Tall-1 receptor homologues

Details Tall-1 receptor homologues Tall-1 receptor homologues

2000-05-05

2002-11-05

Spector, Lorraine (Department: 1646)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S350000, C536S023500, C435S069100

Reexamination Certificate

active

06475987

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to ligand involved in B lymphocyte activation and proliferation, TALL-1, and to its receptor, TALL-1 receptor. More particularly, the present invention relates to TALL-1 and TALL-1 receptor, to homologues of such proteins, to nucleic acid molecules encoding such proteins, and to methods of making and using such proteins.
BACKGROUND OF THE INVENTION
Members of the tumor necrosis factor (TNF) ligand family play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis, modulation of immune response and induction of inflammation (Smith et al., (1994),
Cell
76:959-962; Grewal et al., (1996), The role of CD40 ligand in immunity and auto-immunity. Page 125-134. In Immune Tolerance, editors: J. Banchereau, B. Dodet, R.
Schwartz, E. Trannoy. Elsevier Press: Paris.; Nataga, (1997),
Cell
88:355-365; Baker et al., (1998),
Onocogene
17:3261-3270; Ashkenazi et al., (1999),
Curr. Opin. Cell Biol.
11:255-260). At least sixteen members of the TNF ligand family have been identified. These include TNF, FasL, Lymphotoxin-&agr;, Lymphotoxin-&bgr;, TRA1L/APO-2L, CD27L, CD30L, CD40L, 4-1BBL, OX40L, TRANCE/RANKL, LIGHT, TWEAK, TL 1, APRIL/TALL-2 and TALL-1 (Smith et al., (1994),
Cell
76:959-962; Grewal et al., (1996), The role of CD40 ligand in immunity and auto-immunity. Page 125-134. In Immune Tolerance, editors: J. Banchereau, B. Dodet, R. Schwartz, E. Trannoy. Elsevier Press: Paris.; Nataga, (1997),
Cell
88:355-365; Baker et al., (1998),
Onocogene
17:3261-3270; Ashkenazi et al., (1999),
Curr. Opin. Cell Biol.
11:255-260; Shu et al., (1999),
J. Leukocyte Biology
65:680-683; Schneider et al., (1999),
J. Exp. Med.
189:1747-1756; Moore et al., (1999),
Science
285:260-263; Mukhopadhyay et al., (1 999),
J. Biol. Chem.
274:15978-15981). Most TNF family members are synthesized as type II transmembrane precursors. Their extracellular domains can be cleaved by metalloproteinases to form soluble cytokines. The soluble and membrane-bound TNF ligand family members bind to receptors belonging to the TNF receptor family, which are type I transmembrane proteins with characteristic cysteine rich motifs (Smith et al., (1994),
Cell
76:959-962; Nataga, (1997),
Cell
88:355-365; Baker et al., (1998),
Oncogene
17:3261-3270; Ashkenazi et al., (1999),
Curr. Opin. Cell Biol.
11:255-260).
Members of the TNF family interact with their cognate receptors either through cell-cell interactions or as soluble proteins after their extracellular domains are cleaved by metalloproteinases (Smith et al., (1 994),
Cell
76:959-962; Nataga, (1 997),
Cell
88:355 -365). The TNF receptor family contains about 20 members. Stimulation of TNF receptor family members by their ligands triggers overlapping and divergent intracellular signal transduction pathways, including those that lead to apoptosis, NF-&kgr;B and AP1 activation (Smith et al., (1994),
Cell
76:959-962; Nataga, (1997),
Cell
88:355-365). Therefore regulation of TNF family members that specifically affect immune responses is desirable.
A wide variety of medical treatments require regulation of the immune response in a patient. Such treatments include, for example, vaccinations, treatments for autoimmune diseases, immunodeficiency diseases, immunoproliferative diseases, and treatments involving the transplantation of organs and skin. Traditional reagents and methods used to regulate a subject's immune response often results in unwanted side effects. For example, immunosuppressive reagents such as cyclosporin A, azathioprine, and prednisone are used to suppress the immune system of a patient with an autoimmune disease or patients receiving transplants. Such reagents, however, suppress a patient's entire immune response, thereby crippling the ability of the patient to mount an immune response against infectious agents not involved in the original disease. Due to such harmful side effects and the medical importance of immune regulation, reagents and methods to regulate specific parts of the immune system have been the subject of study for many years.
