EP1203024A1 - Recepteurs du facteur de necrose des tumeurs humain tr13 et tr14 - Google Patents

Recepteurs du facteur de necrose des tumeurs humain tr13 et tr14

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Publication number
EP1203024A1
EP1203024A1 EP00947411A EP00947411A EP1203024A1 EP 1203024 A1 EP1203024 A1 EP 1203024A1 EP 00947411 A EP00947411 A EP 00947411A EP 00947411 A EP00947411 A EP 00947411A EP 1203024 A1 EP1203024 A1 EP 1203024A1
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EP
European Patent Office
Prior art keywords
seq
polypeptide
amino acid
nucleotide sequence
nucleic acid
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.)
Withdrawn
Application number
EP00947411A
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German (de)
English (en)
Other versions
EP1203024A4 (fr
Inventor
Steven M. Ruben
Jian Ni
Paul E. Young
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Human Genome Sciences Inc
Original Assignee
Human Genome Sciences Inc
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Publication of EP1203024A1 publication Critical patent/EP1203024A1/fr
Publication of EP1203024A4 publication Critical patent/EP1203024A4/fr
Withdrawn legal-status Critical Current

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    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
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Definitions

  • the present invention relates to two novel members of the tumor necrosis factor family of receptors. More specifically, isolated nucleic acid molecules are provided encoding the novel human tumor necrosis factor receptors, TR13 and TR14. TR13 and TR14 polypeptides are also provided, as are vectors, host cells, and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of TR13 and/or TR14 activity.
  • cytokines Many biological actions, for instance, response to certain stimuli and natural biological processes, are controlled by factors, such as cytokines. Many cytokines act through receptors by engaging the receptor and producing an intra-cellular response.
  • tumor necrosis factors (TNF) alpha and beta are cytokines, which act through TNF receptors to regulate numerous biological processes, including protection against infection and induction of shock and inflammatory disease.
  • the TNF molecules belong to the "TNF-ligand” superfamily, and act together with their receptors or counter-ligands, the "TNF- receptor” superfamily. So far, nine members of the TNF ligand superfamily have been identified and ten members of the TNF-receptor superfamily have been characterized.
  • TNF- ⁇ lymphotoxin- ⁇
  • LT- ⁇ lymphotoxin- ⁇
  • TNF- ⁇ TNF- ⁇
  • LT- ⁇ found in complex heterotrimer LT-2- ⁇
  • FasL CD40L
  • CD27L CD30L
  • 4- IBBL IBBL
  • OX40L nerve growth factor
  • NGF nerve growth factor
  • the superfamily of TNF receptors includes the p55TNF receptor, p75TNF receptor, TNF receptor-related protein, FAS antigen or APO-1, CD40, CD27, CD30, 4-1BB, OX40, low affinity p75 and NGF-receptor (A. Meager, Biologicals 22:291-295 (1994)).
  • TNF-ligand superfamily Many members of the TNF-ligand superfamily are expressed by activated T-cells, implying that they are necessary for T-cell interactions with other cell types which underlie cell ontogeny and functions. (A. Meager, supra).
  • Considerable insight into the essential functions of several members of the TNF receptor family has been gained from the identification and creation of mutants that abolish the expression of these proteins.
  • naturally occurring mutations in the FAS antigen and its ligand cause lymphoproliferative disease (R. Watanabe-Fukunaga et al., Nature 356:314 (1992)), perhaps reflecting a failure of programmed cell death.
  • Mutations of the CD40 ligand cause an X-linked immunodeficiency state characterized by high levels of immunoglobulin M and low levels of immunoglobulin G in plasma, indicating faulty T-cell-dependent B-cell activation (R.C. Allen et al., Science 259:990 (1993)).
  • Targeted mutations of the low affinity nerve growth factor receptor cause a disorder characterized by faulty sensory innovation of peripheral structures (K.F. Lee et al., Cell 69:137 (1992)).
  • TNF- ⁇ and LT- ⁇ are capable of binding to two TNF receptors (the 55- and 75-kd TNF receptors).
  • TNF- ⁇ and LT- ⁇ are involved in the pathogenesis of a wide range of diseases, including endotoxic shock, cerebral malaria, tumors, autoimmune disease, AIDS and graft-host rejection (B. Beutler and C. Von Huffel, Science 264:661-668 (1994)). Mutations in the p55 receptor cause increased susceptibility to microbial infection. Moreover, an about 80 amino acid domain near the C-terminus of TNFR1 (p55) and
  • Fas was reported as the "death domain,” which is responsible for transducing signals for programmed cell death (Tartaglia et al., Cell 74:845 (1993)).
  • Apoptosis or programmed cell death, is a physiologic process essential to the normal development and homeostasis of multicellular organisms (H. whilr, Science 267:1445-1449 (1995)). Derangements of apoptosis contribute to the pathogenesis of several human diseases including cancer, neurodegenerative disorders, and acquired immune deficiency syndrome (C.B. Thompson, Science 267: 1456-1462 (1995)). Recently, much attention has focused on the signal transduction and biological function of two cell surface death receptors, Fas/APO-1 and TNFR-1 (J.L. Cleveland et al., Cell 81:479-482 (1995); A. Fraser et al., Cell 85:781-784 (1996); S.
  • Fas/APO-1 and TNFR-1 While family members are defined by the presence of cysteine-rich repeats in their extracellular domains, Fas/APO-1 and TNFR-1 also share a region of intracellular homology, appropriately designated the "death domain," which is distantly related to the Drosophila suicide gene, reaper (P. Golstein et al., Cell 81: 185-6 (1995); K. White et al., Science 264:677-83 (1994)). This shared death domain suggests that both receptors interact with a related set of signal transducing molecules that, until recently, remained unidentified. Activation of Fas/APO-1 recruits the death domain-containing adapter molecule FADD/MORT1 (A.M.
  • TNFR-1 can signal an array of diverse biological activities-many of which stem from its ability to activate NF-kB (L.A. Tartaglia et al, Immunol Today 73:151-153 (1992)). Accordingly, TNFR-1 recruits the multivalent adapter molecule TRADD, which like FADD, also contains a death domain (H. Hsu et al., Cell 57:495-504 (1995); H. Hsu et al, Cell 84:299-308 (1996)). Through its associations with a number of signaling molecules including FADD, TRAF2, and RIP, TRADD can signal both apoptosis and NF-kB activation(H. Hsu et al, Cell 54:299-308 (1996); H. Hsu et al, Immunity 4:381-396 (1996)).
  • TRAIL acts independently from the FAS ligand (S.R. Wiley et al., supra). It has also been shown that TRAIL activates apoptosis rapidly, within a time frame that is similar to death signaling by Fas/Apo-IL, but much faster than TNF-induced apoptosis. S.A. Marsters et al., Current Biology 6:150-152 (1996). The inability of TRAIL to bind TNFR-1 , Fas, or the recently identified DR3, suggests that TRAIL may interact with a unique receptor(s).
  • TNF family ligands and receptors are varied and influence numerous functions, both normal and abnormal, in the biological processes of the mammalian system. There is a clear need, therefore, for identification and characterization of such receptors and ligands that influence biological activity, both normally and in disease states. In particular, there is a need to isolate and characterize additional novel receptors that bind TRAIL.
  • the present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding the TR13 receptor having the amino acid sequence shown in SEQ ID NO:2 ( Figures 1A-C), amino acid sequence shown in SEQ ID NO:40 ( Figures 7A-D) or the amino acid sequence encoded by the cDNA clone deposited as American Type Culture Collection (“ATCC”) Deposit No. PTA-349 (HWLHM70) on July 13, 1999, and/or the amino acid sequence encoded by the cDNA clone deposited as American Type Culture Collection (“ATCC”) Deposit No. PTA-507 (HWLHN83) on August 12, 1999.
  • the ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209.
  • TR13 receptor polynucleotides and polypeptides would apply equally to all variants and fragments thereof (e.g., fragments of the TR13 receptor disclosed and described herein in Figures 1A-C, Figure 7A-D, SEQ ID NO: l, SEQ ID NO:2, SEQ ID NO:39, SEQ ID NO:40 and/or contained or encoded by one or both of the deposited cDNA clones HWLHM70 and HWLHN83).
  • the present invention also relates to recombinant vectors, which include the isolated nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells and for using them for production of TR13 polypeptides (e.g., the TR13 polypeptide sequence shown in Figures 1A- C and/or Figures 7A-D, or a fragment thereof) by recombinant techniques.
  • TR13 polypeptides e.g., the TR13 polypeptide sequence shown in Figures 1A- C and/or Figures 7A-D, or a fragment thereof
  • the invention further provides an isolated TR13 polypeptide (e.g., the TR13 polypeptide sequence shown in Figures 1A-C and/or Figures 7A-D or fragments thereof) having an amino acid sequence encoded by a polynucleotide described herein (e.g., the polynucleotide sequence shown in SEQ ID NO:l and/or SEQ ID NO:39, or a fragment thereof).
  • a polynucleotide described herein e.g., the polynucleotide sequence shown in SEQ ID NO:l and/or SEQ ID NO:39, or a fragment thereof.
  • the present invention also provides diagnostic assays such as quantitative and diagnostic assays for detecting levels of TR13 polynucleotide and/or protein (e.g., the TR13 protein shown in Figures 1A-C and/or Figures 7A-D, or fragments thereof).
  • diagnostic assays such as quantitative and diagnostic assays for detecting levels of TR13 polynucleotide and/or protein (e.g., the TR13 protein shown in Figures 1A-C and/or Figures 7A-D, or fragments thereof).
  • a diagnostic assay in accordance with the invention for detecting over-expression of TR13, or soluble form thereof, compared to normal control tissue samples may be used to detect the presence of tumors.
