TALL-1 nucleic acid molecules, proteins, receptors and methods of use thereof

Abstract

The amino acid and nucleic acid sequence of a protein expressed by monocytes and macrophages, called TALL-1, are disclosed. Homologues, mimetics and antibodies that bind to TALL-1 are disclosed. Also disclosed is the TALL-1 receptor, and homologues of such receptor. The invention includes methods for regulating the interaction between TALL-1 and its receptor and for identifying compounds capable of such regulation. The invention also includes methods for regulating B lymphocyte proliferation, activation, and/or survival.

What is claimed is:  
     
         1 . An isolated TALL-1 protein.  
     
     
         2 . The isolated protein of  claim 1 , wherein said protein comprises an amino acid sequence selected from the group consisting of: 
 a. SEQ ID NO:2; and,    b. a homologue of SEQ ID NO:2, wherein said homologue comprises an amino acid sequence selected from the group consisting 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.  
   
     
     
         3 . The isolated protein of  claim 1 , wherein said protein comprises an amino acid sequence selected from the group consisting 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.    
     
     
         4 . The isolated protein of  claim 1 , wherein said protein comprises an amino acid sequence selected from the group consisting 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.    
     
     
         5 . The isolated protein of  claim 1 , wherein said 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.    
     
     
         6 . The isolated protein of  claim 1 , wherein said protein comprises at least about 30 contiguous amino acids of SEQ ID NO:2.  
     
     
         7 . The isolated protein of  claim 1 , wherein said protein comprises at least about 50 contiguous amino acids of SEQ ID NO:2.  
     
     
         8 . The isolated protein of  claim 1 , wherein said protein comprises at least about 130 contiguous amino acids of SEQ ID NO:2.  
     
     
         9 . The isolated protein of  claim 1 , wherein said protein comprises amino acid residues 134 through 285 of SEQ ID NO:2.  
     
     
         10 . The isolated protein of  claim 1 , wherein said protein comprises an amino acid sequence represented by SEQ ID NO:2.  
     
     
         11 . The isolated protein of  claim 1 , wherein said protein is encoded by a nucleic acid molecule comprising a nucleic acid sequence that hybridizes under low stringency conditions to the complement of a nucleic acid sequence represented by SEQ ID NO:1.  
     
     
         12 . The isolated protein of  claim 1 , wherein said protein is encoded by a nucleic acid molecule comprising a nucleic acid sequence that hybridizes under moderate stringency conditions to the complement of a nucleic acid sequence represented by SEQ ID NO:1.  
     
     
         13 . The isolated protein of  claim 1 , wherein said protein is encoded by a nucleic acid molecule comprising a nucleic acid sequence that hybridizes under high stringency conditions to the complement of a nucleic acid sequence represented by SEQ ID NO:1.  
     
     
         14 . The isolated protein of  claim 1 , wherein said protein is encoded by a nucleic acid molecule comprising a nucleic acid sequence represented by SEQ ID NO:1.  
     
     
         15 . The isolated protein of  claim 1 , wherein said 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.  
     
     
         16 . The isolated protein of  claim 1 , wherein said protein is soluble.  
     
     
         17 . The isolated protein of  claim 1 , wherein said protein has a biological activity selected from the group consisting of: (a) binding to a TALL-1 receptor; (b) costimulation of B lymphocyte proliferation; (c) costimulation of B lymphocyte activation; and (d) support of B lymphocyte survival.  
     
     
         18 . The isolated protein of  claim 1 , wherein said protein binds to a TALL-1 receptor.  
     
     
         19 . The isolated protein of  claim 1 , wherein said homologue does not activate a TALL-1 receptor.  
     
     
         20 . An isolated antibody that specifically binds to the isolated protein of  claim 1 .  
     
     
         21 . An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a protein comprising an amino acid sequence selected from the group consisting of: 
 a. SEQ ID NO:2; and,    b. a homologue of SEQ ID NO:2, wherein said homologue comprises an amino acid sequence selected from the group consisting of: 
 (i) an amino acid sequence comprising at least 130 contiguous amino acids of SEQ ID NO:2; and,  
 (ii) an amino acid sequence comprising at least positions 134-285 of SEQ ID NO:2.  
   