The present invention can be used to overcome traditional problems with immunoregulatory reagents by more specifically regulating cells, ligands and receptors of the immune system in vivo.
SUMMARY OF THE INVENTION
The present invention generally relates to TALL-1 nucleic acid molecules, proteins (including homologues), antibodies, and methods of making and using the same. The present invention also relates to TALL-1 receptor nucleic acid molecules, proteins (including homologues), antibodies, and methods of using the same. In particular, the present invention relates to methods of regulating the interaction between TALL-1 and the TALL-1 receptor to regulate monocyte, macrophage and B lymphocyte mediated immune responses.
One embodiment of the present invention relates to an isolated TALL-1 protein. Preferably, the isolated TALL-1 protein comprises an amino acid sequence selected from the group of: (a) SEQ ID NO:2; and (b) a homologue of SEQ ID NO:2. The homologue comprises an amino acid sequence selected from the group of: (i) an amino acid sequence that is at least about 40% identical to SEQ ID NO:2 over at least 175 amino acids of SEQ ID NO:2; and, (ii) an amino acid sequence that is at least about 40% identical to SEQ ID NO:2 over positions 134-285 of SEQ ID NO:2. In a more preferred embodiment, the protein comprises an amino acid sequence selected from the group of: (a) an amino acid sequence that is at least about 60% identical to SEQ ID NO:2 over at least 175 amino acids of SEQ ID NO:2; and, (b) an amino acid sequence that is at least about 60% identical to SEQ ID NO:2 over positions 134-285 of SEQ ID NO:2. In an even more preferred embodiment, the protein comprises an amino acid sequence selected from the group of: (a) an amino acid sequence that is at least about 80% identical to SEQ ID NO:2 over at least 175 amino acids of SEQ ID NO:2; and, (b) an amino acid sequence that is at least about 80% identical to SEQ ID NO:2 over positions 134-285 of SEQ ID NO:2. In an even more preferred embodiment, the protein comprises an amino acid sequence selected from the group consisting of: (a) an amino acid sequence that is at least about 90% identical to SEQ ID NO:2 over at least 175 amino acids of SEQ ID NO:2; and, (b) an amino acid sequence that is at least about 90% identical to SEQ ID NO:2 over positions 134-285 of SEQ ID NO:2.
In another embodiment, the isolated TALL-1 protein of the present invention has an amino acid sequence comprising at least about 30 contiguous amino acids of SEQ ID NO:2. Preferably, the protein has an amino acid sequence comprising at least about 50 contiguous amino acids of SEQ ID NO:2, and more preferably, at least about 130 contiguous amino acids of SEQ ID NO:2. In a particularly preferred embodiment, the protein comprises amino acid residues 134 through 285 of SEQ ID NO:2. In another particularly preferred embodiment, the protein comprises an amino acid sequence represented by SEQ ID NO:2.
In another embodiment, the isolated TALL-1 protein of the present invention is encoded by a nucleic acid molecule comprising a nucleic acid sequence that hybridizes under low stringency conditions, and preferably, moderate stringency conditions, and more preferably, high stringency conditions, to the complement of a nucleic acid sequence represented by SEQ ID NO:1. In a particularly preferred embodiment, the protein is encoded by a nucleic acid molecule comprising a nucleic acid sequence represented by SEQ ID NO:1. In another particularly preferred embodiment, the protein is encoded by a nucleic acid molecule comprising a nucleic acid sequence represented by nucleotide positions 402 through 855 of SEQ ID NO:1.
In one embodiment of the present invention, an isolated TALL-1 protein is soluble. In another embodiment, the isolated TALL-1 protein is a membrane protein. Preferably, the isolated TALL-1 protein of the present invention has TALL-1 biological activity

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