  • the present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding the TR14 receptor having the amino acid sequence shown in SEQ ID NO:61 ( Figures 10A-H), and/or the amino acid sequence encoded by the cDNA clone deposited as American Type Culture Collection ("ATCC") Deposit No. PTA-348 (HMSHK47) on July 13, 1999. While the sequence of SEQ ID NO:61 and Figures 10A-H are preferred embodiments of TR14 receptor protein, the present invention provides alternative isolated nucleic acid molecule embodiments comprising a polynucleotide encoding the TR14 receptor having the amino acid sequence shown in SEQ ID NO:5 ( Figures 4A-D).
  • sequence of amino acid residues T-78 to M-231 of SEQ ID NO:61 is identical to the sequence of amino acid residues T-73 to M-226 of SEQ ID NO:5. It would be apparent to the skilled artisan that the various methods of use, including, but not limited to, diagnostic and therapeutic uses described herein, for the TR13 receptor polynucleotides and polypeptides would apply equally to all variants and fragments thereof (e.g., fragments of the TR14 receptor disclosed and described in
  • SEQ ID NO:4 SEQ ID NO:5 and/or contained or encoded by the deposited cDNA clone (HMSHK47)).
  • the present invention also relates to recombinant vectors, which include the isolated nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells and for using them for production of TR14 polypeptides by recombinant techniques.
  • the invention further provides an isolated TR14 polypeptide (e.g., the TR14 polypeptide sequence shown in Figures 10A-H or, alternatively, Figures 4A-D, or fragments thereof) having an amino acid sequence encoded by a polynucleotide described herein (e.g., the polynucleotide sequence shown in SEQ ID NO:60, or, alternatively SEQ ID NO:4, or fragments thereof).
  • a polynucleotide described herein e.g., the polynucleotide sequence shown in SEQ ID NO:60, or, alternatively SEQ ID NO:4, or fragments thereof.
  • the present invention also provides diagnostic assays such as quantitative and diagnostic assays for detecting levels of TR14 polynucleotide and/or protein (e.g., the TR14 polypeptide sequence disclosed in Figures 10A-H or 4A-D, or fragments thereof).
  • diagnostic assays such as quantitative and diagnostic assays for detecting levels of TR14 polynucleotide and/or protein (e.g., the TR14 polypeptide sequence disclosed in Figures 10A-H or 4A-D, or fragments thereof).
  • a diagnostic assay in accordance with the invention for detecting over-expression of TR14, or soluble form thereof, compared to normal control tissue samples may be used to detect the presence of tumors.
  • Tumor Necrosis Factor (TNF) family ligands are known to be among the most pleiotropic cytokines, inducing a large number of cellular responses, including cell proliferation, cytotoxicity, anti-viral activity, immunoregulatory activities, hematopoiesis, and the transcriptional regulation of several genes.
  • Cellular response to TNF-family ligands include not only normal physiological responses, but also diseases associated with increased apoptosis or the inhibition of apoptosis.
  • Apoptosis-programmed cell death is a physiological mechanism involved in the deletion of peripheral T lymphocytes of the immune system, and its dysregulation can lead to a number of different pathogenic processes.
  • Diseases associated with increased cell survival, unregulated cell proliferation, or the inhibition of apoptosis include cancers, autoimmune disorders, viral infections, inflammation, graft vs. host disease, acute graft rejection, and chronic graft rejection.
  • Diseases associated with increased apoptosis include AIDS, neurodegenerative disorders, myelodysplastic syndromes, ischemic injury, toxin-induced liver disease, septic shock, cachexia, and anorexia.
  • the invention further provides a method for inhibiting TR13 mediated signaling and/or apoptosis induced by a TNF-family ligand, which involves administering to a cell which expresses the TR13 polypeptide (i.e., the TR13 polypeptide shown in Figures 1A-C and/or Figures 7A-D, or a fragment thereof) an effective amount of a TR13 antagonist capable of decreasing TR 13 mediated apoptosis and/or decreasing TR13 mediated signaling.
  • TR13 mediated signaling is decreased to treat a disease wherein increased apoptosis is exhibited.
  • the invention further provides a method for promoting TR13 mediated signalling and/or apoptosis induced by a TNF-family ligand, which involves administering to a cell which expresses the TR13 polypeptide (e.g., the TR13 polypeptide shown in Figures 1A-C and/or Figures 7A-D, or a fragment thereof) an effective amount of a TR13 agonist capable of increasing TR13 mediated apoptosis and/or increasing TR13 mediated signaling.
  • TR13 mediated signaling is increased to treat a disease wherein decreased apoptosis is exhibited.
  • the invention further provides a method for inhibiting TR14 mediated signaling and/or apoptosis induced by a TNF-family ligand, which involves administering to a cell which expresses the TR14 polypeptide an effective amount of a TR14 antagonist capable of decreasing TR14 mediated apoptosis and/or capable of decreasing TR14 mediated signaling.
  • TR14 mediated signaling is decreased to treat a disease wherein increased apoptosis is exhibited.
  • the invention further provides a method for promoting TR14 mediated signaling and/or apoptosis induced by a TNF-family ligand, which involves administering to a cell which expresses the TR14 polypeptide an effective amount of a TR14 agonist capable of increasing TR14 mediated apoptosis and/or capable of increasing TR14 mediated signaling.
  • TR14 mediated signaling is increased to treat a disease wherein decreased apoptosis is exhibited.
  • the present invention is directed to a method for enhancing TR13 mediated signaling induced by a TNF-family ligand (e.g., APRIL and Neutrokine-alpha (International Application Publication No.
  • TR13 mediated activity is increased to treat a disease wherein decreased apoptosis is exhibited.
  • candidate "agonist” or “antagonist” of the present invention can enhance or inhibit TR13 mediated signaling can be determined using art-known TNF-family ligand/receptor cellular response assays, including those described in more detail below.
  • a screening method for determining whether a candidate agonist or antagonist is capable of enhancing or inhibiting a cellular response to a TR13 TNF-family ligand.
  • the method involves contacting cells which express the TR13 polypeptide (e.g., the polypeptide shown in Figures 1A-C and/or Figures 7A-D, or a fragment thereof) with a candidate compound and a TNF-family ligand (e.g., Neutrokine-alpha or APRIL), assaying a cellular response, and comparing the cellular response to a standard cellular response, the standard being assayed when contact is made with the ligand in absence of the candidate compound, whereby an increased cellular response over the standard indicates that the candidate compound is an agonist of the ligand/receptor signaling pathway and a decreased cellular response compared to the standard indicates that the candidate compound is an antagonist of the ligand/receptor signaling pathway.
  • TR13 polypeptide e.g., the polypeptide shown
  • a cell expressing a TR13 polypeptide (e.g., the polypeptide shown in Figures 1A-C and/or Figures 7A-D, or a fragment thereof) can be contacted with either an endogenous or exogenously administered TNF-family ligand.
  • the present invention is directed to a method for enhancing apoptosis TR14 mediated signaling induced by a TNF-family ligand, which involves administering to a cell which expresses the TR14 polypeptide (e.g., the polypeptide shown in Figures 10A-H, or, alternatively 4A-D, or a fragment thereof) an effective amount of an agonist capable of increasing TR14 mediated activity.
  • TR14 mediated activity is increased to treat a disease wherein decreased apoptosis is exhibited.
  • TR14 polynucleotides and polypeptides stimulate epithelial cell proliferation and/or development to ameliorate the diseases and disorders described in this section.
  • Members of the TNF family of proteins are known to signal through the NF- ⁇ B singaling pathway.
  • NF- ⁇ B is a transcription factor activated by a wide certain agents to stimulate cell activation and differentiation. It is believed that the TR14 receptor of the instant invention signals through the NF- ⁇ B pathway to activate proliferation and development of cells.
  • TR14 polynucleotides and polypeptides of the invention as well as antibodies and peptides that agonize TR14 may be used in accordance with the invention to stimulate NF- ⁇ B-mediated epithelial cell proliferation, including but not limited to ectodermal dysplasia.
  • Whether any candidate "agonist” or “antagonist” of the present invention can enhance or inhibit TR14 mediated signaling can be determined using art-known TR14 TNF-family ligand/receptor cellular response assays, including those described in more detail below.
  • a screening method is provided for determining whether a candidate agonist or antagonist is capable of enhancing or inhibiting a cellular response to a TNF-family ligand.
  • the method involves contacting cells which express the TR14 polypeptide with a candidate compound and a TNF-family ligand, assaying a cellular response, and comparing the cellular response to a standard cellular response, the standard being assayed when contact is made with the ligand in absence of the candidate compound, whereby an increased cellular response over the standard indicates that the candidate compound is an agonist of the ligand/receptor signaling pathway and a decreased cellular response compared to the standard indicates that the candidate compound is an antagonist of the ligand/receptor signaling pathway.
  • a cell expressing the TR14 polypeptide e.g., the polypeptide shown in Figures 10A-H, or, alternatively 4A-D
  • a cell expressing the TR14 polypeptide can be contacted with either an endogenous or exogenously administered TNF-family ligand.
  • Figures 1A-C shows the nucleotide (SEQ ID NO: l) and deduced amino acid sequence
  • amino acids from about 105 to about 170, about 251 to about 265, about 331 to about 410, and about 580 to about 610 constitute the cysteine-rich domains (amino acid residues from about 105 to about 170, about 251 to about 265, about 331 to about 410, and about 580 to about 610 in SEQ ID NO:2) and are represented by the underlined amino acid regions; amino acids from about 139 to about 142, about 140 to about 143, about 153 to about 156, about 293 to about 296, about 325 to about 328, about 421 to about 424, about 466 to about 469, about 696 to about 699, and about 728 to about 731 constitute potential sites of N-glycosylation (amino acid residues from about 139 to about 142, about 140 to about 143, about 153 to about 156, about 293 to about 296, about 325 to about 328, about 421 to about 424, about 728 to about 731 constitute potential sites of N-glycosy
  • Figures 2A-C show the regions of similarity between the amino acid sequences of the TR13 receptor protein (SEQ ID NO:2), and the OX40 protein (SEQ ID NO:3).
