Compositions and methods for wt1 specific immunotherapy

Abstract

Compositions and methods for the therapy of malignant diseases, such as leukemia and cancer, are disclosed. The compositions comprise one or more of a WT1 polynucleotide, a WT1 polypeptide, an antigen-presenting cell presenting a WT1 polypeptide, an antibody that specifically binds to a WT1 polypeptide; or a T cell that specifically reacts with a WT1 polypeptide. Such compositions may be used, for example, for the prevention and treatment of metastatic diseases.

1 . A polypeptide comprising an immunogenic portion of a native WT1, or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with WT1-specific antisera and/or T-cell lines or clones is not substantially diminished, wherein the polypeptide comprises no more than 16 consecutive amino acid residues present within a native WT1 polypeptide. 
     
     
         2 . A polypeptide according to  claim 1 , wherein the immunogenic portion binds to a MHC class I molecule. 
     
     
         3 . A polypeptide according to  claim 1 , wherein the immunogenic portion binds to a MHC class II molecule. 
     
     
         4 . A polypeptide according to  claim 1 , wherein the polypeptide comprises a sequence selected from the group consisting of:
 (a) sequences recited in one or more of Tables II-XLVI;   (b) SEQ ID NO:34, 35, 88, 49, 147, 185, 198 and 199;   (c) variants of the foregoing sequences that differ in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with antigen-specific antisera and/or T-cell lines or clones is not substantially diminished; and   (d) mimetics of the foregoing sequences, wherein the ability of the mimetic to react with antigen-specific antisera and/or T-cell lines or clones is not substantially diminished.   
     
     
         5 . A polypeptide according to  claim 1 , wherein the polypeptide comprises 4-16 consecutive amino acids of a native WT1 polypeptide. 
     
     
         6 . A polypeptide according to  claim 1 , wherein the polypeptide comprises 8-10 consecutive amino acids of a native WT1 polypeptide. 
     
     
         7 . A polypeptide comprising an immunogenic portion of amino acid residues 1-174 of a native WT1 polypeptide, or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with WT1 specific T-cell lines or clones is not substantially diminished, wherein the polypeptide comprises no more than 16 consecutive amino acid residues present within amino acids 175-449 of the native WT1 polypeptide. 
     
     
         8 . A polynucleotide encoding a polypeptide according to  claim 1 . 
     
     
         9 . A pharmaceutical composition, comprising:
 (a) a first component selected from:
 a. a polynucleotide encoding a WT1 polypeptide, wherein the polypeptide comprises an immunogenic portion of a native WT1 or a variant thereof that differs in one or more substitutions, deletions, additions and/or insertions such that the ability of the variant to react with antigen-specific antibodies and/or T cell lines or clones is not substantially diminished; 
 b. an antibody or antigen-binding fragment thereof that specifically binds to a WT1 polypeptide; 
 c. a T cell that specifically reacts with a WT1 polypeptide; 
 d. a WT1 polypeptide that comprises an immunogenic portion of a native WT1 or variant thereof that differs in one or more substitutions, deletions, additions, and/or insertions such that the ability of the variant to react with antigen-specific antibodies and/or T cell lines or clones is not substantially diminished; and 
   (b) a pharmaceutically acceptable carrier or excipient.   
     
     
         10 . A method for enhancing or inducing an immune response in a human patient, comprising administering to a patient a pharmaceutical composition according to  claim 9 . 
     
     
         11 . A pharmaceutical composition according to  claim 9 , further comprising a non-specific immune response enhancer. 
     
     
         12 . A method for stimulating and/or expanding T cells, comprising contacting T cells with a WT1 polypeptide, a polynucleotide encoding a WT1 polypeptide and/or an antigen presenting cell that expresses a WT1 polypeptide under conditions and for a time sufficient to permit the stimulation and/or expansion of the T cells. 
     
     
         13 . A method according to  claim 12 , wherein the T cells are present within bone marrow, peripheral blood or a fraction of bone marrow or peripheral blood. 
     
     
         14 . A method according to  claim 12 , wherein the bone marrow, peripheral blood or fraction is obtained from a patient afflicted with a malignant disease associated with WT1 expression. 
     
     
         15 . A method for stimulating and or expanding T cells in a mammal, comprising administering to a mammal a pharmaceutical composition comprising:
 (a) one or more of:
 (i) a WT1 polypeptide; 
 (ii) a polynucleotide encoding a WT1 polypeptide; or 
 (iii) an antigen-presenting cell that expresses a WT1 polypeptide; and 
   (b) a physiologically acceptable carrier or excipient;   and thereby stimulating and/or expanding T cells in a mammal.   
     
     
         16 . A method for inhibiting the development of a malignant disease associated with WT1 expression in a patient, comprising administering to a patient cells expressing T cell receptors for T cells specific for WT1.