
O

OO O O O ...~p vp N ~ ,~ ~ N ~:,j~ ~p opSrio0000oW o00000 ~y: . ~ ~ ~' '-'"'' a ~

c hh r.,h h h h ~n ~ '., O ...: ~ vy oo ,-.~ ..-,.-,O ..,....-.
ri o ~
.:-. ~

OO d~ O Od 0 O OO~Nx~~~~~ O O~ O~ O O OO O O O
T' o xx . x xp x x ~x x x x O x x xx x Ox x , p x x ~~ p o ~

~ ~ ~
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N NO ~ N M

' ~ ~

~. i ~ ~ t~.to h ' O\
O N
~' E'-~ ~ P, ~' P, Cn rj~ p w p p O O O W p O

.H, .N a~ O

N .-r M ,-, U .--n O o0 ..~ N ~ V '~h' .

~ ~ .-iM M
o ~. ~ ~ ~ ~
o ~ a a w E-~ C7 ~ a., a w -~N M d' vW O h o0 01O .-~N M ~hv~~Oh ooO~O

h o0 00 0000000000000000O~
h~ ~ h ~ U ~ ~ h h h h l~h t~h h hh h O O O~O~ O~ ~ O~O~O~01O~O~01O~
l 1 M O~O l l Md'~ ~ V7 M ~ ~O O p p h 00h N d' M M h .--~ON ~ hO O
N N

~ N ~ i , M i ~ i ~ N M, NM N

00 .--~d' ~ i ~ d' M ~ ip ~ ~v 00M . ~ ~ ~ M
.-~

~ ~ N N N M N O~N N~

h o0 Ov O --~N Md'W Dh o0 N N N N N N N

N N N M M M MM M MM M

O h ~ ~ ~ O ~ ~ "'~~ N M M h-O ~ho000~O
p ' ~100 M h ~ N O~d'O O~O N
0100~ 01 V7 O O '~' 00d' M 01h h M00O~0101O
~ ~ M N ~ ~ 'cth ~ N l~-M ~t1hh 00 O ~O M ' N ~D ~ N N hV'1h NN N
h~Ov~ Y7 Ov o0 OvO ' W O h o0 ~nv lWOOWO v'W o0 O t 0 ~ v7h~D
~

y w inN h p'h oo~h Ov Qd ~ Q ~ ~ ~ d U C7~-~~ >>~>~

UU U U U U U ~

C~P~0.1Pa pa ~ PaPa 0.~ Pa ~ Pa~PaOapaGaGa xx x x x x ~ ~xx xx x x x x x x xx x N

s0 ~p .-i ,-i.-i ~ i i "U p O i -i . .- ,- ~a ~ N a .-o_o ~ ~n ~ ~ ~

M d'~ ~ . ~I~ d' ,-; ~ ,-;
~ p ~ ~ p x x x p p n oo N
oa a o .-. o x x C/~ M ~o x ~

T7 21b .b,.d "d O T3O "d ' O TJ
~ ""' ~
d x ~x ~ x,~ ~
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N N NN -~~N ,-i,~N~ N NN N N NN N ~ M .-m--~ M N ~ ~' .-W' , ~ .~ N
~

cto00000000000nj~:00000000000000000000~ 000000 0000 v0 O o0 ~

~n,-~,-..-r.~.~.~p r,.~.-,,~.~.~.~.-.,.-,.-~.~~n .~.~.~ .-r,~ d' O ,~d' p~ ~ p a N M MM M MM O ,-,MM M MM M M MM M N M MM M M ~ ~ M
~ O M 'b 0 0 00 0 00 o p 00 0 00 0 0 00 0 0 0 00 o 0 0 0 o p ,., a 0 >~

x x xx x xx H ~ xx x xx x x xx x xa x xx~ x x ~x~ x ~

0o v~N

bD
H ~ ~~ ' d ~ ~,~a ~~ c~
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Ov N ' 0 .~ In t ~ ~
a M N I c ~ ,-.~ Nt , ~ I I I IM , I , , ~ ~ ~ ~~" ~, i~r M
~