  • Figure 3 shows an analysis of the TR13 amino acid sequence (SEQ ID NO:2). Alpha, beta, turn and coil regions; hydrophilicity and hydrophobicity; amphipathic regions; flexible regions; antigenic index and surface probability are shown.
  • amino acid residues from about Ml to about A9, about K12 to about L20, about N47 to about T55, about H58 to about S66, about D63 to about S71 , about P77 to about F85, about A90 to about Q98, about F136 to about Q144, about S152 to about C160, about R159 to about A 167, about A211 to about M219, about M235 to about V243, about V266 to about V274, about W277 to about S285, about 1290 to about F298, about A310 to about V318, about E343 to about C351 , about 1360 to about H368, about G391 to about 1399, about F409 to about T417, about S436 to about Y
  • Figures 4A-D shows the nucleotide (SEQ ID NO:4) and deduced amino acid sequence (SEQ ID NO:5) of the TR14 receptor.
  • the predicted extracellular domain constitutes amino acids from about 1 to about 133 (amino acid residues from 1 to 133 of SEQ ID NO:5) and are represented by the underlined amino acids; amino acids from about 65 to about 85 constitute a conserved cysteine-rich domain (amino acid residues from about 65 to about 85 of SEQ ID NO:5) and is represented by the italized amino acid residues; amino acids from about 134 to about 150 constitute the predicted transmembrane domain (amino acid residues from about 134 to about 150 in SEQ ID NO:5) which are represented by the double underlined amino acid residues; amino acid residues from about 151 to about 226 constitutes the predicted intracellular domain (amino acid residues from about 151 to about 226 of SEQ ID NO:5) and are represented by the lower case amino acid residues; amino acids from about 178 to about
  • Figures 5A-B show the regions of similarity between the amino acid sequences of the TR14 receptor protein (SEQ ID NO:5), and the Tumor Necrosis Factor Receptor protein (SEQ ID NO:6).
  • Figure 6 shows an analysis of the TR14 amino acid sequence (SEQ ID NO:5). Alpha, beta, turn and coil regions; hydrophilicity and hydrophobicity; amphipathic regions; flexible regions; antigenic index and surface probability are shown.
  • amino acid residues from about T3 to about S 11 , from about V 16 to about R24, from about Q44 to about M52, from about F85 to about G93, from about T 103 to about V 111 , from about F161 to about G169, from about V187 to about A195, from about P218 to about M226 of SEQ ID NO:5 (Figures 4A-D) correspond to the highly antigenic regions of the TR14 protein, predicted using the Jameson- Wolf antigenic index (See Figure 6 and Table II). These highly antigenic fragments correspond to the amino acid residues illustrated in Figures 4A-D and in SEQ ID NO:5.
  • Figures 7A-D shows the nucleotide (SEQ ID NO:39) and deduced amino acid sequence (SEQ ID NO:40) of the full-length TR13 receptor.
  • the predicted signal sequence constitutes amino acids from about 1 to about 41 (amino acid residues from about 1 to about 41 of SEQ ID NO:40) and are represented by the dotted underlined amino acids; amino acids from about 42 to about 906 constitutes the predicted extracellular domain (amino acid residues from 42 to 906 of SEQ ID NO:40) and are represented by the single underlined amino acids; amino acids from about 271 to about 421 and from about 585 to about 595 constitute conserved cysteine-rich domains (amino acid residues from about 271 to about 421 and from about 585 to about 595 of SEQ ID NO:40) and is represented by the italized amino acid residues; amino acids from about 907 to about 931 constitute the predicted transmembrane domain (amino acid residues from about 907 to about 931 in SEQ
  • Figures 8A-B show the regions of similarity between the amino acid sequences of the full-length TR13 receptor protein (SEQ ID NO:40), and the Tumor Necrosis Factor Receptor II homolog (gblAAB94382.1) (SEQ ID NO: 41).
  • Figure 9 shows an analysis of the full-length TR13 amino acid sequence disclosed in Figures 7A-D (SEQ ID NO:40).
  • Alpha, beta, turn and coil regions; hydrophilicity and hydrophobicity; amphipathic regions; flexible regions; antigenic index and surface probability are shown.
  • Figures 10A-H show a preferred nucleotide (SEQ ID NO:60) and deduced amino acid sequence (SEQ ID NO:61) of the TR14 receptor.
  • SEQ ID NO:60 a preferred nucleotide
  • SEQ ID NO:61 deduced amino acid sequence
  • Figure 11 shows an analysis of the full-length TR14 amino acid sequence disclosed in Figures 10A-H (SEQ ID NO:61).
  • Alpha, beta, turn and coil regions; hydrophilicity and hydrophobicity; amphipathic regions; flexible regions; antigenic index and surface probability are shown.
  • the data are presented in tabular form, amino acid by amino acid, in Table IV, below.
  • the present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding a TR13 polypeptide having the amino acid sequence shown in Figures 1A-C (SEQ ID NO:2) and/or Figures 7A-D (SEQ ID NO:40) and/or fragments or variants thereof.
  • the TR13 polypeptide of the present invention shares sequence homology with the human OX40 homologue ( Figures 2A-C) and the tumor necrosis factor receptor II homolog ( Figures 8A-B).
  • the nucleotide sequence shown in Figures 1A-C was obtained by sequencing a cDNA clone (HWLHM70), which was deposited on July 13, 1999 at the American Type Culture Collection, and given Accession Number PTA-349.
  • the nucleotide sequence shown in Figures 7A-D was obtained, in part, by sequencing a cDNA clone (HWLHN83), which was deposited on August 12, 1999 at the American Type Culture Collection, and given Accession Number PTA-507.
  • the deposited clone is inserted in the pSportl clone (Life Technologies, Rockville, MD) using the Sail and Notl restriction endonuclease cleavage sites.
  • the present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding a TR14 polypeptide having the amino acid sequence shown in Figures 10A-H (SEQ ID NO:51), or, alternatively 4A-D (SEQ ID NO:5) and/or fragments or variants thereof, which were determined by sequencing a cloned cDNA.
  • the TR14 polypeptide of the present invention shares sequence homology with the Tumor Necrosis Factor Receptor ( Figures 5A-B).
  • SEQ ID NO:60 The nucleotide sequence shown in Figures 10A-H (SEQ ID NO:60) was obtained by sequencing a cDNA clone (HMSHK47), which was deposited on July 13, 1999 at the American Type Culture Collection, and given Accession Number PTA-348. The deposited clone is inserted in the pBluescript clone (Life Technologies, Rockville, MD) using the EcoRI restriction endonuclease cleavage sites. While SEQ ID NO:60 is a preferred sequence for TR14, an alternative TR14 related sequence is shown in Figures 4A-D (SEQ ID NO:4).
  • nucleotide sequences determined by sequencing a DNA molecule herein were determined using an automated DNA sequencer (such as the Model 3700 and Model 373 from Applied Biosystems, Inc.), and all amino acid sequences of polypeptides encoded by DNA molecules determined herein were predicted by translation of a DNA sequence determined as above. Therefore, as is known in the art for any DNA sequence determined by this automated approach, any nucleotide sequence determined herein may contain some errors. Nucleotide sequences determined by automation are typically at least about 90% identical, more typically at least about 95% to at least about 99.9% identical to the actual nucleotide sequence of the sequenced DNA molecule. The actual sequence can be more precisely determined by other approaches including manual DNA sequencing methods well known in the art.
  • a single insertion or deletion in a determined nucleotide sequence compared to the actual sequence will cause a frame shift in translation of the nucleotide sequence such that the predicted amino acid sequence encoded by a determined nucleotide sequence will be completely different from the amino acid sequence actually encoded by the sequenced DNA molecule, beginning at the point of such an insertion or deletion.
  • a nucleic acid molecule of the present invention encoding a TR13 polypeptide may be obtained using standard cloning and screening procedures, such as those for cloning cDNAs using mRNA as starting material.
  • the nucleic acid molecule described in SEQ ID NO:l was discovered in a cDNA library derived from activated monocytes.
  • the nucleic acid molecule described in SEQ ID NO: 39 was discovered in a cDNA library derived from normal human colon.
  • TR13 polynucleotides of the invention have also been identified in cDNA libraries from the following tissues: pancreas tumor, endometrial tumor, adult small intestine, colon cancer, breast cancer cell line, resting T-cell, amygdala, rectum, T-cell helper, pineal gland, apoptotic T-cell, epididymus, greater omentum, prostate BPH, osteoclastoma, endometrial stromal cells, stromal cell, substantia nigra, activated T-cell, tonsil, and testes tissue.
  • the determined TR13 nucleotide sequence of SEQ ID NO: l contains an open reading frame encoding a protein of about 750 amino acid residues, and a deduced molecular weight of about 82 kDa.
  • the amino acid sequence of the predicted TR13 receptor is shown in SEQ ID NO:2 from amino acid residue about 1 to residue about 750.
  • this TR13 polypeptide shares the greatest degree of homology with human OX40 (See Figures 2A-C), including significant sequence homology over multiple cysteine rich domains.
  • the determined TR13 nucleotide sequence of SEQ ID NO:39 contains an open reading frame encoding a protein of about 1001 amino acid residues, with a predicted signal encompassing amino acids about 1 to about 41 , a predicted extracellular domain encompassing amino acids from about 42 to about 906, a transmembrane domain encompassing amino acids from about 907 to about 931 , and an intracellular domain encompassing amino acids from about 932 to 1001 , of SEQ ID NO:40, and a deduced molecular weight of about 110 kDa.
  • the amino acid sequence of the predicted TR13 receptor is shown in SEQ ID NO:40 from amino acid residue about 1 to residue about 1001. Of known members of the TNF receptor family, this TR13 polypeptide shares the greatest degree of homology with the tumor necrosis factor receptor II homolog (See Figures 8A-B), including significant sequence homology over multiple cysteine rich domains.
  • a nucleic acid molecule of the present invention encoding a TR14 polypeptide may be obtained using standard cloning and screening procedures, such as those for cloning cDNAs using mRNA as starting material.
