Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2000-08-03
2003-02-18
Eyler, Yvonne (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C536S023500, C435S320100, C435S325000, C435S252100, C435S007100, C530S350000
Reexamination Certificate
active
06521422
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of recombinant genetics. In particular, the present invention relates to a novel receptor ligand, designated Fhm, belonging to the TNF ligand supergene family and nucleic acid molecules encoding the same. The invention also relates to vectors, host cells, anti-Fhm antibodies, and recombinant methods for producing Fhm polypeptides. The invention also relates to the use of the recombinant Fhm polypeptide to identify putative binding partners/receptors. In addition, provided for are methods and reagents for the diagnosis of diseases associated with abnormal Fhm or abnormal expression of its putative receptor, and methods and pharmaceutical compositions for the treatment of diseases associated with abnormal Fhm or abnormal expression of Fhm and/or itsreceptor. The invention also discloses pharmaceutical compositions for use in the treatment of these diseases.
BACKGROUND OF THE INVENTION
Technical advances in the identification, cloning, expression and manipulation of nucleic acid molecules have greatly accelerated the discovery of novel therapeutics based upon deciphering the human genome. Rapid nucleic acid sequencing techniques can now generate sequence information at unprecedented rates, and coupled with computational analyses, allow the assembly of overlapping sequences into entire genome and the identification of polypeptide-encoding regions. Comparison of a predicted amino acid sequence against a database compilation of known amino acid sequences can allow one to determine the extent of homology to previously identified sequence and/or structure landmarks. Cloning and expression of a polypeptide-encoding region of a nucleic acid molecule provides a polypeptide product for structural and functional analysis. Manipulation of nucleic acid molecules and encoded polypeptides to produce variants and derivatives thereof may confer advantageous properties on a product for use as a therapeutic.
However, in spite of the significant technical advances in genome research over the past decade, the potential for development of novel therapeutics based on the human genome is still largely unrealized. While a number of genes encoding potentially beneficial protein therapeutics, or those encoding polypeptides which may act as “targets” for therapeutic molecules, have been identified using recombinant DNA technology, the structure and function of a vast number of genes in the genome of mammals are yet unknown.
Identification and Characterization of TNF-Family of Ligands and Receptors
Tumor necrosis factor (TNF) was first identified in the serum of mice and rabbits which had been infected with bacillus of Calmette and Guerin(BCG) and which had been injected with endotoxin. TNF activity in the serum of these animals was recognized on the basis of its cytotoxic and anti-tumor activities. This TNF activity, referred to as TNF-&agr;, is produced particularly by activated monocytes and macrophages, and has been implicated in normal growth processes as well as in a variety of diseases.
Following the discovery of TNF-&agr;, independent research led to the identification of another cytokine associated with inflammatory responses lymphotoxin-&agr; (LT-&agr;), which was shown to be produced exclusively by lymphocytes. LT-&agr; was subsequently shown to be 30% homologous with TNF-&agr;, and was renamed TNF-&bgr;. It is now clear that TNF-&agr; and TNF-&bgr; are members of a gene family that includes yet another member termed LT-&bgr; (Browning et al.,
Cell
72:847-856, 1993). The three genes are tightly linked within the MHC complex and show similar organization. Moreover, the biologically active forms of TNF-&agr; and TNF-&bgr; are homotrimers and share many of the same biological activities including competing for the same cell-surface receptors (Agarwal et al.,
Nature
318:665-667, 1985). Two distinct but structurally homologous receptors have been identified, and each has been shown to bind both the ligands and mediate their effects.
However, it has been recognized that TNFs are only representative members of the rapidly expanding supergene familiy that includes TNF-&agr;, TNF-&bgr;/lymphotoxin-&agr; (LT-&agr;), lymphotoxin-&bgr; (LT-&bgr;), FasL, CD40L, CD30L, CD27L, 4-1BBL, and TNF-related apoptosis-inducing ligand (TRAIL), RANKL, GITRL and TNF-2. See generally Orlinick et al.,
Cell Signal,
10(8):543-551 (1998). The distinctive but overlapping cellular responses induced by members of the TNF family of ligands following their interaction(s) with their cognate cell-surface receptors result in clearly defined developmental and regulatory changes in cells of the lymphoid, hematopoietic, and other lineages. For example, the TNF family of ligands are involved in growth regulation and differentiation of cells which are involved in inflamation, immune processes and hematopoiesis (Bayert, R. and Fiers, W.,
Tumor Necrosis Factor and Lymphokines
in: Cytokines eds. Anthony Mire-Sluis and Robin Thorpe, Academic Press San Diego Calif., 1998). The TNF family of ligands activates the immune defenses against parasites, and act directly or indirectly as mediators in immune reactions and inflammatory processes. However, administration of TNF and/or other members of the TNF family can also be accompanied by harmful phenomena such as shock and tissue damage (Bayert, R. and Fiers, W., supra). The main physiological role of the TNF family of ligands is the activation of first-line reaction of an organism to microbial, parasitic, viral infections, or to mechanical stress and cancer. For example, TNF-related apoptosis-inducing ligand (TRAIL) has been demonstrated to induce apoptosis of a number of different types of cancer cells as well as virally infected cells.
Furthermore, a number of observations have also led to the conclusion that the TNF family of ligands are also involved in a variety of pathological conditions including cachexia, toxic shock syndrome, inflammatory diseases such as rheumatoid and osteoarthritis, and in lethality resulting from graft-versus-host reaction (GVHR) rapid necrosis of tumors, apoptosis, immunostimulation and resistance to parasites and viruses. (Bayert, R. and Fiers, W., supra).
Like other cytokines, the members of the TNF family of ligands act via specific cell-surface receptors. The receptors, with two exceptions, are type 1 membrane-associated proteins. Sequence homology amongst them is almost entirely confined to their extracellular domains. For example, two TNF receptors have been cloned which differ in size and in binding affinity (Bayert, R. and Fiers, W., supra). Both receptors bind TNF-&agr; and TNF-&bgr; and are membrane associated proteins. The two receptors consist of extracellular domains which bind TNF (and are homologous for 28%), single transmembrane domains, and intracellular domains which are totally different from each other and which do not contain any recognizable structural motifs that have been associated with any particular function. Based on similarities in their extracellular domains, these receptors belong to a receptor gene superfamily that includes the low-affinity nerve growth factor (NGF) receptor, the Fas antigen, the TNFR-RP, TRAIL-R, PV-A53R, RANK, GITR, and the OX40 antigen found on activated T-cells (Smith et al.,
Cell,
76(6):959-962, 1994; Baker and Reddy,
Oncogene,
12(1):1-9, 1996).
In addition to the membrane associated receptor molecules described above, a number the receptors belonging to the TNF-receptor supergene family exist as soluble ligand binding proteins. Many of the soluble forms of the transmembrane receptors were subsequently identified as containing only the extracellular ligand binding domain(s) of the receptors. For example, a soluble form of TNF receptor has been found in urine and serum (See U.S. Pat. No.: 5,843,789 and Nophar et al.,
EMBOJ.,
9(10):3269-3278, 1990), and has been shown to arise by proteolytic cleavage of cell surface TNF-receptors (Wallach et al.,
Agents Actions Suppl.,
35:51-57 1991). These soluble forms of receptor molecules have been impli
Boyle William James
Hsu Hailing
Wooden Scott Kenneth
Amgen Inc.
Andres Janet L.
Eyler Yvonne
Marshall Gerstein & Borun
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