C7 x N a.. C7 ~, C7~, ad ~
v~ a ~, v~ d a C7 d a N M~ V)~O[~00O~O.~N M~ ~ ~Ot~00O~O .-nNM ti'V~ ~O [~00 O~O~O~O~OvO~O~OvOvOO O OO O O OO O ~ .-~.-~.-, ,-~.-~.-~ ,-i O~O~O~O~Q\01~ 010101O~0101~ O~~ 0101O~O~ O~0101 O~~ O~ O~01 d' ~ I~~ M ~N ~ M ~~ 00(~M d\Q 00o ~ V~ ~~ ~ d' M N M M M O ~~ t 1 O\NO V7V1 V'1 ~ N
M ~ M d' V' .-,I I~,I '~. "'~I '.'"M ~ --~~ N ~' -n , ~ I I II , II I I I ,I I I ~ I I
I p I II I
O ~ ~

N ~~,M ~~ N .~.~M M W d MN ~ ~ f~ o O~

N .-r.-nN N N N M N

01O .-nN M ~tV'1\O(~00OvO .-nN M ~I-~WO I~oo OvO.~ N M ~ vWD

M ~ d'~ Wit''d''Cht1'r1'V''~hV1V7V1V'1v~1nW V1~n V1~O~O ~O~D ~O l~l0 M NO o000W O N ~t~OO ~O~O~nN ooM t~N ~ NO~ ~Dd- ~ .-mn O~O .~O~N ~O~ ~ O O~ M d'M M O No0'd'M O~I~dW ~ OW p v'1N

M O~.~M ~Od'l~O~l~~N 000000O~M I~M o0l~ M o0N M Ov 01 N ~O

l~M[~[~[~.~~DN M'chl~N M~ M ~1 ~Od'O~ M d' N [~00 00N N~ OvNN d'N MV~~ l~O~d M l~~ l~O~ .~l~00 I~M Q\ 0000 I~V7v'1IWO o0tn00V'1v100I~~d'00O~Wp1InI~ IWOV~ O~Qv o0 l~00 ct~M o0pp.~.~O Md'O N..-V~ VlI~M ~Oo0 .~Nv') d'~!1O vDQ1 ~'OvV~d'00~po0~nOWE'-'I~MWit't~O VN M .-,v7NN ~1'l0 OW J N

~ rxxA A ~o rxx az o a,w a H H3 ~ x x dd d d d raw PaGi7~U U UU U U ~~ ~ ~~ ~ ~ q~ ~ ~ G WW W W W W W

~ 0.~~ ~ ~~ ~ ~ Pa0.1C~1Ga0.1CG~ ~~ ~ ~ ~ ~0.l ~ ~ ~ ~ 0.l x ~

x x xx x x x x xx x xx x x xx x x x xx x x x x 2y O M
~ ~ ' c x '~ .~ ..-nN
G

x a x ~ ~ ~ ~ x ~ ~a o x o ~ b "d b b .b-o a a ~ ~ x ~
~

N N .-,N N N .~ N~' ~ .-.~ ca . M N N ,-. N N .~ ,-,N ~ r,N N NN
N N "
.-n .
N

O o_0v~00o_0o_0o_0 o0~ 0000 ~ V1 O V~ l0~ ~_~Oo00000o ~ ~00 ,-i,-,~ ~ O
O
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O M NM M M M M~ M M ~ M ~ N ~_,_ M ~M M M_ N 'ch ~ p p M M
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o 0 00 0 0 0 o0 0 0 o a o 0 , o o 00 ~,. x xx x x ~t x0 a 0 x x ~ ~

~ x x x a x ~ x ~ x x ~x x xx a ~ ~

M
cnv'i ~ O~O d w0 ~ N

.--n i .-w N pp i N
~ ~ ~ -0 O
~

O N ,t~"~ i ~ ~ i ~ ' j~ O
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o ~ ~ w ~ a ~ d E-i U

0 0 0 o r~ d o v~
$ o M ' a.. O O ,~ O
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N N dy d V~ ~D .~ O
M --n~-, ~

,-, .~ .-n .r N

d d a w dd v w" ~
: :

a ia ~ ,.
v, O~O~ N M ~ V1~O I~00 Ov O .-~N M ~hV1~Ol~00O~O
NN N N N NN N N N M

M M M M M MM M Md' Q~O~O\01O~ 01 0101 O~O\ O\ O~ O~O~ Q\p~p~O~O\D\O~O\

h 'd' l~N -~ N ooO ~n~--.op ~ O ~ ~ ~ M M v~~N O t~

N ~d- N O N N o ,~ o N M ~ ~chM M
~ N ~N o ~ N

N ~ n i ~' i i M i i i W' i ~
,~O ~ f~ ~n ~~, vW--~~ Ov ~ ~t ~ t~' Nt~l~~D
N ~!' -. --n M -~ . . N~ O O M ,--n V O v~M l~M V'1 --r .--.--v M ) N