     
     
         22 . The isolated nucleic acid molecule of  claim 21 , wherein said homologue comprises an amino acid sequence comprising at least 150 contiguous amino acids of SEQ ID NO:2.  
     
     
         23 . The isolated amino acid molecule of  claim 21 , wherein said homologue comprises an amino acid sequence comprising at least 175 contiguous amino acids of SEQ ID NO:2.  
     
     
         24 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence encodes a protein comprising an amino acid sequence represented by SEQ ID NO:2.  
     
     
         25 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence encodes a protein comprising an amino acid sequence comprising amino acids 134-285 of SEQ ID NO:2.  
     
     
         26 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence comprises at least 390 contiguous nucleotides of SEQ ID NO:1.  
     
     
         27 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence hybridizes under low stringency conditions to the complement of SEQ ID NO:1.  
     
     
         28 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence hybridizes under moderate stringency conditions to the complement of SEQ ID NO:1.  
     
     
         29 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence hybridizes under high stringency conditions to the complement of SEQ ID NO:1.  
     
     
         30 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence comprises SEQ ID NO:1.  
     
     
         31 . The isolated nucleic acid molecule of  claim 21 , wherein said nucleic acid sequence comprises nucleotides 402 through 855 of SEQ ID NO:1.  
     
     
         32 . A recombinant nucleic acid molecule, comprising an isolated nucleic acid molecule as set forth in  claim 21  operatively linked to a transcription control sequence.  
     
     
         33 . A recombinant cell comprising an isolated nucleic acid molecule as set forth in  claim 21 , wherein said cell expresses said recombinant nucleic acid molecule.  
     
     
         34 . A recombinant virus, comprising an isolated nucleic acid molecule as set forth in  claim 21 .  
     
     
         35 . A recombinant nucleic acid molecule comprising an expression vector operatively linked to a nucleic acid molecule comprising a nucleic acid sequence encoding a protein having TALL-1 biological activity, wherein said protein comprises an amino acid sequence selected from the group consisting of: 
 a. SEQ ID NO:2; and,    b. a homologue of SEQ ID NO:2, wherein said homologue comprises an amino acid sequence selected from the group consisting 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.  
   
     
     
         36 . A method to produce a TALL-1 protein, comprising culturing an isolated cell to express the recombinant nucleic acid molecule of  claim 35 , under conditions whereby a TALL-1 protein encoded by said recombinant nucleic acid molecule is produced.  
     
     
         37 . An isolated TALL-1 receptor homologue, wherein said homologue comprises an amino acid sequence that is: 
 a. at least about 40% identical to SEQ ID NO:11 over at least 35 amino acids of SEQ ID NO:11; and,    b. less than 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:11 and SEQ ID NO:17.    
     
     
         38 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is at least about 65% identical to SEQ ID NO:11.  
     
     
         39 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is at least about 75% identical to SEQ ID NO:11.  
     
     
         40 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is at least about 90% identical to SEQ ID NO:11.  
     
     
         41 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is less than about 95% identical to said amino acid sequence selected from the group consisting of SEQ ID NO:11 and SEQ ID NO:17.  
     
     
         42 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is less than about 90% identical to said amino acid sequence selected from the group consisting of SEQ ID NO:11 and SEQ ID NO:17.  
     
     
         43 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is encoded by a nucleic acid molecule comprising a nucleic acid sequence that hybridizes under moderate stringency conditions to the complement of SEQ ID NO:10.  
     
     
         44 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is encoded by a nucleic acid molecule comprising a nucleic acid sequence that hybridizes under high stringency conditions to the complement of SEQ ID NO:10.  
     
     
         45 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue binds to TALL-1.  
     
     
         46 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue is a soluble TALL-1 receptor.  
     
     
         47 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue activates NF-κB in a cell expressing said homologue through a TRAF5, TRAF6, NIK, IKKα and IKKβ dependent pathway.  
     
