US2003103986A1PendingUtilityA1

TACI-immunoglobulin fusion proteins

56
Priority: May 24, 2001Filed: May 20, 2002Published: Jun 5, 2003
Est. expiryMay 24, 2021(expired)· nominal 20-yr term from priority
Inventors:Mark W. RixonJane A. Gross
A61P 37/02A61P 37/00A61P 7/06A61P 7/00A61P 7/10A61P 3/10A61P 37/06A61P 9/00A61P 35/02A61P 31/04A61P 35/00A61P 25/00A61P 29/00C07K 2319/00A61P 13/12C07K 16/241C07K 14/70578A61K 38/00A61P 19/02A61K 45/06A61K 39/3955A61P 17/06A61P 11/06A61P 21/04A61P 11/00C07K 2319/30A61P 19/00A61K 39/395A61P 1/00
56
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Claims

Abstract

Molecules that interfere with the binding of a tumor necrosis factor receptor with its ligand, such as a soluble receptor, have proven usefulness in both basic research and as therapeutics. The present invention provides improved soluble transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI) receptors.

Claims

exact text as granted — not AI-modified
We claim:  
     
         1 . A method for inhibiting the proliferation of tumor cells, comprising administering to the tumor cells a composition that comprises a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI)-immunoglobulin fusion protein, wherein the TACI-immunoglobulin fusion protein comprises: 
 (a) a TACI receptor moiety that consists of a fragment of a polypeptide that has the amino acid sequence of amino acid residues 30 to 154 of SEQ ID NO: 2, wherein the TACI receptor moiety comprises at least one of (i) amino acid residues 34 to 66 of SEQ ID NO: 2, and (ii) amino acid residues 71 to 104 of SEQ ID NO: 2, and wherein the TACI receptor moiety binds at least one of ZTNF2 or ZTNF4, and    (b) an immunoglobulin moiety comprising a constant region of an immunoglobulin.    
     
     
         2 . The method of  claim 1 , wherein the TACI receptor moiety comprises amino acid residues 34 to 66 of SEQ ID NO: 2, and amino acid residues 71 to 104 of SEQ ID NO: 2.  
     
     
         3 . The method of  claim 1 , wherein the TACI receptor moiety comprises amino acid residues 34 to 104 of SEQ ID NO: 2.  
     
     
         4 . The method of  claim 1 , wherein the TACI receptor moiety has the amino acid sequence of amino acid residues 30 to 110 of SEQ ID NO: 2  
     
     
         5 . The method of  claim 1 , wherein the immunoglobulin moiety comprises a heavy chain constant region.  
     
     
         6 . The method of  claim 5 , wherein the immunoglobulin moiety comprises a human heavy chain constant region.  
     
     
         7 . The method of  claim 6 , wherein the heavy chain constant region is an IgG1 heavy chain constant region.  
     
     
         8 . The method of  claim 7 , wherein the immunoglobulin moiety is an IgG1 Fe fragment that comprises C H2 , and C H3  domains.  
     
     
         9 . The method of  claim 8 , wherein the immunoglobulin moiety is an IgG1 Fe fragment comprising the amino acid sequence of SEQ ID NO: 33.  
     
     
         10 . The method of  claim 9 , wherein TACI-immunoglobulin fusion protein has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 54.  
     
     
         11 . The method of  claim 1 , wherein the TACI-immunoglobulin fusion protein is a dimer.  
     
     
         12 . The method of  claim 1 , wherein the composition is administered to cells cultured in vitro.  
     
     
         13 . The method of  claim 1 , wherein the composition is a pharmaceutical composition that comprises the TACI-immunoglobulin fusion protein and a pharmaceutically acceptable carrier, and wherein the pharmaceutical composition is administered to a mammalian subject, which has a tumor.  
     
     
         14 . The method of  claim 13 , wherein the administration of the pharmaceutical composition inhibits the proliferation of B lymphocytes in the mammalian subject.  
     
     
         15 . A method for inhibiting the proliferation of tumor cells in a mammalian subject, comprising administering to the mammalian subject a pharmaceutical composition that comprises a pharmaceutically acceptable carrier and a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI)-immunoglobulin fusion protein, wherein the TACI-immunoglobulin fusion protein has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 54.  
     
     
         16 . The method of  claim 15 , wherein the TACI-immunoglobulin fusion protein is a dimer.  
     
     
         17 . A fusion protein, comprising: 
 (a) a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI) receptor moiety, wherein the TACI receptor moiety consists of a fragment of a polypeptide that has the amino acid sequence of amino acid residues 30 to 154 of SEQ ID NO: 2, wherein the TACI receptor moiety comprises at least one of (i) amino acid residues 34 to 66 of SEQ ID NO: 2, and (ii) amino acid residues 71 to 104 of SEQ ID NO: 2, and wherein the TACI receptor moiety binds at least one of ZTNF2 or ZTNF4, and    (b) an immunoglobulin moiety that comprises a constant region of an immunoglobulin.    
     
