Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-09-16
2001-10-02
Spector, Lorraine (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S252300, C435S361000, C435S007100, C436S501000, C530S350000, C530S351000, C536S023500
Reexamination Certificate
active
06297022
ABSTRACT:
FIELD OF INVENTION
The present invention relates to tumor necrosis factor receptor (TNF-R) related polypeptides (proteins) and their ligands, hereinafter referred to as TR1, TR3, TR5, and TL3. The invention also relates to inhibiting or activating the action of such polypeptides using agonists or antagonists by the screening methods described herein.
BACKGROUND OF THE INVENTION
Many biological actions are a response to certain stimuli and natural biological processes, and are controlled by factors, such as cytokines. These cytokines act through target cell receptors by engaging the receptor and producing an intracellular response.
For example, 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, ten members of the TNF ligand superfamily have been identified and thirteen members of the TNF-receptor superfamily have been characterized.
Among the ligands there are included TNF-a, lymphotoxin-a (LT-a, also known as TNF-b), LT-b (found in complex heterotrimer LT-a2-b), FasL, CD40L, CD27L, CD30L, 4-1BBL, OX40L and TRAIL ((Wiley et al. Immunity 3: 673-682 (1995)) All but one of these (LTa) are expressed as type II membrane proteins. 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,NGF-receptor(Meager, A., Biologicals, 22:291-295 (1994)).
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. (Meager, A., 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. For example, naturally occurring mutations in the FAS antigen and its ligand cause lymphoproliferative disease (Watanabe-Fukunaga, R., 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 immunoglubulin M and low levels of immunoglobulin G in plasma, indicating faulty T-cell-dependent B-cell activation (Allen, R. C. 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 (Lee, K. F. et al, Cell 69:737 (1992)).
TNF and LT-a are capable of binding to two TNF receptors (the 55- and 75-kd TNF receptors). A large number of biological effects elicited by TNF and LT-a, acting through their receptors, include hemorrhagic necrosis of transplanted tumors, cytotoxicity, a role in endotoxic shock, inflammation, immunoregulation, proliferation and anti-viral responses, as well as protection against the deleterious effects of ionizing radiation. TNF and LT-a are involved in the pathogenesis of a wide range of diseases, including endotoxic shock, cerebral malaria, tumors, autoimmuine disease, AIDS and graft-host rejection (Beutler, B. and Von Huffel, C., Science 264:667-668 (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)). Other regions of the TNF receptor intracellular domain are responsible for the activation of transcription through NF-kB (Cheng and Baltimore Genes and Development 10: 963-973 (1996)). More recent evidence has suggested that receptors may induce signals in cells expressing membrane bound TNF family ligand in a process known as “reverse signaling” (Wiley et al., J. Immunol. 157:3635-3639.
The effects of TNF family ligands and TNF family 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 normal and in disease states. In particular, there is a need to isolate and characterize novel members of the TNF receptor family and their ligands.
This indicates that these Tumor necrosis factor receptors (TNF-R) and their ligands have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of Tumor necrosis factor receptor (TNF-R) family and their ligands which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, chronic and acute inflammation, arthritis, septicemia, autoimmune diseases (eg inflammatory bowel disease, psoriasis), transplant rejection, graft vs. host disease, infection, stroke, ischemia, acute respiratory disease syndrome, restenosis, brain injury, AIDS, Bone diseases, cancer (eg lymphoproliferative disorders), atheroschlerosis, and Alzheimers disease.
SUMMARY OF THE INVENTION
The present invention relates to tumor necrosis factor receptor (TNF-R) related polypeptides and their ligarids, hereinafter referred to as TR1, TR3, TR5, and TL3. The invention also relates to methods to identify agonists and antagonists of TR1, TR3, TR5 and TL3. The agonists and antagonists thus identified can be used to treat chronic and acute inflammation, arthritis, septicemia, autoimmune diseases (eg inflammatory bowel disease, psoriasis), transplant rejection, graft vs. host disease, infection, stroke, ischemia, acute respiratory disease syndrome, restenosis, brain injury, AIDS, bone diseases, cancer (eg lymphoproliferative disorders), atheroschlerosis, and Alzheimers disease, among others, caused by imbalance of TR1, TR3, TR5, or TL3.
DESCRIPTION OF THE INVENTION
“TR1, or TR1 polypeptide or TR1 protein” refers, among others, generally to a polypeptide having the amino acid sequence set forth in SEQ ID NO: 1 as well as polypeptides comprising the amino acid sequence of SEQ ID NO: 1; and polypeptides comprising the amino acid sequence which have at least 70% identity to that of SEQ ID NO: 1 over its entire length. Furthermore, TR1 also refers to a polypeptide which comprises a sequence which has 70% identity to a fragment of SEQ ID NO: 1. “TR1 or TR1 polypeptide or TR1 protein” also includes derivatives, such as fusion proteins, of the above polypeptides, and some of these derivatives are further illustrated below.
“TR3 or TR3 polypeptide or TR3 protein” refers, among others, generally to a polypeptide having the amino acid sequence set forth in SEQ ID NO:2 as well as polypeptides comprising the amino acid sequence of SEQ ID NO: 2; and polypeptides comprising the amino acid sequence which have at least 70% identity to that of SEQ ID NO:3 over its entire length. Furthermore, TR3 also refers to a polypeptide which comprises a sequence which has 70% identity to a fragment of SEQ ID NO: 2. “TR3 or TR3 polypeptide or TR3 protein” also includes derivatives, such as fusion proteins, of the above polypeptides, and some of these derivatives are further illustrated below.
“TR5 or TR5 polypeptide or TR5 protein” refers, among others, generally to a polypeptide having the amino acid sequence set forth in SEQ ID NO:3 as well as polypeptides comprising the amino acid sequence of SEQ ID NO: 3; and polypeptides comprising the amino acid sequence which have at least 70% identity to that of SEQ ID NO:3 over its entire length. Furthermore, TR5 also refers to a polypeptide which comprises a sequence which has 70% identity to a fragment of SEQ ID NO: 3. “TR5 or TR5 polypeptide or TR5 protein” also includes derivatives, such a
McDonnell Peter C.
Young Peter R
Zou Jun
Han William T.
King William T.
Kinzig Charles M.
O'Hara Eileen B.
SmithKline Beecham Corporation
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