  • the nucleic acid molecule contained in deposited clone HMSHK47 (described in SEQ ID NO:60) was discovered in a cDNA library derived from colon.
  • the gene of the present invention has also been identified in cDNA libraries from the following tissues: activated T-cell, endometrial tumor, thymus, and 12 week early stage human tissue.
  • the determined nucleotide sequence of the TR14 cDNA of SEQ ID NO:60 contains an open reading frame encoding a protein of about 231 amino acid residues, with a predicted extracellular domain encompassing amino acids from about 1 to about 138, a transmembrane domain encompassing amino acids from about 139 to about 155, and an intracellular domain encompassing amino acids from about 156 to about 231 of SEQ ID NO:61 and a deduced molecular weight of about 25 kDa.
  • the TR14 nucleotide sequence of SEQ ID NO:4 contains an open reading frame encoding a protein of about 226 amino acid residues, with a predicted extracellular domain encompassing amino acids from about 1 to about 133, a transmembrane domain encompassing amino acids from about 134 to about 150 (from about 139 to about 155 of SEQ ID NO:61), and an intracellular domain encompassing amino acids from about 151 to about 226 of SEQ ID NO:4 (acids from about 156 to about 231 of SEQ ID NO:61) and a deduced molecular weight of about 24.5 kDa.
  • the TR14 polypeptide of the SEQ ID NO:5 shares the greatest degree of homology with tumor necrosis factor receptor (See Figures 5A-B).
  • the present invention also encompasses mature form(s) of the TR13 and/or TR14 polypeptides of the present invention.
  • proteins secreted by mammalian cells have a signal or secretory leader sequence which is cleaved from the mature protein once export of the growing protein chain across the rough endoplasmic reticulum has been initiated.
  • Most mammalian cells and even insect cells cleave secreted proteins with the same specificity.
  • cleavage of a secreted protein is not entirely uniform, which results in two or more mature species on the protein.
  • the cleavage specificity of a secreted protein is ultimately determined by the primary structure of the complete protein, that is, it is inherent in the amino acid sequence of the polypeptide.
  • the present invention provides a nucleotide sequence encoding the mature form of the TR13 polypeptide having the amino acid sequence encoded by the cDNA clone identified as ATCC Deposit No. PTA-349 (HWLHM70), and/or of the amino acid sequence shown in Figures 1A-C (SEQ ID NO:2).
  • the mature form of TR13 polypeptide having the amino acid sequence encoded by, for example, the cDNA clone identified as ATCC Deposit No.
  • PTA-349 is meant, the mature form(s) of the TR13 receptor produced by expression in a mammalian cell (e.g., COS cells, as described below) of the complete open reading frame encoded by the human DNA sequence of the clone contained in the deposited vector.
  • a mammalian cell e.g., COS cells, as described below
  • the mature form of the TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-349 (HWLHM70) may or may not differ from the predicted mature TR13 protein shown in SEQ ID NO:2 (amino acids from about 1 to about 750) depending on the accuracy of the predicted cleavage site based on computer analysis.
  • Polypeptides encoded by the nucleotide sequences are also encompassed by the invention.
  • the present invention provides a nucleotide sequence encoding the mature form of the TR13 polypeptide having the amino acid sequence encoded by the cDNA clone identified as ATCC Deposit No. PTA-507 (HWLHN83), and/or of the amino acid sequence as shown in Figures 7A-D (SEQ ID NO:40).
  • the mature form of the TR13 polypeptide having the amino acid sequence encoded by, for example, the cDNA clone identified as ATCC Deposit No.
  • PTA-507 is meant, the mature form(s) of the TR13 receptor produced by expression in a mammalian cell (e.g., COS cells, as described below) of the complete open reading frame encoded by the human DNA sequence of the clone contained in the deposited vector.
  • a mammalian cell e.g., COS cells, as described below
  • the mature form of the TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-507 (HWLHN83) may or may not differ from the predicted mature TR13 protein shown in SEQ ID NO:40 (amino acids from about 42 to about 1001) depending on the accuracy of the predicted cleavage site based on computer analysis. Polypeptides encoded by these nucleotide sequences are also encompassed by the invention.
  • the predicted amino acid sequence of the TR13 polypeptide of the present invention was analyzed by a computer program ("PSORT"). See K. Nakai and M. Kanehisa, Genomics 74:897-911 (1992). PSORT is an expert system for predicting the cellular location of a protein based on the amino acid sequence. As part of this computational prediction of localization, the methods of McGeoch and von Heinje are incorporated. Thereafter, the complete amino acid sequences were further analyzed by visual inspection, applying a simple form of the (-1,-3) rule of von Heinje. von Heinje, supra.
  • the TR13 protein is predicted to consist of residues from about 1-750 in SEQ ID NO:2, and/or 1-1001 in SEQ ID NO:40.
  • the mature form of the polypeptide sequence disclosed in SEQ ID NO:40 is predicted to consist of residues from about 42 to 1001.
  • the predicted full-length TR13 polypeptide encoded by the deposited cDNA clones comprises about 1001 amino acids, but may be anywhere in the range of about 700 to about 1200 amino acids.
  • the domains described herein have been predicted by computer analysis, and accordingly, depending on the analytical criteria used for identifying various functional domains, the exact "address" of, for example, the extracelluar domain, intracelluar domain, cysteine-rich domains, and transmembrane domain of TR13 may differ slightly (e.g., the address may "shift" by about 1 to about 20 residues, more likely about 1 to about 5 residues).
  • the exact location of the TR13 cysteine-rich domains in Figures 1A-C (SEQ ID NO:2) and/or Figures 7A-D (SEQ ID NO:40) may vary slightly (e.g., the address may "shift" by about 1 to about 20 residues, more likely about 1 to about 5 residues) depending on the criteria used to define the motifs.
  • the invention further provides polypeptides having various residues deleted from the N-terminus and/or C- terminus of the full-length TR13, including polypeptides lacking one or more amino acids from the N-termini of the extracellular domain described herein, which constitute soluble forms of the extracellular domain of the TR13 polypeptides.
  • predicted full-length TR14 polypeptide encoded by the deposited cDNA clone comprises about 231 amino acids as shown in SEQ ID NO:61 , but may be anywhere in the range of 175-275 amino acids.
  • predicted full-length TR14 polypeptide comprises about 226 amino acids, but may be anywhere in the range of 175-275 amino acids, but may be anywhere in the range of about 45 to about 200 amino acids.
  • the domains described herein have been predicted by computer analysis, and accordingly, that depending on the analytical criteria used for identifying various functional domains, the exact "address" of, for example, the extracelluar domain, intracelluar domain, cysteine-rich domains, and transmembrane domain of TR14 may differ slightly (e.g., the address may "shift" by about 1 to about 20 residues, more likely about 1 to about 5 residues).
  • the exact location of the TR14 extracellular domain and/or cysteine- rich domains in Figures 10A-H (SEQ ID NO:61) or, alternatively Figures 4A-D (SEQ ID NO:5) may vary slightly (e.g., the address may "shift" by about 1 to about 20 residues, more likely about 1 to about 5 residues) depending on the criteria used to define the domain.
  • the polypeptide sequence of TR14 is longer than the sequence depicted in Figures 10A-H or, alternatively Figures 4A-D, the skilled artisan would appreciate that the sequence could affect the ultimate location of the extracellular, transmembrane, or intracellular domain.
  • the invention further provides polypeptides having various residues deleted from the N-terminus and/or C-terminus of the full-length TR14, including polypeptides lacking one or more amino acids from the N-termini of the extracellular domain described herein, which constitute soluble forms of the extracellular domain of the TR14 polypeptides.
  • nucleic acid molecules of the present invention may be in the form of RNA, such as mRNA, or in the form of DNA, including, for instance, cDNA and genomic DNA obtained by cloning or produced synthetically.
  • the DNA may be double-stranded or single-stranded.
  • Single-stranded DNA may be the coding strand, also known as the sense strand, or it may be the non-coding strand, also referred to as the anti-sense strand.
  • isolated nucleic acid molecule(s) is intended a nucleic acid molecule, DNA or RNA, which has been removed from its native environment
  • recombinant DNA molecules contained in a vector are considered isolated for the purposes of the present invention.
  • Further examples of isolated DNA molecules include recombinant DNA molecules maintained in heterologous host cells or purified (partially or substantially) DNA molecules in solution.
  • Isolated RNA molecules include in vivo or in vitro RNA transcripts of the DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.
  • a nucleic acid molecule contained in a clone that is a member of a mixed clone library e.g., a genomic or cDNA library
  • a mixed clone library e.g., a genomic or cDNA library
  • a chromosome isolated or removed from a cell or a cell lysate e.g., a "chromosome spread", as in a karyotype
  • Isolated nucleic acid molecules of the present invention include, for example, DNA molecules comprising, or alternatively consisting of, an open reading frame (ORF) shown in Figures 1A-C (SEQ ID NO: l), Figures 7A-D (SEQ ID NO:39) and/or contained in a deposited cDNA clone (e.g., HWLHM70 and HWLHN83); DNA molecules comprising, or alternatively consisting of, the coding sequence for the mature TR13 protein shown in Figures 1A-C (SEQ ID NO: l) and/or Figures 7A-D (SEQ ID NO:39) and/or contained in a deposited cDNA clone (e.g., HWLHM70 and HWLHN83); DNA molecules comprising, or alternatively consisting of, a fragment of the coding sequence for the full-length TR13 protein disclosed in Figures 1A- C and/or Figures 7A-D and/or encoded by a deposited cDNA clone; and
  • Isolated nucleic acid molecules of the present invention include, for example, DNA molecules comprising, or alternatively consisting of, an open reading frame (ORF) shown preferably in Figures 10A-H (SEQ ID NO:60) or, alternatively, in Figures 4A-D (SEQ ID NO:4) and/or contained in the deposited cDNA clone (HMSHK47); DNA molecules comprising, or alternatively consisting of, the coding sequence for the mature TR14 protein shown preferably in Figures 10A-H (amino acids 1-164 of SEQ ID NO:61), or alternatively, in Figures 7A-D (SEQ ID NO:4) and/or contained in the deposited cDNA clone (HMSHK47); DNA molecules comprising, or alternatively consisting of, a fragment of the coding sequence for the full-length TR14 protein disclosed in preferably in Figures 10A-H or, alternatively, in Figures 4A-D and/or encoded by the deposited cDNA clone (HMSHK47);
  • TR13 polypeptide having an amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-349 (HWLHM70).