     
         48 . The isolated TALL-1 receptor homologue of  claim 37 , wherein said homologue costimulates B lymphocyte proliferation in a B lymphocyte expressing said homologue.  
     
     
         49 . An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a TALL-1 receptor homologue, wherein said homologue comprises an amino acid sequence that is: 
 a. at least about 40% identical to SEQ ID NO:11 over at least 35 amino acids of SEQ ID NO:11; and,    b. less than 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:11 and SEQ ID NO:17.    
     
     
         50 . A composition comprising: 
 a. a compound selected from the group consisting of: 
 (i) an isolated TALL-1 protein;  
 (ii) an isolated antibody that selectively binds to said TALL-1 protein of (i);  
 (iii) an isolated TALL-1 receptor; and,  
 (iv) an isolated antibody that selectively binds to said TALL-1 receptor of (iii); and,  
   b. a pharmaceutically acceptable carrier.    
     
     
         51 . The composition of  claim 50 , wherein said compound is an isolated TALL-1 protein.  
     
     
         52 . The composition of  claim 51 , wherein said isolated TALL-1 protein comprises an amino acid sequence selected from the group consisting of: 
 a. SEQ ID NO:2; and,    b. a homologue of SEQ ID NO:2, wherein said homologue comprises an amino acid sequence selected from the group consisting 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:20 over positions 134-285 of SEQ ID NO:2.  
   
     
     
         53 . The composition of  claim 51 , wherein said isolated TALL-1 protein is encoded by a nucleic acid sequence that hybridizes under moderate stringency conditions to the complement of a nucleic acid sequence encoding SEQ ID NO:2.  
     
     
         54 . The composition of  claim 51 , wherein said isolated TALL-1 protein comprises an amino acid sequence represented by SEQ ID NO:2.  
     
     
         55 . The composition of  claim 50 , wherein said compound is an isolated antibody that selectively binds to said TALL-1 protein of (i).  
     
     
         56 . The composition of  claim 50 , wherein said compound is an isolated TALL-1 receptor.  
     
     
         57 . The composition of  claim 56 , wherein said receptor is a soluble TALL-1 receptor.  
     
     
         58 . The composition of  claim 56 , wherein said isolated TALL-1 receptor comprises an amino acid sequence selected from the group consisting of: 
 a. SEQ ID NO:11; and,    b. a TALL-1 receptor homologue comprising an amino acid sequence that is: 
 (i) at least about 40% identical to SEQ ID NO:11 over at least 35 amino acids of SEQ ID NO:11; and,  
 (ii) less than 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:11 and SEQ ID NO:17.  
   
     
     
         59 . The composition of  claim 50 , wherein said compound is an isolated antibody that selectively binds to said TALL-1 receptor of (iii).  
     
     
         60 . A method to activate a TALL-1 receptor, comprising contacting a TALL-1 receptor with a TALL-1 protein.  
     
     
         61 . The method of  claim 60 , wherein said TALL-1 protein comprises an amino acid sequence selected from the group consisting of: 
 a. SEQ ID NO:2; and,    b. a homologue of SEQ ID NO:2, wherein said homologue comprises an amino acid sequence selected from the group consisting 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.  
   
     
     
         62 . A method to regulate B lymphocyte proliferation, activation, and/or survival, comprising regulating the biological activity of a TALL-1 receptor expressed by a B lymphocyte.  
     
     
         63 . The method of  claim 62 , wherein said step of regulating comprises inhibiting the biological activity of said TALL-1 receptor.  
     
     
         64 . The method of  claim 62 , wherein said step of regulating comprises inhibiting the interaction of TALL-1 with said TALL-1 receptor.  
     
     
         65 . The method of  claim 64 , wherein said step of inhibiting comprises contacting TALL-1 expressed by a monocyte or macrophage with a compound that inhibits binding of said TALL-1 to said TALL-1 receptor.  
     
