Composition of an endogenous insulin-like growth factor-II derivative

Abstract

The effects of endogenous insulin-like growth factor can be appreciated by administering compounds capable of increasing free IGF in living bodies. Compounds are described which can elevate the concentration of unbound IGF by converting endogenous IGF (insulin-like growth factor) into free, biologically active IGF or elevating the concentration of the complex of IGF and IGFBP (insulin-like growth factor binding protein) in living bodies. Medicaments can be prepared containing these compounds or these compounds may be used in methods for the prevention and or treatment of IGF-responsive diseases such as diabetes, amyotrophic lateral sclerosis, or osteoporosis.

1 . A method for elevating the concentration of a free insulin-like growth factor, which comprises converting a binary complex composed of an insulin-like growth factor and an insulin-like growth factor binding protein in living bodies into the insulin-like growth factor.  
     
     
         2 . A method for elevating the concentration of a free insulin-like growth factor, which comprises releasing, from a binary complex composed of an insulin-like growth factor and an insulin-like growth factor binding protein in living bodies, the insulin-like growth factor.  
     
     
         3 . A method for elevating the concentration of a free insulin-like growth factor, which comprises inhibiting the binding of an insulin-like growth factor and an insulin-like growth factor binding protein in living bodies.  
     
     
         4 . A method for elevating the concentration of a binary complex composed of an insulin-like growth factor and an insulin-like growth factor binding protein, which comprises converting a ternary complex composed of the insulin-like growth factor, the insulin-like growth factor binding protein and an acid labile subunit in living bodies into the binary complex composed of the insulin-like growth factor and insulin-like growth factor binding protein.  
     
     
         5 . A method for elevating the concentration of a binary complex composed of an insulin-like growth factor and an insulin-like growth factor binding protein, which comprises releasing, from a ternary complex composed of the insulin-like growth factor, the insulin-like growth factor binding protein and an acid labile subunit in living bodies, the binary complex composed of the insulin-like growth factor and insulin-like growth factor binding protein.  
     
     
         6 . A method for elevating the concentration of a binary complex composed of an insulin-like growth factor and an insulin-like growth factor binding protein, which comprises inhibiting the binding of the binary complex of the insulin-like growth factor and the insulin-like growth factor binding protein in living bodies to an acid labile subunit.  
     
     
         7 . A method for elevating the concentration of a free insulin-like growth factor, which comprises converting a ternary complex composed of an insulin-like growth factor, insulin-like growth factor binding protein and an acid labile subunit in living bodies into the insulin-like growth factor.  
     
     
         8 . A method for elevating the concentration of a free insulin-like growth factor, which comprises releasing, from a ternary complex composed of an insulin-like growth factor, insulin-like growth factor binding protein and an acid labile subunit in living bodies, the insulin-like growth factor.  
     
     
         9 . A method for elevating the concentration of a free insulin-like growth factor, which comprises inhibiting the binding of an insulin-like growth factor, insulin-like growth factor binding protein and an acid labile subunit in living bodies.  
     
     
         10 . A compound which converts a binary complex composed of an insulin-like growth factor and an insulin-like growth factor binding protein in living bodies into a free insulin-like growth factor.  
     
     
         11 . A compound which releases a free insulin-like growth factor from a binary complex composed of an insulin-like growth factor and an insulin-like growth factor binding protein in living bodies.  
     
     
         12 . A compound which inhibits the binding of an insulin-like growth factor and an insulin-like growth factor binding protein in living bodies.  
     
     
         13 . A compound which converts a ternary complex composed of an insulin-like growth factor, an insulin-like growth factor binding protein and an acid labile subunit in living bodies into a binary complex composed of the insulin-like growth factor and insulin-like growth factor binding protein.  
     
     
         14 . A compound which releases, from a ternary complex composed of an insulin-like growth factor, an insulin-like growth factor binding protein and an acid labile subunit in living bodies, a binary complex composed of the insulin-like growth factor and insulin-like growth factor binding protein.  
     
     
         15 . A compound which inhibits the binding of a complex of an insulin-like growth factor and an insulin-like growth factor binding protein in living bodies to an acid labile subunit.  
     
     
         16 . A compound which converts a ternary complex composed of an insulin-like growth factor, an insulin-like growth factor binding protein and an acid labile subunit in living bodies into a free insulin-like growth factor.  
     
     
         17 . A compound which releases, from a ternary complex composed of an insulin-like growth factor, insulin-like growth factor binding protein and an acid labile subunit in living bodies, a free insulin-like growth factor.  
     
     
         18 . A compound which releases a free insulin-like growth factor by inhibiting the binding of an insulin-like growth factor, an insulin-like growth factor binding protein and an acid labile subunit in living bodies.  
     
     
         19 . A compound which substantially binds neither to an insulin-like growth factor receptor nor to an insulin receptor but binds to an insulin-like growth factor binding protein.  
     
     
         20 . An insulin-like growth factor derivative, which substantially binds neither to an insulin-like growth factor receptor nor to an insulin receptor but binds to an insulin-like growth factor binding protein.  
     
     
         21 . An insulin-like growth factor derivative, which substantially binds neither to an insulin-like growth factor receptor nor to an insulin receptor but binds to an insulin-like growth factor binding protein, and has an amino acid sequence similar to an insulin like growth factor except for the addition, depletion or substitution of one or more than one amino acid residue.  
     
     
         22 . An insulin-like growth factor derivative, which substantially binds neither to an insulin-like growth factor receptor nor to an insulin receptor but binds to an insulin-like growth factor binding protein, and has an amino acid sequence similar to human insulin-like growth factor-II except that the 27-th tyrosine residue and 43-rd valine residue each has been substituted with a leucine residue.  
     
     
         23 . An anti-insulin-like growth factor binding protein antibody, which substantially binds neither to an insulin-like growth factor receptor nor to an insulin receptor but binds to an insulin-like growth factor binding protein.  
     
     
         24 . An anti-insulin-like growth factor binding protein antibody, which substantially binds neither to an insulin-like growth factor receptor nor to an insulin receptor but binds to an insulin-like growth factor binding protein-3.  
     
     
         25 . A medicament, which comprises a compound as recited in any one of  claims 10  to  19 .  
     
     
         26 . A medicament, which comprises an insulin-like growth factor derivative as recited in any one of  claims 20  to  22 .  
     
     
         27 . A medicament, which comprises an anti-insulin-like growth factor binding protein antibody as recited in  claim 23  or  24 .  
     
     
         28 . A screening method of a compound as recited in any one of  claims 10  to  19 , which comprises labeling any one of the insulin-like growth factor, insulin-like growth factor binding protein and acid labile subunit so as to be directly or indirectly detectable.