  • nucleic acid molecules are provided that encode the mature form of the TR13 polypeptide disclosed in Figures 1A-C and/or encoded by the cDNA contained in ATCC Deposit No. PTA-349.
  • nucleic acids are provided that the full-length TR13 polypeptide disclosed in Figures 1A-C and/or encoded by the deposited cDNA clone, but lacking the N-terminal methionine.
  • nucleic acid molecules are provided that encode The invention further provides an isolated nucleic acid molecule having the nucleotide sequence shown in SEQ ID NO:l or the nucleotide sequence of the TR13 cDNA contained in the above- described deposited cDNA clone, or a nucleic acid molecule having a sequence complementary to one of the above sequences.
  • isolated molecules particularly DNA molecules, are useful, for example, as probes for gene mapping by in situ hybridization with chromosomes, and for detecting expression of the TR13 gene in human tissue, for instance, by Northern blot analysis.
  • the invention provides isolated nucleic acid molecules encoding the TR13 polypeptide having an amino acid sequence as encoded by the cDNA clone contained in ATCC Deposit No. PTA-507 (HWLHN83).
  • nucleic acid molecules are provided that encode the mature form of the TR13 polypeptide disclosed in Figures 7A-D, and/or encoded by the cDNA contained in ATCC Deposit No. PTA-507.
  • nucleic acid molecules are provided that encode the full-length TR13 polypeptide disclosed in Figures 7A-D, and/or encoded by the deposited cDNA clone, but lacking the N- terminal methionine.
  • the invention further provides an isolated nucleic acid molecule having the nucleotide sequence shown in SEQ ID NO:39 or the nucleotide sequence of the TR13 cDNA contained in the above-described deposited cDNA clone, or a nucleic acid molecule having a sequence complementary to one of the above sequences.
  • isolated molecules particularly DNA molecules, are useful, for example, as probes for gene mapping by in situ hybridization with chromosomes, and for detecting expression of the TR13 gene in human tissue, for instance, by Northern blot analysis.
  • the invention provides isolated nucleic acid molecules encoding the TR14 polypeptide having an amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-348 (HMSHK47).
  • nucleic acid molecules are provided that encode the full-length TR14 polypeptide disclosed in Figures 10A-H or, alternatively, in Figures 4A-D, and/or encoded by the deposited cDNA clone, but lacking the N-terminal methionine.
  • the invention further provides an isolated nucleic acid molecule having the nucleotide sequence shown preferably in SEQ ID NO:60 or, alternatively, in SEQ ID NO:4 or the nucleotide sequence of the TR14 cDNA contained in the above-described deposited cDNA clone, or a nucleic acid molecule having a sequence complementary to one of the above sequences.
  • isolated molecules particularly DNA molecules, are useful, for example, as probes for gene mapping by in situ hybridization with chromosomes, and for detecting expression of the TR14 gene in human tissue, for instance, by Northern blot analysis.
  • the invention provides nucleic acid molecules having nucleotide sequences related to extensive portions of SEQ ID NO: 1 which have been determined from the following related cDNA clones: HETAQ12R (SEQ ID NO:8), HETAK82R (SEQ ID NO:9), HETBH18R (SEQ ID NO:10), HEPAB26R (SEQ ID NO: 1 1), HETAN38R (SEQ ID NO: 12), HPWDD30R (SEQ ID NO:13), HETAT05R (SEQ ID NO: 14), HETDQ39R (SEQ ID NO:15), HETEM84R (SEQ ID NO: 16), and HSIDV42R (SEQ ID NO: 17).
  • the invention provides nucleic acid molecules having nucleotide sequences related to extensive portions of SEQ ID NO:39 which have been determined from the following related cDNA clones: HETAQ12R (SEQ ID NO:48), HETAK82R (SEQ ID NO:49), HETBM71R (SEQ ID NO:50), HETBH18R (SEQ ID NO:51), HEPAB26R (SEQ ID NO:52), HETAN38R (SEQ ID NO:53), HPWDD30R (SEQ ID NO:54), HETAT05R (SEQ ID NO:55), HETDQ39R (SEQ ID NO:56), HPWBL93R (SEQ ID NO:57), HETEM84R (SEQ ID NO:58), and HSIDV42R (SEQ ID NO:59).
  • the invention provides nucleic acid molecules having nucleotide sequences related to extensive portions of SEQ ID NOS:60 and 4 which have been determined from the following related cDNA clones: HSABD50R (SEQ ID NO: 18), HTXMX53R (SEQ ID NO: 19), HE2OR74R (SEQ ID NO:20), HMSHK47R (SEQ ID NO:21), and HMSHK59R (SEQ ID NO:22).
  • the present invention is further directed to fragments of the isolated TR13 nucleic acid molecules described herein.
  • a fragment of an isolated DNA molecule having the nucleotide sequence of a deposited cDNA clone e.g., HWLHN83 and/or HWLHM70
  • the nucleotide sequence shown in Figures 1A-C (SEQ ID NO:l) and/or Figures 7A-D (SEQ ID NO:39) is intended DNA fragments at least about 15nt, and more preferably at least about 20 nt, or at least 25 nt, still more preferably at least about 30 nt, or at least 35 nt, and even more preferably, at least about 40 nt, or at least about 50 nt in length which are useful, for example, as diagnostic probes and primers as discussed herein.
  • fragments 50-1500 nt in length are also useful according to the present invention, as are fragments corresponding to most, if not all, of the nucleotide sequence of the deposited cDNA or as shown in SEQ ID NO:l and/or SEQ ID NO:39.
  • a fragment at least 20 nt in length for example, is intended fragments which include 20 or more contiguous bases from the nucleotide sequence of a deposited cDNA clone or the nucleotide sequence as shown in Figures 1A-C (SEQ ID NO: l) and/or Figures 7A-D (SEQ ID NO:39).
  • “about” includes the particularly recited size, or may be larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini.
  • the present invention is further directed to fragments of the isolated TR14 nucleic acid molecules described herein.
  • a fragment of an isolated DNA molecule having the nucleotide sequence of the deposited cDNA clone (HMSHK47), or the nucleotide sequence shown preferably in Figures 10A-H (SEQ ID NO:60) or, alternatively in Figures 4A-D (SEQ ID NO:4), or the complementary strand thereto is intended DNA fragments at least about 15nt, and more preferably at least about 20 nt, or at least 25 nt, still more preferably at least about 30 nt, or at least 35 nt, and even more preferably, at least about 40 nt, or at least 50 nt, in length which are useful, for example, as diagnostic probes and primers as discussed herein.
  • fragments 50-1500 nt in length are also useful according to the present invention, as are fragments corresponding to most, if not all, of the nucleotide sequence of the deposited cDNA or as shown preferably in Figures 10A-H (SEQ ID NO:60) or, alternatively in Figures 4A-D (SEQ ID NO:4).
  • a fragment at least 20 nt in length for example, is intended fragments which include 20 or more contiguous bases from the nucleotide sequence of the deposited cDNA or the nucleotide sequence as shown in preferably in SEQ ID NO:60, or, alternatively, in SEQ ID NO:4.
  • “about” includes the particularly recited size, or may be larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini.
  • TR13 polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively, consist of, a sequence from about nucleotide 1 to about 50, from about 51 to about 108, from about 109 to about 159, from about 160 to about 210, from about 211 to about 261 , from about 262 to about 273 , from about 274 to about 324, from about 325 to about 375, from about 376 to about 426, from about 427 to about 477, from about 478 to about 528, from about 529 to about 579, from about 580 to about 630, from about 631 to about 681, from about 682 to about 732, from about 733 to about 744, from about 745 to about 798, from about 799 to about 849, from about 850 to about 900, from about 901 to about 951 , from about 952 to about 1002, from about 1003 to about 1053, from about 1054 to about 1104, from about 1105 to about 1155,
  • polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively consist of, a sequence from about nucleotide 1 to about 362, from about 705 to about 830, from about 31 to about 2280, from about 343 to 414, from about 415 to about 459, from about 460 to about 540, 343 to about 540, from about 781 to about 804, from about 805 to about 830, from about 781 to about 822, from about 1021 to about 1260, from about 1768 to about 1812, from about 1813 to about 1866, from about 1768 to about 1866, from about 31 to about 540, from about 660 to about 984, from about 1057 to about 1470, from about 1672 to about 1806, and/or from about 1924 to about 2256 of the polynucleotide sequence shown in Figures 1 A-C (SEQ ID NO: 1 ), or the complementary strand thereto.
  • TR13 polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively, consist of, a sequence from about nucleotide 1 to about 50, from about 51 to about 108, from about 109 to about 159, from about 160 to about 210, from about 211 to about 261, from about 262 to about 273, from about 274 to about 324, from about 325 to about 375, from about 376 to about 426, from about 427 to about 477, from about 478 to about 528, from about 529 to about 579, from about 580 to about 630, from about 631 to about 681 , from about 682 to about 732, from about 733 to about 744, from about 745 to about 798, from about 799 to about 849, from about 850 to about 900, from about 901 to about 951 , from about 952 to about 1002, from about 1003 to about 1053, from about 1054 to about 1104, from about 1105 to about 1 155, from
  • polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively consist of, a sequence from about nucleotide 1 to about 42, from about 181 to about 2775, from about 984 to about 1142, from about 1485 to about 1610, from about 2361 to about 2718, from about 61 to about 3060, from about 58 to about 3060, from about 58 to about 183, from about 58 to about 2775, from about 2776 to about 2850, from about 2851 to about 3060, from about 868 to about 1320, from about 868 to about 915, from about 925 to about 957, about 960 to about 1017, about 1042 to about 1140, about 1267 to about 1320, about 870 to about 1320, about 1810 to about 1842, about 2038 to about 2079, about 2185 to about 2289, about 2995 to about 3054, about 190 to about 237, about 418 to about 462, about 58 to about 843, about 847 to
  • polynucleotides which hybridize to any 1 , 2 , 3, 4, 5 or more of these polynucleotide fragments are also encompassed by the invention. Moreover, polypeptides encoded by these polynucleotides and/or polynucleotide fragments are also encompassed by the invention. Moreover, polypeptides encoded by the polynucleotides and/or polynucleotide fragments are also encompassed by the invention.
