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  Novel receptor that causes cell deathUSPTO Application #: 20070298460Title: Novel receptor that causes cell death Abstract: Isolated apoptosis inducing receptors, DNAs encoding such receptors, and pharmaceutical compositions made therefrom, are disclosed. The isolated receptors can be used to regulate an immune response. The receptors are also useful in screening for inhibitors thereof. (end of abstract) Agent: Immunex Corporation Law Department - Seattle, WA, US Inventors: Mariapia A. Degli-Esposti Rankin, Raymond G. Goodwin USPTO Applicaton #: 20070298460 - Class: 435069100 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Micro-organism, Tissue Cell Culture Or Enzyme Using Process To Synthesize A Desired Chemical Compound Or Composition, Recombinant Dna Technique Included In Method Of Making A Protein Or Polypeptide The Patent Description & Claims data below is from USPTO Patent Application 20070298460. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a continuation of U.S. patent application Ser. No. 08/943,776, filed Oct. 3, 1997; which claims the benefit of U.S. provisional patent application Ser. No. 60/044,456, filed Oct. 4, 1996. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates generally to the field of cytokine receptors, and more specifically to cytokine receptor proteins having immunoregulatory activity. BACKGROUND OF THE INVENTION [0003] Efficient functioning of the immune system requires a fine balance between cell proliferation and differentiation and cell death, to ensure that the immune system is capable of reacting to foreign, but not self antigens. Central tolerance refers to the mechanisms which lead to positive and negative selection of T cells in the thymus where T cells are positively or negatively selected depending on their capacity to interact with self MHC antigens expressed in the thymus. In the periphery, mature T cells which interact with self antigens expressed uniquely in the periphery are deleted, as are T cells which have been activated by foreign antigen. This is known as peripheral tolerance. [0004] Deletion of inappropriately activated T cells is believed to occur via programmed cell death known as apoptosis, which is distinct from cell death due to necrosis. Two members of the TNF family, Fas ligand (FasL) and TNF, have been reported to be involved in some of the effector mechanisms which control immune tolerance (reviewed in Cleveland and Ihle, Cell 81:479; 1995). FasL and TNF mediate their biological effects by binding their respective receptors, which are members of the TNFR superfamily (Smith et al., Cell 76:959; 1994). [0005] Fas (the receptor for FasL) and TNF receptor type I (TNFRI) both contain a unique motif within their cytoplasmic regions, which has been termed the death domain (Tartaglia et al., Cell 74:845, 1993; Itoh and Nagata, J. Biol. Chem. 268:10932, 1993). Overexpression of the death domain in transient transfection systems has been shown to result in apoptosis. The biological effects of Fas/FasL and TNF/TNFRI interactions are thought to occur through both distinct and similar signaling pathways (Schultze-Osthoff et al., EMBO J. 13:4587, 1994; Wong and Goeddel, J. Immunol. 152:1751, 1994). [0006] The lpr and gld mouse models have implicated the Fas/FasL system in peripheral tolerance; however, peripheral T cell deletion does occur in lpr mice. This Fas-independent apoptosis of mature T cells has been shown to be partly TNF mediated (Zheng et al., Nature 377:348, 1995) These data imply that multiple apoptotic mechanisms, including unrecognized ones, may be involved in peripheral tolerance. Moreover, the mechanisms mediating central tolerance remain unknown. Investigation into the existence and identity of other molecule(s) that play a role in apoptosis is desirable. Identifying such molecules would provide an additional means of regulating apoptosis, as well as providing further insight into the development of self-tolerance by the immune system and the etiology of autoimmune diseases. SUMMARY OF THE INVENTION [0007] The present invention identifies a novel receptor, referred to as Apoptosis Inducing Receptor (AIR) that induces apoptosis of certain cells on which it is expressed. The receptor is a Type I transmembrane protein having 417 amino acid residues. Soluble forms of the receptor can be prepared and used to regulate cell death in a therapeutic setting; accordingly, pharmaceutical compositions comprising soluble forms of the novel receptor are also provided. Soluble