US2009317397A1PendingUtilityA1

Soluble CTLA4 mutant molecules and uses thereof

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Assignee: BRISTOL MYERS SQUIBB COPriority: Jun 27, 1991Filed: Jun 30, 2009Published: Dec 24, 2009
Est. expiryJun 27, 2011(expired)· nominal 20-yr term from priority
Inventors:Peter S. LinsleyJeffrey A. LedbetterNitin K. DamleWilliam BradyPhilip M. Wallace
C07K 2319/30A61K 38/00A61K 2039/505C07K 16/2827C07K 14/70521C07K 16/2818C07K 2317/34C07K 14/7155C07K 16/247C07K 16/00C07K 2317/73C07K 2319/00
70
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Claims

Abstract

The invention identifies the CTLA4 receptor as a ligand for the B7 antigen. The complete amino acid sequence encoding human CTLA4 receptor gene is provided. Methods are provided for expressing CTLA4 as an immunoglobulin fusion protein, for preparing hybrid CTLA4 fusion proteins, and for using the soluble fusion proteins, fragments and derivatives thereof, including monoclonal antibodies reactive with B7 and CTLA4, to regulate T cell interactions and immune responses mediated by such interactions.

Claims

exact text as granted — not AI-modified
1 . A soluble CTLA4 mutant molecule having the extracellular domain of CTLA4 which binds B7-1 and/or B7-2. 
     
     
         2 . The soluble CTLA4 mutant molecule of  claim 1 , further comprising an amino acid sequence which alters the solubility of the soluble CTLA4 mutant molecule. 
     
     
         3 . The soluble CTLA4 mutant molecule of  claim 2 , wherein the amino acid sequence comprises a human immunoglobulin constant region. 
     
     
         4 . The soluble CTLA4 mutant molecule of  claim 1 , wherein the soluble CTLA4 mutant molecule is any of HS2, HS4, HS6, HS7, HS8, and HS9. 
     
     
         5 . The soluble CTLA4 mutant molecule of  claim 1 , wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4 having the amino acid motif MYPPPY (SEQ ID NO:35), wherein the second proline in the amino acid motif MYPPPY (SEQ ID NO:35) is replaced with alanine. 
     
     
         6 . A nucleic acid molecule comprising a nucleotide sequence encoding the amino acid sequence corresponding to the soluble CTLA4 mutant molecule of  claim 1 . 
     
     
         7 . A vector comprising the nucleotide sequence of  claim 6 . 
     
     
         8 . A host vector system comprising the vector of  claim 7  in a suitable host cell. 
     
     
         9 . The host vector system of  claim 8 , wherein the suitable host cell is a prokaryotic cell or a eukaryotic cell. 
     
     
         10 . A method for producing a soluble CTLA mutant protein comprising growing the host vector system of  claim 8  so as to produce the protein in the host cell and recovering the protein so produced. 
     
     
         11 . A soluble CTLA mutant protein produced by expressing the mutant molecule of  claim 1  in a host vector system. 
     
     
         12 . A method for regulating a T cell interaction with a B7-1 and/or B7-2 positive cell comprising contacting the B7-1 and/or B7-2 positive cell with the soluble CTLA4 mutant molecule of  claim 1  so as to regulate the T cell interaction. 
     
     
         13 . The method of  claim 12 , wherein the soluble CTLA4 mutant molecule is any of HS2, HS4, HS6, HS7, HS8, and HS9. 
     
     
         14 . The method of  claim 12 , wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4 having the amino acid motif MYPPPY, wherein the second proline in the amino acid motif MYPPPY (SEQ ID NO:35) is replaced with alanine. 
     
     
         15 . The method of  claim 12 , wherein the B7-1 and/or B7-2 positive cell is an antigen presenting cell. 
     
     
         16 . The method of  claim 12 , wherein the interaction of the CTLA4-positive T cells with the B7-1 and/or B7-2 positive cells is inhibited. 
     
     
         17 . A method for treating a pathological condition mediated by T cell interactions with B7-1 and/or B7-2 positive cells comprising administering to a subject the soluble CTLA4 mutant molecule of  claim 1 , in an amount effective to regulate T cell interactions with said B7-1 and/or B7-2 positive cells. 
     
     
         18 . The method of  claim 17 , wherein said T cell interactions are inhibited. 
     
     
         19 . The method of  claim 17 , wherein the pathological condition is graft versus host disease. 
     
     
         20 . A method for inhibiting the interaction of CTLA4 positive T cells with B7-1 and/or B7-2 positive cells in vivo comprising contacting CTLA4-positive T cells with an antibody or antibody fragment, reactive with an extracellular domain of CTLA4, wherein CTLA4 comprises amino acids 1-187 of SEQ ID NO:14, thereby inhibiting CTLA4-positive T cell interactions with B7-1 and/or B7-2 positive cells. 
     
     
         21 . A method for treating a pathological condition in a subject comprising contacting in the subject CTLA4-positive T cells with an antibody or antibody fragment, reactive with an extracellular domain of CTLA4, wherein CTLA4 comprises amino acids 1-187 of SEQ ID NO:14, thereby treating the pathological condition. 
     
     
         22 . A method for blocking CTLA4-B7-1 and/or CTLA4-B7-2 interactions in the subject comprising contacting in the subject CTLA4-positive T cells with an antibody or antibody fragment, reactive with an extracellular domain of CTLA4, wherein CTLA4 comprises amino acids 1-187 of SEQ ID NO:14, thereby blocking CTLA4-B7-1 and/or CTLA4-B7-2 interactions in the subject. 
     
     
         23 . The method of  claims 20 ,  21 , or  22 , wherein the antibody or antibody fragment recognizes and binds the extracellular domain of human CTLA4 comprising amino acids 1-125 of SEQ ID NO:14. 
     
     
         24 . The method of  claims 20 ,  21 , or  22 , wherein the antibody or antibody fragment recognizes and binds the extracellular domain of CTLA4 comprising amino acids 1-125 of SEQ ID NO:14, and wherein said binding prevents the binding of CTLA4 to B7-1 and/or B7-2 antigen. 
     
     
         25 . The method of  claims 20 , or  21 , wherein the said antibody or antibody fragment blocks CTLA4-B7-1 and/or CTLA4-B7-2 interactions. 
     
     
         26 . The method of  claims 20 ,  21 , or  22 , wherein the antibody fragment is a Fab, F(ab′) 2 , or Fv fragment. 
     
     
         27 . The method of  claims 20 ,  21 , or  22 , wherein the antibody or antibody fragment is a monoclonal antibody.

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