  • the polynucleotide fragments of the invention encode a polypeptide which demonstrates a TR13 functional activity.
  • a polypeptide demonstrating a TR13 "functional activity” is meant, a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) TR13 protein.
  • Such functional activities include, but are not limited to, biological activity (e.g., cell proliferation activity), antigenicity (ability to bind (or compete with a TR13 polypeptide for binding) to an anti-TR13 antibody), immunogenicity (ability to generate antibody which binds to a TR13 polypeptide), ability to form multimers with TR13 polypeptides of the invention, and ability to bind to a receptor or ligand for a TR13 polypeptide.
  • biological activity e.g., cell proliferation activity
  • antigenicity ability to bind (or compete with a TR13 polypeptide for binding) to an anti-TR13 antibody
  • immunogenicity ability to generate antibody which binds to a TR13 polypeptide
  • ability to form multimers with TR13 polypeptides of the invention and ability to bind to a receptor or ligand for a TR13 polypeptide.
  • various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc.
  • competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoradiometric
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.
  • binding can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky, E., et al., Microbiol. Rev. 59:94-123 (1995).
  • physiological correlates of TR13 binding to its substrates can be assayed.
  • assays described herein may routinely be applied to measure the ability of TR13 polypeptides and fragments, variants derivatives and analogs thereof to elicit a particular biological activity (e.g., to inhibit TRAIL induced apoptosis, to regulate (e.g., inhibit) B cell proliferation (see, e.g., Example 33), to regulate proliferation of other cells, and/or to inhibit hematopoiesis in vitro or in vivo).
  • compositions of the invention may regulate (e.g., inhibit apoptosis) and/or to regulate (e.g., inhibit) proliferation of hematopoietic cells.
  • assays desribed herein see e.g., Example 15 and Example 33
  • otherwise known in the art may be applied or routinely modified to assay for the ability of the compositions of the invention to inhibit or stimulate B cell proliferation.
  • TR14 polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively, consist of, a sequence from about nucleotide 1 to about 50, from about 51 to about 108, from about 109 to about 159, from about 160 to about 210, from about 21 1 to about 261 , from about 262 to about 273, from about 274 to about 324, from about 325 to about 375, from about 376 to about 426, from about 427 to about 477, from about 478 to about 528, from about 529 to about 579, from about 580 to about 630, from about 631 to about 681 , from about 682 to about 732, from about 733 to about 744, from about 745 to about 798, from about 799 to about 849, from about 850 to about 900, from about 901 to about 951 , from about 952 to about 1002, from about 1003 to about 1053, from about 1054 to about 1 104, from about 1105 to about 1
  • polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively, consist of, a sequence from about nucleotide 1 to about 1451, from about 1761 to about 2251, from about 89 to about 766, from about 89 to about 487, from about 488 to about 538, from about 539 to about 766, from about 92 to about 160, from about 212 to about 243 , from about 281 to about 313, from about 314 to about 343, from about 281 to about 343, from about 325 to about 433, and/or 550 to about 766 of the polynucleotide sequence shown in Figures 10A-H (SEQ ID NO:60), or the complementary strand thereto.
  • TR14 polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively, consist of, a sequence from about nucleotide 1 to about 50, from about 51 to about 108, from about 109 to about 159, from about 160 to about 210, from about 21 1 to about 261 , from about 262 to about 273, from about 274 to about 324, from about 325 to about 375, from about 376 to about 426, from about 427 to about 477, from about 478 to about 528, from about 529 to about 579, from about 580 to about 630, from about 631 to about 681 , from about 682 to about 732, from about 733 to about 744, from about 745 to about 798, from about 799 to about 849, from about 850 to about 900, from about 901 to about 951 , from about 952 to about 1002, from about 1003 to about 1053, from about 1054 to about 1 104, from about 1105 to about 11
  • polynucleotide fragments of the invention include, for example, fragments that comprise, or alternatively, consist of, a sequence from about nucleotide 1 to about 1451 , from about 1761 to about 2251 , from about 3133 to about 3861 , from about 89 to about 766, from about 89 to about 487, from about 488 to about 538, from about 539 to about 766, from about 92 to about 160, from about 212 to about 243, from about 281 to about 313, from about 314 to about 343, from about 281 to about 343, from about 325 to about 433, and/or 550 to about 766 of the polynucleotide sequence shown in Figures 4A-D (SEQ ID NO:4), or the complementary strand thereto.
  • polynucleotide fragments of the invention encode a polypeptide which demonstrates a TR14 functional activity.
  • a polypeptide demonstrating a TR14 “functional activity” is meant, a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) TR14 protein.
  • Such functional activities include, but are not limited to, biological activity, antigenicity (ability to bind (or compete with a TR14 polypeptide for binding) to an anti-TR14 antibody), immunogenicity (ability to generate antibody which binds to a TR14 polypeptide), ability to form multimers with TR14 polypeptides of the invention, and ability to bind to a receptor or ligand for a TR14 polypeptide.
  • various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc.
  • competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich” immunoassays, immunoradiometric
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.
  • binding can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123 (1995).
  • physiological correlates of TR14 binding to its substrates can be assayed.
  • assays described herein may routinely be applied to measure the ability of TR14 polypeptides and fragments, variants derivatives and analogs thereof to elicit a particular biological activity (e.g., to inhibit TRAIL induced apoptosis, to regulate (e.g., inhibit) B cell proliferation (see, e.g., Example 33), and/or to inhibit hematopoiesis in vitro or in vivo).
  • compositions of the invention may regulate (e.g., inhibit apoptosis) and/or to regulate (e.g., inhibit) proliferation of hematopoietic cells.
  • assays desribed herein see e.g., Example 15 and Example 33
  • otherwise known in the art may be applied or routinely modified to assay for the ability of the compositions of the invention to inhibit or stimulate B cell proliferation.
  • Preferred nucleic acid fragments of the present invention include nucleic acid molecules encoding a member selected from the group: a polypeptide comprising or alternatively, consisting of any combination of one, two, three or all four TR13 cysteine rich domains (amino acid residues from about 105 to about 170, from about 251 to about 264, from about 331 to about 410 and from about 580 to about 610 in Figures 1A-C (amino acids from about 105 to about 170, from about 251 to about 265, from about 331 to about 410 and from about 580 to about 610 in SEQ ID NO:l).
  • a polypeptide comprising or alternatively, consisting of any combination of one, two, three or all four TR13 cysteine rich domains (amino acid residues from about 105 to about 170, from about 251 to about 264, from about 331 to about 410 and from about 580 to about 610 in Figures 1A-C (amino acids from about 105 to about 1
  • amino acid residues constituting these domains may be the particularly recited ranges for each domain or may vary slightly (e.g., by about 1 , 2, 3, 4, 5, 10, or 15 residues at either extreme or at both extremes) depending on the criteria used to define each domain.
  • Additional preferred nucleic acid fragments of the present invention include nucleic acid molecules encoding a member selected from the group: a polypeptide comprising or alternatively, consisting of the TR13 receptor extracellular domain (amino acids 1 to 906 in Figures 7A-D); a polypeptide comprising or alternatively, consisting of, the mature TR13 receptor extracellular domain (amino acids 42 to 906 in Figures 7A-D); a polypeptide comprising or alternatively, consisting of, one or more of the TR13 cysteine rich domains disclosed in Figures 7A-D (e.g., amino acid residues from about 271 to about 421, from about 271 to about 286, about 290 to about 300, about 301 to about 320, about 329 to about 361 , about 404 to about 421 , and from about 585 to about 595 in Figures 7A-D (amino acid residues from about 271 to about 421 , from about 271 to about 286, about 290 to about 300, about 301 to
  • amino acid residues constituting these domains may be the particularly recited ranges for each domain or may vary slightly (e.g., by about 1 , 2, 3, 4, 5, 10, or 15 residues at either extreme or at both extremes) depending on the criteria used to define each domain.
  • polypeptides which comprise, or alternatively consist of, the amino acid sequence of amino acid residues from about 105 to about 170, from about 251 to about 265, from about 331 to about 410, and from about 580 to about 610 of SEQ ID NO:5 (corresponding to amino acid residues from about 105 to about 170, from about 251 to about 265, from about 331 to about 410, and from abour 580 to about 610 of Figures 4A-D).
  • the polynucleotides encoding TR13 polypeptides of the invention comprise or alternatively consist of, polynucleotide sequences encoding any combination of 2, 3, or all four of the cysteine-rich motifs of TR13.
  • "about” includes the particularly recited ranges, larger or smaller by several (5, 4, 3, 2 , or 1) nucleotides, at either terminus or at both termini. Polypeptides encoded by these polynucleotides are also encompassed by the invention.
  • polypeptides which comprise, or alternatively consist of, the amino acid sequence of amino acid residues from about 271 to about 421 , from about 271 to about 286, from about 290 to about 300, from about 301 to about 320, about 329 to about 361 , about 404 to about 421 , and about 585 to about 595 of SEQ ID NO:40 (corresponding to amino acid residues from about 271 to about 421 , from about 271 to about 286, from about 290 to about 300, from about 301 to about 320, about 329 to about 361 , about 404 to about 421 , and about 585 to about 595 of Figures 7A-D).