forms of the receptor will also be useful in vitro to block apoptosis of AIR-expressing cells, or to screen for agonists or antagonists of AIR activity. The cytoplasmic domain of AIR will be useful in developing assays for inhibitors of AIR-induced cell death. Such inhibitors will have use in regulating cell death in a therapeutic setting as well as in vitro. Deleted forms and fusion proteins comprising the novel receptor are also disclosed. Agonists of AIR activity can be used to kill tumor cells that express AIR, or kill T cells expressing AIR in autoimmune diseases. These and other aspects of the present invention will become evident upon reference to the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIG. 1 presents an alignment of AIR and TNFRI death domain sequences. The 83 amino acid sequence of the TNFRI death domain is compared to the homologous sequence from the AIR cytoplasmic region. Identical and conserved amino acids (+) are shown in the middle line. DETAILED DESCRIPTION OF THE INVENTION [0009] A new TNF receptor-like sequence was identified in the EST database. Oligonucleotide primers were synthesized based on the EST sequence, and a full-length cDNA was cloned from a peripheral blood T cell library. The encoded protein was designated AIR, for Apoptosis Inducing Receptor. The receptor is a Type I transmembrane protein having 417 amino acid residues, with a predicted 24 amino acid signal sequence, a 173 amino acid extracellular domain, a 27 amino acid transmembrane domain, and a 193 amino acid cytoplasmic tail. The cytoplasmic region of AIR displayed significant amino acid homology (48% identity, 64% similarity) to the 83 amino acid sequence which encodes the Type I TNF receptor death domain. This region, conserved between TNFRI and Fas, is necessary and sufficient for transduction of an apoptotic signal to a cell expressing AIR. [0010] A search of the NCBI databank identified five expressed sequence tags (ESTs) having regions of identity with AIR DNA. These ESTs (NCBI accession numbers H41522, H46374, H46211, H46662, and H46424) are all human cDNA fragments. The NCBI records do not disclose any polypeptide encoded by the ESTs, and do not indicate what the reading frame, if any, might be. However, even if the knowledge of the reading frame revealed herein by disclosure of complete AIR coding regions is used to express the ESTs, none of the encoded polypeptides would have the biological properties of the presently-claimed AIR polypeptides. In other words, if each of the five ESTs were inserted into expression vectors downstream from an initiator methionine codon, in the reading frame elucidated herein, none of the resulting expressed polypeptides would contain a sufficient portion of the AIR protein to induce apoptosis. Apoptosis and the TNF/TNFR Superfamilies [0011] Efficient functioning of the immune system requires a fine balance between cell proliferation and differentiation and cell death. Central tolerance refers to the mechanisms which lead to positive and negative selection of T cells in the thymus. It is believed that T cells are positively or negatively selected depending on their capacity to interact with self MHC antigens expressed in the thymus: autoreactive T cells are eliminated, while those that recognize non-self antigens are selected for survival and differentiation. In the periphery, mature T cells which interact with self antigens expressed uniquely in the periphery are deleted, as are T cells which have been activated by foreign antigen. These mechanisms ensure that the immune system is capable of reacting to foreign, but not self antigens and that activated lymphocytes are removed after they have fulfilled their role Two members of the TNFR superfamily, Fas and TNFRI, are believed to play an important role in some of the effector mechanisms which control peripheral tolerance. Fas has been reported to mediate apoptosis and is believed to play a role in clonal deletion of self-reactive T-cells (Itoh et al., Cell 66:233, 1991; Watanabe-Fukunage et al., Nature 356:314, 1992). DNAs encoding Fas ligand have been isolated; binding of the Fas ligand to cells expressing Fas antigen has been demonstrated to induce apoptosis (Suda et al., Cell, 75:1169, 1993; Takahashi et al., International Immunology 6:1567, 1994). The lpr and gld mouse models have implicated the Fas/FasL system in the processes which lead to elimination of T cells after they have been activated by self or foreign antigen in the periphery. However, some peripheral T cell deletion still occurs in lpr