EP1261742A2 - Acides nucleiques, proteines et anticorps - Google Patents

Acides nucleiques, proteines et anticorps

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Publication number
EP1261742A2
EP1261742A2 EP01916069A EP01916069A EP1261742A2 EP 1261742 A2 EP1261742 A2 EP 1261742A2 EP 01916069 A EP01916069 A EP 01916069A EP 01916069 A EP01916069 A EP 01916069A EP 1261742 A2 EP1261742 A2 EP 1261742A2
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EP
European Patent Office
Prior art keywords
seq
polypeptide
sequence
polynucleotides
polynucleotide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP01916069A
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German (de)
English (en)
Inventor
Craig A. Rosen
Steven C. Barash
Steven M. Ruben
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Human Genome Sciences Inc
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Human Genome Sciences Inc
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Publication date
Application filed by Human Genome Sciences Inc filed Critical Human Genome Sciences Inc
Priority claimed from PCT/US2001/001354 external-priority patent/WO2001057182A2/fr
Publication of EP1261742A2 publication Critical patent/EP1261742A2/fr
Withdrawn legal-status Critical Current

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Definitions

  • 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/h ⁇ atopoietic 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.
  • 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.
  • vectors, host cells, and recombinant and synthetic methods for producing human immune/hematopoietic polynucleotides, polypeptides, and/or antibodies are provided.
  • 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.
  • 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.
  • hematopoiesis 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".
  • interleukin-3 IL-3
  • GM-CSF granulocyte macrophage colony stimulationg factor
  • SCF Stem cell factor
  • 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.
  • 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 .
  • 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.
  • T cells undergo a process of positive selection in which T cells are selected for their ability to interact with the major histocompatibility antigens.
  • T cells 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.
  • Th CD4+ T helper
  • lymph nodes 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 e.g., dendritic cells, macrophages, B cells
  • APCs e.g., dendritic cells, macrophages, B 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.
  • 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.
  • 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
  • the cells of the acquired immune system B and T cells
  • 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.
  • 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.
  • Fc receptors for a more extensive review of the immune system, see Fundamental Immunology , 4th edition, ed. William Paul, Lippincott- Raven Pub. (1998).
  • an immune response is seldom carried out by a single cell type, but rather requires the coordinated efforts of several cell types.
  • 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.
  • Immunomodulators 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.
  • immunomodulators also known as biological response modifiers
  • 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 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 Molecular Immunology by Abbas et al. (1991 .
  • 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.
  • 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 Thl 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.
  • 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.
  • organ-specific autoimmune disorders such as Crohn's disease, sarcoidosis, acute kidney allograft rejection, some unexplained recurrent abortions.
  • Thl and Th2 subsets see Romagnani, Ann. Allergy Asthma Immunol. 85:9-18 (2000).
  • 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.
  • 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 immunomodulators Intracellular immunomodulators.
  • Immunomodulatory proteins are not only cytokines or cytokine receptors.
  • intracellular immunomodulatory proteins 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.
  • NF-AT Nuclear Factor of Activated T cells
  • the immunophilin:drug complexes are able to inhibit clonal expansion of T cells by inhibiting IL-2 synthesis.
  • 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.
  • 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.
  • 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.
  • 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.
  • vectors, host cells, and recombinant and synthetic methods for producing human immune/hematopoietic polynucleotides, polypeptides, and/or antibodies are provided.
  • the invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the 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.
  • 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
  • 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,
  • ORFs SEQ ID NO:Y. Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4:181-186
  • 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.
  • 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 33 P 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.
  • PSL Phosphor Stimulating Luminescence
  • an OMIM identification number is provided in Table 1A, column 9 labeled "OMIM Disease Reference(s)".
  • OMIM Disease Reference(s) A key to the OMIM reference identification numbers is provided in Table 5.
  • Table IB 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 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).
  • 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 1A.
  • 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 1 A.
  • the third column provides the sequence identifier, "SEQ ID NO:X”, for the contig polynucleotide sequences.
  • the fourth column provides the analysis method by which the homology/identity disclosed in the row was determined.
  • NR non-redundant protein database
  • PFAM protein families
  • 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.
  • 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 1 A.
  • the third column provides the unique contig identifier, "Contig ID”, for contigs disclosed in Table 1 A.
  • 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.
  • 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.
  • preferably excluded from the polynucleotides of the invention are at least one, two, three, four, five, ten, or more of the polynucleotide sequence(s) having the accession number(s) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone).
  • preferably excluded from the invention are the specific polynucleotide sequence(s) 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).
  • Table 4 provides a key to the tissue/cell source identifier code disclosed in
  • 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.
  • tissue/cell source is a library
  • column 7 identifies the vector used to generate the library.
  • 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. 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/).
  • Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 8, as determined from the Morbid Map database.
  • Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application.
  • Table 7 shows the cDNA libraries sequenced, tissue source description, vector information and ATCC designation numbers relating to these cDNA libraries.
  • Table 8 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.
  • 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.
  • 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.
  • 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.
  • 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 1 A) or the complement thereof, a cDNA sequence contained in Clone ID NO:Z (as described in column 1 of Table 1 A 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 IB or a fragment or variant thereof; or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table IB or the complement thereof.
  • 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.
  • 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).
  • 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 IB, or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table IB 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
  • 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 1 A column 7 and Table 4).
  • hematopoietic tissues e.g., bone marrow, fetal liver, and fetal spleen
  • 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
  • normal or diseased tissues as shown in Table 1 A column 7 and Table 4
  • 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.
  • HGS Human Genome Sciences, Inc.
  • each clone is identified by a cDNA Clone ID (identifier generally referred to herein as Clone ID NO:Z).
  • Clone ID NO:Z 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.
  • ATCC American Type Culture Collection
  • 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".
  • Table 1A correlates the Clone ID NO:Z names with SEQ ID NO:X.
  • SEQ ID NO:X the Clone ID NO:Z names with SEQ ID NO:X.
  • 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.
  • 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 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.
  • 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.
  • 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).
  • 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).
  • 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 IB or the complement thereof.
  • “Stringent hybridization conditions” refers to an overnight incubation at 42 degree C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x 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.
  • 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.
  • washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X SSC).
  • 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.
  • 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).
  • 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.
  • 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.
  • polynucleotide can be composed of triple- stranded 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.
  • 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.
  • 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.
  • SEQ ID NO:X refers to a polynucleotide sequence described, for example, in
  • 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.
  • 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).
  • 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.
  • the first column in Table 1 A provides a unique "Clone ID NO:Z" for a cDNA clone related to each contig sequence disclosed in Table 1A.
  • This clone ID references the cDNA clone which contains at least the 5' most sequence of the assembled contig and at least a portion of SEQ ID NO:X was determined by directly sequencing the referenced clone.
  • the reference clone may have more sequence than described in the sequence listing or the clone may have less. In the vast majority of cases, however, the clone is believed to encode a full-length polypeptide. In the case where a clone is not full-length, a full-length cDNA can be obtained by methods known in the art and/or as described elsewhere herein.
  • the second column in Table 1A provides a unique "Contig ID” identification for each contig sequence.
  • the third column provides the "SEQ ID NO:X” identifier for each of the immune/hematopoietic associated 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 "SEQ ID NO:X” that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A, column 5, as SEQ ID NO:Y. Where the nucleotide position number "To" is lower than the nucleotide position number "From”, the preferred ORF is the reverse complement of the referenced polynucleotide sequence.
  • the fifth column in Table 1A provides the corresponding SEQ ID NO:Y for the polypeptide sequence encoded by the preferred ORF delineated in column 4.
  • the invention provides an amino acid sequence comprising, or alternatively consisting of, a polypeptide encoded by the portion of SEQ ID NO:X delineated by "ORF (From-To)". Also provided are polynucleotides encoding such amino acid sequences and the complementary strand thereto.
  • polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, five or more of the predicted epitopes as described in Table 1A.
  • Table 1A provides an expression profile and library code: count for each of the contig sequences (SEQ ID NO:X) disclosed in Table 1 A, which can routinely be combined with the information provided in Table 4 and used to determine the normal or diseased tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention.
  • the first number in column 7 represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4.
  • the second number in column 7 represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the tissue/cell source.
  • 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 33 P dCTP, using oligo(dT) to prime reverse transcription.
  • Column 8 in Table 1A provides a chromosomal map location for certain polynucleotides of the invention. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a "cluster"; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequence(s) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.