     
         18 . The fusion protein of  claim 17 , wherein the TACI receptor moiety comprises amino acid residues 34 to 66 of SEQ ID NO: 2, and amino acid residues 71 to 104 of SEQ ID NO: 2.  
     
     
         19 . The fusion protein of  claim 17 , wherein the TACI receptor moiety comprises amino acid residues 34 to 104 of SEQ ID NO: 2.  
     
     
         20 . The fusion protein of  claim 17 , wherein the TACI receptor moiety has the amino acid sequence of amino acid residues 30 to 110 of SEQ ID NO: 2  
     
     
         21 . The fusion protein of  claim 17 , wherein the immunoglobulin moiety comprises a heavy chain constant region.  
     
     
         22 . The fusion protein of  claim 21 , wherein the immunoglobulin moiety comprises a human heavy chain constant region.  
     
     
         23 . The fusion protein of  claim 22 , wherein the heavy chain constant region is an IgG1 heavy chain constant region.  
     
     
         24 . The fusion protein of  claim 23 , wherein the immunoglobulin moiety is an IgG1 Fc fragment that comprises C H2 , and C H3  domains.  
     
     
         25 . The fusion protein of  claim 24 , wherein the immunoglobulin moiety is an IgG1 Fc fragment comprising the amino acid sequence of SEQ ID NO: 33.  
     
     
         26 . The fusion protein of  claim 25 , wherein TACI-immunoglobulin fusion protein has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 54.  
     
     
         27 . The fusion protein of  claim 17 , wherein the TACI-immunoglobulin fusion protein is a dimer.  
     
     
         28 . A nucleic acid molecule that encodes the fusion protein of  claim 17 .  
     
     
         29 . The nucleic acid molecule of  claim 28 , wherein the nucleic acid molecule has a nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 53.  
     
     
         30 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI)-immunoglobulin fusion protein, wherein the TACI-immunoglobulin fusion protein has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 54.  
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the TACI-immunoglobulin fusion protein is a dimer.  
     
     
         32 . A method for reducing circulating blood levels of ZTNF4 in a mammalian subject, comprising administering to the mammalian subject a pharmaceutical composition that comprises a pharmaceutically acceptable carrier and a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI)-immunoglobulin fusion protein, wherein the TACI-immunoglobulin fusion protein comprises: 
 (a) a TACI receptor moiety that consists of a fragment of a polypeptide that has the amino acid sequence of amino acid residues 30 to 154 of SEQ ID NO: 2, wherein the TACI receptor moiety comprises at least one of (i) amino acid residues 34 to 66 of SEQ ID NO: 2, and (ii) amino acid residues 71 to 104 of SEQ ID NO: 2, and wherein the TACI receptor moiety binds ZTNF4, and    (b) an immunoglobulin moiety comprising a constant region of an immunoglobulin,    wherein administration of the pharmaceutical composition reduces the circulating level of ZTNF4 in the blood of the mammalian subject.    
     
     
         33 . The method of  claim 32 , wherein the TACI receptor moiety comprises amino acid residues 34 to 66 of SEQ ID NO: 2, and amino acid residues 71 to 104 of SEQ ID NO: 2.  
     
     
         34 . The method of  claim 32 , wherein the TACI receptor moiety comprises amino acid residues 34 to 104 of SEQ ID NO: 2.  
     
     
         35 . The method of  claim 32 , wherein the TACI receptor moiety has the amino acid sequence of amino acid residues 30 to 110 of SEQ ID NO: 2  
     
     
         36 . The method of  claim 32 , wherein the immunoglobulin moiety comprises a heavy chain constant region.  
     
     
         37 . The method of  claim 36 , wherein the immunoglobulin moiety comprises a human heavy chain constant region.  
     
     
         38 . The method of  claim 37 , wherein the heavy chain constant region is an IgG1 heavy chain constant region.  
     
     
         39 . The method of  claim 38 , wherein the immunoglobulin moiety is an IgG1 Fc fragment that comprises C H2 , and C H3  domains.  
     
     
         40 . The method of  claim 39 , wherein the immunoglobulin moiety is an IgG1 Fc fragment comprising the amino acid sequence of SEQ ID NO: 33.  
     
     
         41 . The method of  claim 40 , wherein TACI-immunoglobulin fusion protein has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 54.  
     
     
         42 . The method of  claim 32 , wherein the TACI-immunoglobulin fusion protein is a dimer.  
     
     
         43 . A method for reducing circulating blood levels of ZTNF4 in a mammalian subject, comprising administering to the mammalian subject a pharmaceutical composition that comprises a pharmaceutically acceptable carrier and a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI)-immunoglobulin fusion protein, wherein the TACI-immunoglobulin fusion protein has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 54, and wherein administration of the pharmaceutical composition reduces the circulating level of ZTNF4 in the blood of the mammalian subject.  
     
     
         44 . The method of  claim 43 , wherein the TACI-immunoglobulin fusion protein is a dimer.

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