  • the polynucleotides encoding TR13 polypeptides of the invention comprise or alternatively consist of, polynucleotide sequences encoding any combination of 2, 3, or all four of the cysteine-rich motifs of TR13 disclosed in Figures 7A-D.
  • "about” includes the particularly recited ranges, larger or smaller by several (5 , 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. Polypeptides encoded by these polynucleotides are also encompassed by the invention.
  • nucleic acid fragments of the invention encode a full-length TR13 polypeptide lacking the nucleotides encoding the amino terminal methionine (e.g., nucleotides 34-750 in SEQ ID NO: 1), as it is known that the methionine is cleaved naturally and such sequences may be useful in genetically engineering TR13 expression vectors.
  • Polypeptides encoded by such nucleic acids are also contemplated by the invention.
  • Preferred nucleic acid fragments of the invention encode a full-length TR13 polypeptide lacking the nucleotides encoding the amino terminal methionine (e.g., nucleotides 61-1001 in Figures 7A-D and SEQ ID NO:39), as it is known that the methionine is cleaved naturally and such sequences may be useful in genetically engineering TR13 expression vectors. Polypeptides encoded by such nucleic acids are also contemplated by the invention. Preferred nucleic acid fragments of the present invention further include nucleic acid molecules encoding epitope-bearing portions of the TR13 receptor protein.
  • nucleic acid fragments of the present invention include nucleic acid molecules encoding: a polypeptide comprising or alternatively consisting of, amino acid residues from about 1 to about 170 in Figures 1A-C (corresponding to about amino acid 1 to about 170 in SEQ ID NO:2); a polypeptide comprising or alternatively consisting of, amino acid residues from about 210 to about 318 in Figures 1A-C (corresponding to about amino acid 210 to about 318 in SEQ ID NO:2); a polypeptide comprising or alternatively consisting of, amino acid residues from about 343 to about 480 in Figures 1A-C (corresponding to about amino acid 343 to about 480 in SEQ ID NO:2); a polypeptide comprising or alternatively consisting of, amino acid residues from about 548 to about 592 in Figures 1A-C (corresponding to about amino acid 548 to about 592 in SEQ ID NO:2); and a polypeptide comprising or alternatively consisting of, amino acid residues from about
  • nucleic acid fragments of the present invention further include nucleic acid molecules encoding antigenic fragments of the TR13 receptor protein.
  • nucleic acid fragments of the present invention include nucleic acid molecules encoding: a polypeptide comprising or alternatively consisting of, amino acid residues from about Ml to about A9, about K12 to about L20, about N47 to about T55, about H58 to about S66, about D63 to about S71, about P77 to about F85, about A90 to about Q98, about F136 to about Q144, about S152 to about C160, about R159 to about A167, about A211 to about M219, about M235 to about V243, about V266 to about V274, about W277 to about S285, about 1290 to about F298, about A310 to about V318, about E343 to about C351 , about 1360 to about H368, about G391 to about 1399, about F409 to about T417, about S436 to about Y444,
  • Additional preferred nucleic acid fragments of the present invention further include nucleic acid fragments encoding: a polypeptide comprising or alternatively consisting of, amino acid residues from about 1 to about 262 in Figures 7A-D (corresponding to about amino acid 1 to about 262 in SEQ ID NO:40); a polypeptide comprising or alternatively consisting of, amino acid residues from about 264 to about 423 in Figures 7A-D (corresponding to about amino acid 264 to about 423 in SEQ ID NO:40); a polypeptide comprising or alternatively consisting of, amino acid residues from about 437 to about 789 in Figures 7A-D (corresponding to about amino acid 437 to about 789 in SEQ ID NO:40); and a polypeptide comprising or alternatively consisting of, amino acid residues from about 791 to about 1001 in Figures 7A-D (corresponding to about amino acid 791 to about 1001 in SEQ ID NO:40).
  • nucleic acid fragments of the present invention encoding antigenic fragments of the TR 13 receptor protein include nucleic acid molecules encoding: a polypeptide comprising or alternatively consisting of, amino acid residues from about Ml to about H9, about V 14 to about 122, about H47 to about H55, about C61 to about R69, about L82 to about E90, about D102 to about P110, about K109 to about SI 17, about F124 to about H132, about M141 to about E149, about S146 to about C154, about S157 to about W165, about F168 to about T176, about N182 to about N190, about Q207 to about A215, about P213 to about M221 , about M221 to about E229, about V233 to about V241 , about T253 to about V2
  • nucleic acid molecules encoding polypeptides which comprise, or alternatively consist of, preferably amino acids Cys-31 to Cys-104 of Figures 10A-B and SEQ ID NO:61, or, alternatively, the amino acid sequence of amino acid residues from about 70 to about 90 of Figure 10A and SEQ ID NO:61 (corresponding to amino acid residues from about 65 to about 85 of Figures 4A-D or SEQ ID NO:5).
  • Preferred nucleic acid fragments of the present invention include nucleic acid molecules encoding a member selected from the group: a polypeptide comprising or alternatively, consisting of, the TR14 receptor extracellular domain (preferably amino acid residues from about 1 to 138 in Figures 10A-H or, alternatively, from about 1 to about 133 in Figures 4A-D); a polypeptide comprising or alternatively, consisting of, the TR14 cysteine rich domain (preferably amino acid residues from about 31 to about 104 of Figures 10A-H, or amino acid residues from about 70 to 90 in Figures 10A, or, alternatively, from about 65 to about 85 in Figures 4A-D); a polypeptide comprising or alternatively, consisting of the TR14 transmembrane domain (preferably amino acid residues from about 139 to 155 in Figures 10A- H or, alternatively, 134 to about 150 in Figures 4A-D); and a polypeptide comprising or alternatively, consisting of, the TR14 intracellular domain (preferably
  • amino acid residues constituting these domains may be the particularly recited ranges for each domain or may vary slightly (e.g., by about 1 , 2, 3, 4, 5, 10, or 15 residues at either extreme or at both extremes) depending on the criteria used to define each domain.
  • nucleic acid fragments of the invention encode a full-length TR14 polypeptide lacking the nucleotides encoding the amino terminal methionine (e.g., nucleotides 70-759 of Figures 10A-H or SEQ ID NO:60, or nucleotides 102-765 in SEQ ID NO:4), as it is known that the methionine is cleaved naturally and such sequences may be useful in genetically engineering TR14 expression vectors.
  • Polypeptides encoded by such nucleic acids are also contemplated by the invention.
  • Preferred nucleic acid fragments of the present invention further include nucleic acid molecules encoding epitope-bearing portions of the TR14 receptor protein.
  • preferred epitope-bearing polypeptides of the present invention comprise, or alternatively consist of, one, two, three, four, five, six, or all six of the immunogenic epitopes of the TR14 protein shown in SEQ ID NO: 61 as residues: Asp-2 to Asp-10, Thr-17 to Asp-38, Pro-45 to Ser-52, Pro-88 to Arg-95, Thr-108 to Glu-115, Thr-131 to Glu-136, Phe-166 to Gly-174, Ala- 180 to AIa-200, and Gln-224 to Met-231.
  • Fragments and/or variants of these polypeptides are encompassed by the invention.
  • Polynucleotides encoding these polypeptides are also encompassed by the invention, as are antibodies that bind these polypeptides.
  • nucleic acid fragments of the present invention include nucleic acid molecules encoding: a polypeptide comprising or alternatively consisting of, amino acid residues from about 2 to about 24 in Figures 4A-D (corresponding to about amino acid 2 to about 24 in SEQ ID NO:5); a polypeptide comprising or alternatively consisting of, amino acid residues from about 42 to about 52 in Figures 4A-D (corresponding to about amino acid 42 to about 52 in SEQ ID NO:5); a polypeptide comprising or alternatively consisting of, amino acid residues from about 80 to about 115 in Figures 4A-D (corresponding to about amino acid 80 to about 115 in SEQ ID NO:5 and about amino acid 85 to about 120 of SEQ ID NO:61); and a polypeptide comprising or alternatively consisting of, amino acid residues from about 155 to about 226 in Figures 4A-D (corresponding to about amino acid 155 to about 226 in SEQ ID NO:5 and about amino acid 160 to about amino acid 231 of SEQ
  • nucleic acid fragments of the present invention further include nucleic acid molecules encoding antigenic fragments of the TR14 receptor protein.
  • nucleic acid fragments of the present invention include nucleic acid molecules encoding: a polypeptide comprising or alternatively consisting of, amino acid residues of SEQ ID NO:5 ( Figures 4A-D) from about T3 to about S 1 1 , from about V 16 to about R24, from about Q44 to about M52, from about F85 to about G93 (about F90 to about G98 of SEQ ID NO:61), from about T103 to about Vl l l (about T108 to about VI 16 of SEQ ID NO:61), from about F161 to about G169 (about F165 to about G174 of SEQ ID NO:61), from about V187 to about A195 (from about V192 to about A200 of SEQ ID NO:61), from about P218 to about M226 (about P223 to about M231 of SEQ ID NO:61) correspond to the highly antigenic regions
  • the nucleic acid molecule of the invention encodes a polypeptide comprising, or alternatively consisting of, a functional attribute of TR13.
  • Preferred embodiments of the invention in this regard include fragments that comprise alpha- helix and alpha-helix forming regions ("alpha-regions"), beta-sheet and beta-sheet forming regions ("beta-regions"), turn and turn-forming regions ("turn-regions”), coil and coil-forming regions ("coil-regions”), hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions and high antigenic index regions of TR13.
  • the data representing the structural or functional attributes of TR13 (SEQ ID NO:40) set forth in Figure 9 and/or Table III, as described above, was generated using the various modules and algorithms of the DNA*STAR set on default parameters.
