Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1999-06-15
2001-11-06
Mertz, Prema (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C435S069100
Reexamination Certificate
active
06313269
ABSTRACT:
FIELD OF INVENTION
This invention relates to newly identified polynucleotides, polypeptides encoded by them and to the use of such polynucleotides and polypeptides, and to their production. More particularly, the polynucleotides and polypeptides of the present invention relate to Tumor Necrosis Factor Related family, hereinafter referred to as TR6. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides.
BACKGROUND OF THE INVENTION
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 intracellular response.
For example, tumor necrosis factors (TNF) alpha and beta are cytokines which act through TNF receptors to regulate numerous biological processes, including in host defense processes such as protection against infections, and pathological conditions such as shock responses and inflammatory disease condistions. TNF-X belongs to the “TNF-ligand” superfamily of which 19 members have been identified so far. These ligands mediate their effects through interactions with cell surface or secreted, decoy, receptors, expressed by many different cell types, and which themselves now form a superfamily with 24 indentified members to date.
Among the ligands there are included TNF-&agr;, lymphotoxin&agr; (LT-&agr;, also known as TNF-&bgr;), LT-&bgr; (found in heterotrimeric complexes, LT-&agr;2-&bgr;), FasL, CD40L, CD27L, CD30L, 4-1BBL, OX40L and nerve growth factor (NGF)). The receptor superfamily includes the p55 and p75 TNF receptor, FAS APO-1, CD40, CD27, CD30, 4-1BB, OX40 and the low affinity p75 NGF-receptor (Meager, A., Biologicals, 22:291-295 (1994)).
Many members of the TNF-ligand superfamily are expressed by cells of the immune and hematopoietic system which underscores their role in differentian of the cells of the immune cells and functional responses in host defense mechanisms (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-&agr; and LT-&agr; are capable of binding to two TNF receptors (the 55- and 75-kd TNF receptors). A large number of biological effects are elicited by TNF-&agr; and LT-&agr;, 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-&agr; and LT-&agr; are involved in the pathogenesis of a wide range of diseases, including endotoxic shock, cerebral malaria, tumors, autoimmuine diseases, allergic disorders, AIDS and graft 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)).
The effects of TNF ligand and TNF receptor families are varied and influence numerous functions, both normal and abnormal, in the biological processes of mammalian and non-mammalian species. 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 novel members of the TNF receptor family.
This indicates that these receptors have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further receptors which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, chronic and acute inflammation, arthritis (including rheumatoid arthritis), septicemia, autoimmune diseases (e.g. inflammatory bowel disease, psoriasis), transplant rejection, graft vs. host disease, infection, stroke, ischernia, acute respiratory disease syndrome, asthma, restenosis, brain injury, AIDS, Bone diseases, cancer atheroschlerosis, and Alzheimers disease.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to TR6 polypeptides and recombinant materials and methods for their production. Another aspect of the invention relates to methods for using such TR6 polypeptides and polynucleotides and recombinant materials. Such uses include the treatment of chronic and acute inflammation, arthritis (including rheumatoid arthritis), septicemia, autoimmune diseases (e.g. inflammatory bowel disease, psoriasis), transplant rejection, graft vs. host disease, infection, stroke, ischemia, acute respiratory disease syndrome, asthma, restenosis, brain injury, AIDS, Bone diseases, cancer, atheroschlerosis, and Alzheimers disease, among others. Another aspect of the invention relates to methods of using such TR6 polynucleotides, polypeptides and recombinant materials for inhibiting angiogenesis and also inhibiting production of TNF-&agr; and eicosanolds.
In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with TR6 imbalance with the identified compounds.
Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate TR6 activity or levels.
DESCRIPTION OF THE INVENTION
Definitions
The following definitions are provided to facilitate understanding of certain terms used frequently herein.
“TR6” refers, among others, to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:2, or an allelic variant thereof.
“Fusion protein” refers to a protein encoded by two, often unrelated, fused genes or fragments thereof. In one example, EP-A-O 464 533 discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, employing an immunoglobulin Fc region as a part of a fusion protein is advantageous for use in therapy and diagnosis resulting in, for example, improved pharmacokinetic properties [see, e.g., EP-A 0232 262]. On the other hand, for some uses it would be desirable to be able to delete the Fc part after the fusion protein has been expressed, detected and purified.
In the case of TR6 fusion protein, in one embodiment for example, the fusion protein can be a fusion of the extracellular portion of TR6 fused with the Fc portion of human IgG. In one exemplified construct of SEQ ID NO: 7 of Table 5, extra amino acid residues were introduced within a hinge region between the TR6 and the IgG Fc portions of the molecule to facilitate cleavage of the protein by Factor Xa. This is sometimes desirable to facilitate the enzymatic cleavage of the IgG Fc portion of the recombinant protein from the TR6 part, either to facilitate binding studies or for generation of antibodies selectively to the TR6 portion of the recombinant protein. However, in clinical applications, although it may sometimes be desirable to introduce enzymatic cleavage si
Deen Keith C.
Marshall Lisa A.
Roshak Amy K.
Tan Kong B.
Truneh Alemseged
Han William T.
King William T.
Mertz Prema
Ratner & Prestia
SmithKline Beecham Corporation
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