mice. This Fas-independent apoptosis of mature T cells has been shown to be partly TNF mediated. [0012] Elimination of these T cells occurs by apoptosis, a morphologically defined type of cell death that can be differentiated from necrosis. Fas and TNFRI both contain a death domain, a unique motif present within their cytoplasmic regions (Tartaglia et al., Cell 74:845, 1993; Itoh and Nagata, J. Biol. Chem. 268:10932, 1993). This domain shows some similarity with a Drosophila protein referred to as reaper which is required for most, if not all programmed cell death in this species (White et al., Science 264:677, 1994). Overexpression of the death domain in transient transfection systems has been shown to result in apoptosis. [0013] The biological effects of Fas/FasL and TNF/TNFRI interactions are thought to occur through both distinct and similar signaling pathways (Schultze-Osthoff et al., EMBO J. 13:4587, 1994; Wong and Goeddel, J. Immunol. 152:1751, 1994). Both receptors couple ligand binding to tyrosine phosphorylation, and both activate sphingomyelinases. Cysteine proteinases have also been implicated in both FasL- and TNF-induced cell death; crmA, a product of the cowpox virus that inhibits cysteine proteases, inhibits both FasL- and TNF-induced apoptosis. Both FasL and TNF induce cell death within a few hours of binding their respective receptors, indicating that both signal pathways modulate latent cytoplasmic effector molecules; however, death induced by TNF tends to be slower than that induced by FasL. [0014] The body of data currently available regarding apoptosis imply that multiple apoptotic mechanisms, including those mediated by Fas and TNFRI as well as additional, unrecognized ligand/receptor interactions, may be involved in peripheral tolerance within the immune system. In addition, the mechanism or mechanisms mediating central tolerance remain unknown. FasL and TNF are unlikely to be involved in the latter, since positive and negative selection in the thymus appear normal in lpr and TNFR knock-out mice. The novel receptor described herein shares certain similarities with both Fas and TNFRI, and could be important in regulating cell death during the development of self-tolerance (either in the periphery or the thymus). DNAs, Proteins and Analogs [0015] The present invention provides isolated AIR polypeptides and analogs (or muteins) thereof having an AIR activity (i.e., causing apoptosis of cells expressing an AIR mutein or analog comprising the death domain when triggered appropriately; or for soluble forms, binding to AIR-specific antiboides or inhibition of apoptosis induced by signalling through AIR). Such proteins are substantially free of contaminating endogenous materials and, optionally, without associated native-pattern glycosylation. Derivatives of AIR within the scope of the invention also include various structural forms of the primary protein which retain biological activity. Due to the presence of ionizable amino and carboxyl groups, for example, an AIR protein may be in the form of acidic or basic salts, or may be in neutral form. Individual amino acid residues may also be modified by oxidation or reduction. The primary amino acid structure may be modified by forming covalent or aggregative conjugates with other chemical moieties, such as glycosyl groups, lipids, phosphate, acetyl groups and the like, or by creating amino acid sequence mutants. Covalent derivatives are prepared by linking particular functional groups to amino acid side chains or at the N- or C-termini. [0016] Derivatives of AIR may also be obtained by cross-linking agents, such as M-maleimidobenzoyl succinimide ester and N-hydroxysuccinimide, at cysteine and lysine residues. The inventive proteins may also be covalently bound through reactive side groups to various insoluble substrates, such as cyanogen bromide-activated, bisoxirane-activated, carbonyldiimidazole-activated or tosyl-activated agarose structures, or by adsorbing to polyolefin surfaces (with or without glutaraldehyde cross-linking). Once bound to a substrate, proteins may be used to selectively bind (for purposes of assay or purification) antibodies raised against the AIR or against other proteins which are similar to the AIR, as well as other proteins that bind AIR or its homologous proteins. Continue reading... Full patent description for Novel receptor that causes cell death Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Novel receptor that causes cell death patent application. 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