Catalytic antibodies and a method of producing same

Abstract

The present invention relates generally to a growth factor precursor and its use to select production of antigen specific catalytic antibodies. Such catalytic antibodies are produced following B cell activation and proliferation induced by catalytic cleavage products of a target antigen portion of the growth factor precursor of the present invention. A particularly useful form of the growth factor precursor is as a nucleic acid vaccine. The nucleic acid vaccine of the present invention preferably further comprises a molecular adjuvant. Another aspect of the present invention comprises a growth factor precursor in multimeric form. The growth factor precursor of the present invention is useful for generating catalytic antibodies for both therapeutic, diagnostic and industrial purposes.

1 - 16 . (canceled) 
     
     
         17 . A catalytic antibody generated according to the method of  claim 27  or  28 . 
     
     
         18 . A nucleic acid molecule according to any one of  claims 20 - 22  further comprising a nucleotide sequence encoding a molecular adjuvant. 
     
     
         19 . A nucleic acid molecule according to  claim 18  wherein the molecular adjuvant is selected from C3d, CTLA4 and CD40L. 
     
     
         20 . An isolated nucleic acid molecule comprising a sequence of nucleotides encoding a recombinant growth factor precursor, wherein said recombinant growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, an antigen cleavable by a catalytic antibody and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin and wherein said variable heavy chain and variable light chain domains in the growth factor precursor, associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by a catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule. 
     
     
         21 . An isolated nucleic acid molecule comprising a sequence of nucleotides encoding a recombinant growth factor precursor, wherein said recombinant growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, an antigen cleavable by a catalytic antibody and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin and wherein said variable heavy chain and variable light chain domains in the growth factor precursor associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by a catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule wherein if said growth factor precursor comprises a single B cell surface molecule binding portion, then the growth factor precursor further comprises a multimerizing inducing element. 
     
     
         22 . An isolated nucleic acid molecule comprising a sequence of nucleotides encoding a recombinant growth factor precursor, wherein said recombinant growth factor precursor comprises the structure:
   I′AX 1 [X 2 ] d [X 3 ] a [A] r I″   
       wherein:
 X 1  and X 3  are B cell surface molecule binding portions; 
 a is 0 or 1 or >1; 
 I′ and I″ are either both present or only one is present and they may be the same or different and each is a blocking reagent for X 1  and/or X 3  and comprise domains from both a variable heavy chain and a variable light chain of an immunoglobulin, and wherein said variable heavy chain and variable light chain domains associate together by intra- and/or inter-domain bonding and substantially prevent at least one of X 1  or X 3  from interacting with a B cell surface molecule; 
 A is the target antigen for which a catalytic antibody is sought; 
 X 2  is an entity providing T cell dependent help to a B cell; 
 d is 0, 1 or >1; 
 r is 0, 1 or >1, 
 wherein a catalytic antibody on the surface of said B cell is capable of cleaving all or part of A from said recombinant or synthetic molecule resulting in the molecule [A′]X 1 X 2 [X 3 ] a [A′] wherein A′ is optionally present and is a portion of A after cleavage with the catalytic antibody wherein said resulting molecule is capable of interacting with said B cell surface molecule through at least one of X 1  or X 3  and inducing B cell mitogenesis of the B cell to which X 1  or X 3  bind. 
 
     
     
         23 . A composition comprising a recombinant or synthetic growth factor precursor and at least one of a pharmaceutical carrier and a diluent, wherein said recombinant or synthetic growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, an antigen cleavable by a catalytic antibody and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin and wherein said variable heavy chain and variable light chain domains in the growth factor precursor, associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by a catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule. 
     
     
         24 . A composition comprising a recombinant or synthetic growth factor precursor and at least one of a pharmaceutical carrier and a diluent, wherein said recombinant or synthetic growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, an antigen cleavable by a catalytic antibody and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin and wherein said variable heavy chain and variable light chain domains in the growth factor precursor associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by a catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule wherein if said growth factor precursor comprises a single B cell surface molecule binding portion, then the growth factor precursor further comprises a multimerizing inducing element. 
     
     
         25 . A composition comprising a catalytic antibody generated to a growth factor precursor, wherein said growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, an antigen cleavable by a catalytic antibody and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin and wherein said variable heavy chain and variable light chain domains in the growth factor precursor, associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by a catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule. 
     
     
         26 . A composition comprising a catalytic antibody generated to a growth factor precursor, wherein said growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, an antigen cleavable by a catalytic antibody and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin and wherein said variable heavy chain and variable light chain domains in the growth factor precursor associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by a catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule wherein if said growth factor precursor comprises a single B cell surface molecule binding portion, then the growth factor precursor further comprises a multimerizing inducing element. 
     
     
         27 . A method of inducing B cell mitogenesis to generate a catalytic antibody to a specific antigen comprising administering to an animal a growth factor precursor, wherein said growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, said antigen cleavable by said catalytic antibody, and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin wherein said variable heavy chain and variable light chain domains associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by said catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule to induce B cell mitogenesis thereby generating said catalytic antibody to said antigen. 
     
     
         28 . A method of inducing B cell mitogenesis to generate a catalytic antibody to a specific antigen comprising administering to an animal a growth factor precursor, wherein said growth factor precursor comprises a recombinant polypeptide chain or a molecule having modular peptide components or a synthetic equivalent thereof, wherein said polypeptide chain or modular peptide molecule comprises at least one B cell surface molecule binding portion, at least one T cell surface molecule binding portion capable of providing T cell dependent help to a B cell, said antigen cleavable by said catalytic antibody and a peptide portion comprising domains from both a variable heavy chain and a variable light chain of an immunoglobulin and wherein said variable heavy chain and variable light chain domains in the growth factor precursor associate together by intra- and/or inter-domain bonding and substantially prevent the at least one B cell surface molecule binding portion from interacting with a B cell surface molecule such that upon cleavage of said antigen by said catalytic antibody, the peptide comprising said variable heavy chain and variable light chain domain permits the at least one B cell surface molecule binding portion to interact with a B cell surface molecule to induce B cell mitogenesis thereby generating said catalytic antibody to said antigen, and wherein if said growth factor precursor comprises a single B cell surface molecule binding portion, then the growth factor precursor further comprises a multimerizing inducing element.