. .-n.~ ~ ~ .~.-n .~,~N

l~00OvO .~ N MdW 1 ~ l~ 00 O~O ~ N M ~vWO t~00 M .~V1.-,O O .~M M 'ch~O M M ~ -al~O\00~Ot!1Oo0 O ~OO~O O~ N Owt I~O ~ V ' 1 d M o0v0l~.-~O .~
N d' Ov ~00 V)00 00 V1 M V~ I~N ~ho000M 0~1N

.-r.-nO~~ M l~' Ml~ ~ M V~ l~ d'l~ M -nO ~M V~M0O
M (~~ t~O~ ~ 01~h ~Ov~ -~ ~

. N 01O t N 01Nl~N l~M
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O ON r,~ ~.,~OW1 M O\ ~ ~O V ~ O\v0tT.~ ~nOvo0 M ~ N.-n ~ ~-,. l~ '-' ~

~ ~ h ~ d O\ O .--~M v7 ~n w x OP, w tx v~ E-~E-~~ N N N U~ ~ aw w ww w w w ww w w w w w w w w w ww w ww ,..~,., ,.

~ ~ , .-~~ ~~ ~ ~~-.
aaw~ aa~ w m a s w w a aa a as w w aaw a~a~ aaaaaa x x x x x x xx x x x x x x x x x xx x xx ~ O O
O

I~ N
Ov d' V _ O ~O

~Y ~n O
o0 l~ N
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O ~ c0 o0 ~ O O

.-, .~ .-yp .~ N .
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O O ~ O
O

~ ~

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o v o lo p N

N

pp r-iri ~'-i ~ ~ ~ ri ri d'r" ~'00 ~ ~ ~ 00 00 ~

v0I W h-~ . ~' .~ .-, ,-, N

N N ~hM ,.., M M

x x xx O~ .~ ~ x x x N N N N NN N NN N .-a~N NN M ~-'N ""
N ~, N N

000000 00000000000000000000 00000000l~ 00 00 ~p V'~Op ~ ~ ~

~--i.--n.~ ~--n.--r.-w.~.-w.~.r.~.~.-.n..-a.-~,~..-ny~ O~ .-.r.-~
'ct' M M M M MM M MM M M MM MM M M'ct rr oo O~
Qp ~ ~
M

0 0 0 0 00 0 00 0 0 00 00 0 00 OO~ OO p~ O O O

x x x x xx x xx x x xx xx x xx xa x~ ~O x x x M vD O .-~ ~-i N o0 O~00~ N p ~ O ~ .~ oo ' ~ N

N N ~O 00 M ~ N ~ ~t .4' ~ I~ ' ' ' s~ 00 N n ~ ~ ~ ' l~ i i i , y v7N > ~ ~i 7, n ~ ~ [~ ~ ~ ,.~ ~ n . , a a "~~ ~ C7 ~ ,~. au , i ~ , ~' ~~ _~ m a~
N

. , .v ai d w ~~~~ ~~ a a ~

0 0 00 0 00 0 0 0 0 ~00000 ~0 0 Do 0 0 N ooO~ ''''r...~. ~' 0 ~pO~'' ~ ~ _ ~
M "

~t ~O ,~p ~ N cy p \p l~ O
.-rN vW~ .~N~h 'ct ~ pp -' N l~ N ' .-~ .-~ .~ vD

cCp ca cCj,~ fy ~ ai b~.--~y0 M N N ~OM
~ ~ t~v~ ~ v~ ' ~ i ~ ~ ~
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~ > ~ .~, ~ ~ ~ H
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w d d ~~ ~ a ~ ~ ~c~~ a ~c a a , , N M ~i'~n~Ol~0001O -~NM 'd'V1~DI~00 01 O .~ N M

d'd'~ '~d'Wit'~ Wit'd'~nv'Wn~n ~nv'1v~~n~n ~n ~O ~O v0v0 v0 01O~O~ O~O101p~p~p~p~01O~O~ G~01O~O~O~ O~ O O~ 0101 01 O o_0N o0 ~D
~ p ' ~O O~ M ~~ 001 ~ VN1V100 M N d' M MO 01 ~ ~ '~'V~ N M .~M V' M V1 'ctN N
M N