  • the data presented in columns VIII, IX, XIII, and XIV of Table III can be used to determine regions of TR13 which exhibit a high degree of potential for antigenicity. Regions of high antigenicity are determined from the data presented in columns VIII, IX, XIII, and/or XIV by choosing values which represent regions of the polypeptide which are likely to be exposed on the surface of the polypeptide in an environment in which antigen recognition may occur in the process of initiation of an immune response. Certain preferred regions in these regards are set out in Figure 3, but may, as shown in
  • Table I be represented or identified by using tabular representations of the data presented in Figure 3.
  • the DNA*STAR computer algorithm used to generate Figure 3 (set on the original default parameters) was used to present the data in Figure 3 in a tabular format (See Table I).
  • the tabular format of the data in Figure 3 may be used to easily determine specific boundaries of a preferred region.
  • Certain preferred regions in these regards are set out in Figure 9, but may, as shown in Table III, be represented or identified by using tabular representations of the data presented in Figure 9.
  • the DNA*STAR computer algorithm used to generate Figure 9 was used to present the data in Figure 9 in a tabular format (See Table III).
  • the tabular format of the data in Figure 9 may be used to easily determine specific boundaries of a preferred region.
  • the above-mentioned preferred regions set out in Figure 3 and in Table I include, but are not limited to, regions of the aforementioned types identified by analysis of the amino acid sequence set out in Figure 1.
  • such preferred regions include Garnier-Robson alpha-regions, beta-regions, turn-regions, and coil-regions, Chou- Fasman alpha-regions, beta-regions, and turn-regions, Kyte-Doolittle hydrophilic regions and Hopp-Woods hydrophobic regions, Eisenberg alpha- and beta-amphipathic regions, Karplus- Schulz flexible regions, Jameson- Wolf regions of high antigenic index and Emini surface- forming regions.
  • the above-mentioned preferred regions set out in Figure 9 and in Table III include, but are not limited to, regions of the aforementioned types identified by analysis of the amino acid sequence set out in Figure 9.
  • such preferred regions include Garnier-Robson alpha-regions, beta-regions, turn-regions, and coil-regions, Chou- Fasman alpha-regions, beta-regions, and turn-regions, Kyte-Doolittle hydrophilic regions and Hopp-Woods hydrophobic regions, Eisenberg alpha- and beta-amphipathic regions, Karplus- Schulz flexible regions, Jameson-Wolf regions of high antigenic index and Emini surface- forming regions.
  • the polynucleotides of the invention encode functional attributes of TR14.
  • Preferred embodiments of the invention in this regard include fragments that comprise alpha-helix and alpha-helix forming regions ("alpha-regions"), beta-sheet and beta-sheet forming regions ("beta-regions"), turn and turn-forming regions ("turn-regions”), coil and coil-forming regions ("coil-regions”), hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions and high antigenic index regions of TR14.
  • the data representing the structural or functional attributes of TR13 (SEQ ID NO:2) set forth in Figure 3 and/or Table I, as described above, was generated using the various modules and algorithms of the DNA*STAR set on default parameters.
  • the data presented in columns VIII, IX, XIII, and XIV of Table I can be used to determine regions of TR13 which exhibit a high degree of potential for antigenicity. Regions of high antigenicity are determined from the data presented in columns VIII, IX, XIII, and/or XIV by choosing values which represent regions of the polypeptide which are likely to be exposed on the surface of the polypeptide in an environment in which antigen recognition may occur in the process of initiation of an immune response.
  • the data representing the structural or functional attributes of TR14 (SEQ ID NO:61 , as set forth in Figure 11 and/or Table IV; or, alternatively, SEQ ID NO:5, as set forth in Figure 6 and/or Table II), as described above, were generated using the various modules and algorithms of the DNA*STAR set on default parameters.
  • the data presented in columns VIII, IX, XIII, and XIV of Table II can be used to determine regions of TR14 which exhibit a high degree of potential for antigenicity.
  • Regions of high antigenicity are determined from the data presented in columns VIII, IX, XIII, and/or XIV by choosing values which represent regions of the polypeptide which are likely to be exposed on the surface of the polypeptide in an environment in which antigen recognition may occur in the process of initiation of an immune response. Certain preferred regions in these regards are set out in Figure 6, but may, as shown in
  • Table II be represented or identified by using tabular representations of the data presented in Figure 6.
  • the DNA*STAR computer algorithm used to generate Figure 6 (set on the original default parameters) was used to present the data in Figure 6 in a tabular format (See Table II).
  • the tabular format of the data in Figure 6 may be used to easily determine specific boundaries of a preferred region.
  • FIG. 11 Certain even more preferred regions in these regards are set out in Figure 11 , but may, as shown in Table IV, be represented or identified by using tabular representations of the data presented in Figure 11.
  • the DNA*STAR computer algorithm used to generate Figure 11 was used to present the data in Figure 11 in a tabular format (See Table IV).
  • the tabular format of the data in Figure 11 may be used to easily determine specific boundaries of a preferred region.
  • the above-mentioned preferred regions set out in Figure 11 and in Table IV include, but are not limited to, regions of the aforementioned types identified by analysis of the amino acid sequence set out in Figures 10A-H.
  • such preferred regions include Garnier-Robson alpha-regions, beta-regions, turn-regions, and coil- regions, Chou-Fasman alpha-regions, beta-regions, and turn-regions, Kyte-Doolittle hydrophilic regions and Hopp-Woods hydrophobic regions, Eisenberg alpha- and beta- amphipathic regions, Karplus-Schulz flexible regions, Jameson-Wolf regions of high antigenic index and Emini surface-forming regions.
  • the above-mentioned preferred regions set out in Figure 6 and in Table II include, but are not limited to, regions of the aforementioned types identified by analysis of the amino acid sequence set out in Figures 4A-D.
  • such preferred regions include Garnier-Robson alpha- regions, beta-regions, turn-regions, and coil-regions, Chou-Fasman alpha-regions, beta-regions, and turn-regions, Kyte-Doolittle hydrophilic regions and Hopp-Woods hydrophobic regions, Eisenberg alpha- and beta-amphipathic regions, Karplus-Schulz flexible regions, Jameson-Wolf regions of high antigenic index and Emini surface-forming regions.
  • Trp 175 A T 139 1 16 * * -020 097

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Abstract

L'invention concerne deux nouvelles protéines, TR13 et TR14, qui sont des membres de la superfamille des récepteurs du facteur de nécrose des tumeurs (TNF). En particulier, l'invention concerne des molécules d'acides nucléiques isolées qui codent pour les protéines humaines TR13 et TR14. L'invention concerne aussi des polypeptides de TR13 et de TR14 ainsi que des vecteurs, des cellules hôtes et des procédés de recombinaison permettant de produire ceux-ci. L'invention concerne de plus des méthodes de criblage visant à identifier des agonistes et des antagonistes de TR13 et de TR14.
EP00947411A 1999-07-16 2000-07-14 Recepteurs du facteur de necrose des tumeurs humain tr13 et tr14 Withdrawn EP1203024A4 (fr)

Applications Claiming Priority (9)

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US14408799P 1999-07-16 1999-07-16
US144087P 1999-07-16
US14945099P 1999-08-18 1999-08-18
US149450P 1999-08-18
US14971299P 1999-08-20 1999-08-20
US149712P 1999-08-20
US15308999P 1999-09-10 1999-09-10
US153089P 1999-09-10
PCT/US2000/019343 WO2001005834A1 (fr) 1999-07-16 2000-07-14 Recepteurs du facteur de necrose des tumeurs humain tr13 et tr14

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EP1203024A1 true EP1203024A1 (fr) 2002-05-08
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US6951738B2 (en) * 1999-07-16 2005-10-04 Human Genome Sciences, Inc. Human tumor necrosis factor receptors TR13 and TR14
AU2002246999A1 (en) * 2001-01-17 2002-07-30 Human Genome Sciences, Inc. Human tumor necrosis factor receptors tr13 and tr14
WO2003047614A1 (fr) * 2001-12-05 2003-06-12 Genset S.A. Agoniste et antagonistes de redax pour traiter les troubles du metabolisme
WO2003047615A1 (fr) * 2001-12-05 2003-06-12 Genset S.A. Traitement de troubles metaboliques au moyen d'agonistes et d'antagonistes de dexar

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US6072047A (en) * 1997-02-13 2000-06-06 Immunex Corporation Receptor that binds trail
ATE397662T1 (de) * 1997-02-27 2008-06-15 Ono Pharmaceutical Co Neues polypeptid, dafür kodierende dna und deren verwendungen
JP2001512013A (ja) * 1997-08-01 2001-08-21 ジェンセット 前立腺に発現される分泌タンパク質の５’ｅｓｔ
ES2267192T3 (es) * 1997-08-01 2007-03-01 Serono Genetics Institute S.A. Ests 5' para proteinas secretadas no especificas de tejido.
JP2002508934A (ja) * 1997-12-29 2002-03-26 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Ｔｎｆレセプターに対して相同性を有する、新規な核酸およびポリペプチド

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Title
DATABASE SWALL [Online] 1 June 1998 (1998-06-01) "Tumor necrosis factor receptor II homolog" Database accession no. O57116 XP002224397 *
LATZA UTE ET AL: "The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen." EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 24, no. 3, 1994, pages 677-683, XP009003157 ISSN: 0014-2980 -& DATABASE SWALL [Online] 1 November 1995 (1995-11-01) "Tumor necrosis factor receptor superfamily member 4 precursor (OX40L receptor) (ACT35 antigen) (TAX-transcriptionally activated glycoprotein 1 receptor) (CD134 antigen)" Database accession no. p43489 XP002224396 *
NAISMITH J H ET AL: "Modularity in the TNF-receptor family" TIBS TRENDS IN BIOCHEMICAL SCIENCES, ELSEVIER PUBLICATION, CAMBRIDGE, EN, vol. 23, no. 2, 1 February 1998 (1998-02-01), pages 74-79, XP004108007 ISSN: 0968-0004 *
See also references of WO0105834A1 *

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WO2001005834A1 (fr) 2001-01-25
AU780060B2 (en) 2005-02-24
WO2001005834A9 (fr) 2002-07-18

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