Protein belonging to the TNF superfamily involved in signal transduction, nucleic acids encoding same, and methods of use thereof
AssigneeThe Rockefeller University
InventorsYongwon Choi, Brian Wong, Regis Josien, Ralph Steinman
Life of this patent
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Abstract
A protein belonging to the TNF superfamily called TRANCE involved in signal transduction, along with nucleic acids comprising DNA sequences and degenerate variants thereof which encode TRANCE are disclosed. Modulators which are TRANCE agonists and TRANCE antagonists are also disclosed, and can be used in pharmaceutical compositions and methods disclosed herein to modulate the active life of mature dendritic cells, T cell activation, and immune response in mammal.
Claims58
An isolated nucleic acid molecule comprising the DNA sequence set forth in FIG. 1 (SEQ ID NO:1) or degenerate variants thereof.
An isolated nucleic acid molecule comprising the DNA sequence set forth in SEQ ID NO:3, or degenerate variants thereof.
A polypeptide having an amino acid sequence as set forth in FIG. 2 (SEQ ID NO:2) or a fragment thereof, or FIG. 4 (SEQ ID NO:4) or a fragment thereof.
The unicellular host according to claim 23, wherein said host cell is selected from the group consisting of E. coli, Pseudonomas, Bacillus, Strepomyces, yeast, CHO, R1.1. B-W, L-M, COS1, COS7, BSC1, BSC40, BMT10 and Sf9 cells.
A mammalian cell containing a TRANCE encoding DNA sequence and modfied in vitro to permit higher expression of TRANCE by means of a homologous recombinational event consisting of inserting a promoter in functional proximity to the TRANCE polypeptide encoding sequence.
A cell according to Claim wherein the promoter is a TRANCE polypeptide promoter and the homologous recombinational event replaces a mutant TRANCE polypeptide promoter.
A cell according to Claim, wherein the promoter insert is not a TRANCE promoter.
A modulator of immune response in a mammal, wherein said modulator is selected from the group consisting of:
- a) a polypeptide having an amino acid sequence set forth in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4) or degenerate variants thereof, or a fragment thereof;
- b) an analog or derivative of a polypeptide having an amino acid as set forth in FIG. 2 (SEQ ID NO:2), SEQ ID NO:4, or degenerate variants thereof, or a fragment thereof;
- fusion protein containing the amino acid sequence of FIG. 2 (SEQ ID NO:2) or a fragment thereof;
- c) a fusion protein wherein its amino acid sequence contains an amino acid sequence of FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4), degenerate variants thereof, or a fragment thereof;
- d) an antibody having an immunogen selected from the group consisting of:
- i) a polypeptide having an amino acid sequence set forth in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4) or degenerate variants thereof, or a fragment thereof;
- ii) an analog or derivative of a polypeptide having an amino acid as set forth in FIG. 2 (SEQ ID NO:2), SEQ ID NO:4, or degenerate variants thereof, or a fragment thereof;
- fusion protein containing the amino acid sequence of FIG. 2 (SEQ ID NO:2) or a fragment thereof;
- iii) a fusion protein wherein its amino acid sequence contains an amino acid sequence of FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4), degenerate variants thereof, or a fragment thereof;
- and
- d) an anti-sense TRANCE nucleic acid comprising at least one phosphodiester analog bond.
An analog or derivative of TRANCE, wherein the chemical moiety is a water-soluble polymer.
An anlog or derivative of claim 31, which is N-terminal monopegylated.
A method for modulating levels of expression of a TRANCE protein in a mammal, comprising the steps of:
- a) fremoving at least one hematopoietic stem cell from the mammal;
- b) destroying remaining hematopoietic stem cells in the mammal;
- c) transfecting the at least one hematopoietic stem cell with a vector containing a nucleic acid molecule which encodes a TRANCE protein such that the nucleic acid molecule becomes incorporated into the genome of the hematopoietic stem cell, forming a transfected hematopoietic stem cell;
- and
- d) introducing the transfected hematopoietic stem into the mammal so that the transfected hematopoietic stem cell can self replicate and differentiate within the mammal.
A method of diagnosing an immune system related condition in a mammal, wherein the method comprises the steps of:
- a) removing a bodily sample from the mammal;
- b) assaying the bodily sample to determine whether TRANCE is expressed in the bodily sample.
Dependencies are inferred from the claim text.