     
         66 . The method of  claim 65 , wherein said compound is selected from the group consisting of: 
 a. an antibody that selectively binds to TALL-1 and inhibits the binding of TALL-1 to said TALL-1 receptor;    b. a soluble TALL-1 receptor; and,    c. a TALL-1 receptor homologue, wherein said homologue comprises an amino acid sequence that is at least about 40% identical over at least 35 amino acids to SEQ ID NO:11, wherein said homologue binds to TALL-1, and wherein said receptor does not activate NF-κB when expressed by a cell.    
     
     
         67 . The method of  claim 65 , wherein said compound is a soluble TALL-1 receptor.  
     
     
         68 . The method of  claim 64 , wherein said step of inhibiting comprises contacting said TALL-1 receptor with a compound that inhibits the interaction of TALL-1 with said TALL-1 receptor.  
     
     
         69 . The method of  claim 68 , wherein said compound is selected from the group consisting of: 
 a. an antibody that selectively binds to said TALL-1 receptor and inhibits the binding of said TALL-1 receptor by TALL-1; and,    b. a TALL-1 homologue, wherein said homologue comprises an amino acid sequence selected from the group consisting 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 to SEQ ID NO:2 over positions 134-285 of SEQ ID NO:2;  
 wherein said homologue binds to said TALL-1 receptor but does not activate said TALL-1 receptor.  
   
     
     
         70 . The method of  claim 62 , wherein said step of regulating comprises stimulating the biological activity of said TALL-1 receptor.  
     
     
         71 . The method of  claim 70 , wherein said method comprises contacting said TALL-1 receptor with a compound that increases TALL-1 receptor activity.  
     
     
         72 . The method of  claim 71 , wherein said compound is selected from the group consisting of: 
 a. an isolated TALL-1 protein; and,    b. an antibody that selectively binds to said TALL-1 receptor and activates said receptor.    
     
     
         73 . The method of  claim 72 , wherein said isolated TALL-1 protein comprises an amino acid sequence selected from the group consisting of: 
 a. SEQ ID NO:2; and,    b. a homologue of SEQ ID NO:2, wherein said homologue comprises an amino acid sequence selected from the group consisting 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.  
   
     
     
         74 . The method of  claim 62 , wherein regulation of B lymphocyte proliferation, activation and/or survival by said method is effective to regulate a B-lymphocyte immune response in an animal.  
     
     
         75 . The method of  claim 62 , wherein inhibition of B lymphocyte proliferation, activation and/or survival by said method is effective to inhibit a B lymphocyte-associated autoimmune disease.  
     
     
         76 . A method to inhibit a B lymphocyte immune response in a patient, comprising inhibiting the interaction of TALL-1 with a TALL-1 receptor in said patient.  
     
     
         77 . A method to inhibit a B lymphocyte-associated autoimmune disease in a patient, comprising inhibiting the interaction of TALL-1 with a TALL-1 receptor in said patient.  
     
     
         78 . A method to identify compounds that regulate the interaction between TALL-1 and a TALL-1 receptor, comprising: 
 a. contacting a TALL-i receptor with a putative regulatory compound;    b. contacting said TALL-1 receptor with a TALL-1 protein comprising an amino acid sequence selected from the group consisting of: 
 (i) SEQ ID NO:2; and,  
 (ii) a homologue of SEQ ID NO:2, wherein said homologue comprises an amino acid sequence selected from the group consisting of: 
 (1) 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,  
 (2) 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 or a homologue of TALL-1;  
 
 wherein said TALL-1 protein binds to and activates said TALL-1 receptor in the absence of said putative regulatory compound; and,  
   c. detecting whether said putative regulatory compound regulates said TALL-1 receptor.    
     
     
         79 . The method of  claim 78 , wherein said step of detecting comprises detecting whether said putative regulatory compound inhibits the binding of said TALL-1 protein to said TALL-1 receptor.  
     
     
         80 . The method of  claim 78 , wherein said step of detecting comprises detecting whether said putative regulatory compound inhibits the activation of said TALL-1 receptor as compared to in the absence of said putative regulatory compound.