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  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne de nouveaux polynucléotides à association immunitaire/hématopoïétique et les polypeptides codés par ces polynucléotides, ici collectivement désignés comme « antigènes immunitaires/hématopoïétiques », ainsi que l'utilisation de ces antigènes immunitaires/hématopoïétiques dans la détection de maladies et/ou troubles à association immunitaire/hématopoïétique, notamment la présence de cancer et de métastases cancéreuses de cellules d'origine hématopoïétique. Cette invention concerne plus spécifiquement des molécules d'acide nucléique à association immunitaire/hématopoïétique isolées, qui codent les nouveaux polypeptides à association immunitaire/hématopoïétique. La présente invention concerne également de nouveaux polypeptides et anticorps immunitaires/hématopoïétiques qui se lient à ces polypeptides. La présente invention concerne également des vecteurs, des cellules hôtes, ainsi que des procédés de recombinaison et de synthèse permettant de produire des polynucléotides et/ou polypeptides à association immunitaire/hématopoïétique humains. La présente invention concerne également des procédés diagnostiques et thérapeutiques permettant de diagnostiquer, de traiter, de prévenir et/ou de pronostiquer des troubles associés au système ou aux cellules immunitaires et des tissus associés à l'hématopoïèse, comprenant des cancers de cellules d'origine hématopoïétique, ainsi que des procédés thérapeutiques permettant de traiter de tels troubles. La présente invention concerne également des procédés de criblage permettant d'identifier des agonistes et des antagonistes des polynucléotides et polypeptides selon cette invention. En outre, cette invention concerne des procédés et/ou des compositions permettant d'inhiber la production et le fonctionnement des polypeptides selon cette invention.
EP01916069A 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps Withdrawn EP1261742A2 (fr)

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PCT/US2001/001354 WO2001057182A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps

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