r', i i iN ~ i, ~ i i~ ~tN ~ i ~ i i ~ M M d' M ' ~' W ~ ,, ~ Ov O V1' O

.-v .- d'~M N O~ N N N.- .~~ ~~ l~ 01 M O M O
~ -n -n . . ~ .-m --i N .-~ ..-nM

01O .-~N MWit'~1\Ol~0001O'~ NM d'h~O (~ 00 01 O .~ N
OO

ppp~~ ~ ~~ ~ ~~ ~ ~ OO O OO O O O ~

Vll~00 V1V1~--nN ~l~O M V1..-nO~O ~ V)00 l~ M .-n~

Ovd'l~ ~Ou1V100l0'ch~O~ 01T l~M o0O~~O O v0 N N o0 I~l~l~ l~I~M ~OI~M l~00O~ ~DV'1~OO~ V1 O 00 [~I~ O

M.M 00 M M-~~OM~ M O~~h~--WO1~~ 011~ O~ ~t O N M 01 ~nt~(~ I~nI~N t~I~l~N I~l~ NO O~Mu1 .--~ ~O N ~O.-~O~

01~ 00 ~nv~~n~n~v'1~nV'1vWO v1v~t~l~Ov Ov 00 01 ~O~O ~D

p~O QvOO ~no000~ .r,O,_, pvpN ON N O o0 I~N N

O v'7~' ~'N~n~WOt~V~00d'N ~Y~no0~I~ O~ l~ l~ -'N M
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LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

~~ TTENANT LES PAGES 1 A 274 NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims (24)

What Is Claimed Is:

1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a polynucleotide fragment of SEQ ID NO:X or a polynucleotide fragment of the cDNA sequence contained in Clone ID NO:Z, which is hybridizable to SEQ ID
NO:X;
(b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(c) a polynucleotide encoding a polypeptide fragment of a polypeptide encoded by SEQ ID NO:X or a polypeptide fragment encoded by the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X;
(d) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y or a polypeptide domain encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(e) a polynucleotide encoding a polypeptide epitope of SEQ ID NO:Y or a polypeptide epitope encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(f) a polynucleotide encoding a polypeptide of SEQ ID NO:Y or the cDNA
sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X, having biological activity;
(g) a polynucleotide which is a variant of SEQ ID NO:X;
(h) a polynucleotide which is an allelic variant of SEQ ID NO:X;
(i) a polynucleotide which encodes a species homologue of the SEQ ID NO:Y;
(j) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(i), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A
residues or of only T residues.

2. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a protein.

3. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID NO:Y
or the polypeptide encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X.

4. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID NO:X or the cDNA
sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X.

5. The isolated nucleic acid molecule of claim 2, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

6. The isolated nucleic acid molecule of claim 3, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

7. A recombinant vector comprising the isolated nucleic acid molecule of claim 1.

8. A method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim 1.

9. A recombinant host cell produced by the method of claim 8.

10. The recombinant host cell of claim 9 comprising vector sequences.

11. An isolated polypeptide comprising an amino acid sequence at least 90%
identical to a sequence selected from the group consisting of:
(a) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(b) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z, having biological activity;

(c) a polypeptide domain of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(d) a polypeptide epitope of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(e) a full length protein of SEQ ID NO:Y or the encoded sequence contained in cDNA
Clone ID NO:Z;
(f) a variant of SEQ ID NO:Y;
(g) an allelic variant of SEQ ID NO:Y; or (h) a species homologue of the SEQ ID NO:Y.

12. The isolated polypeptide of claim 11, wherein the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.

13. An isolated antibody that binds specifically to the isolated polypeptide of claim 11.

14. A recombinant host cell that expresses the isolated polypeptide of claim 11.

15. A method of making an isolated polypeptide comprising:
(a) culturing the recombinant host cell of claim 14 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.

16. The polypeptide produced by claim 15.

17. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polynucleotide of claim 1.

18. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or absence of a mutation in the polynucleotide of claim 1; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.

19. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or amount of expression of the polypeptide of claim 11 in a biological sample; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of the polypeptide.

20. A method for identifying a binding partner to the polypeptide of claim 11 comprising:
(a) contacting the polypeptide of claim 11 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.

21. The gene corresponding to the cDNA sequence of SEQ ID NO:Y.

22. A method of identifying an activity in a biological assay, wherein the method comprises:
(a) expressing SEQ ID NO:X in a cell;
(b) isolating the supernatant;
(c) detecting an activity in a biological assay; and (d) identifying the protein in the supernatant having the activity.

23. The product produced by the method of claim 20.

24. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim 11.