IL-2 selective agonists and antagonists
The invention is directed to a polypeptide comprising a human IL-2 mutein numbered in accordance with wild-type IL-2 wherein said human IL-2 is substituted at at least one of positions 20, 88 or 126, whereby said mutein preferentially activates T cells over NK cells. D20H and I, N88G, I, and R, in particular have a relative T cell-differential activity much greater than native IL-2, with predicted associated reduced in vivo toxicity. The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.
1. An isolated unglycosylated human Interleukin 2 (IL-2) mutein having a substitution at position 88 relative to wild type IL-2 (Seq. ID No. 1), whereby said mutein preferentially activates T cells over Natural Killer cells.
2. The IL-2 mutein of claim 1 , wherein said position 88 is substituted with arginine.
3. The IL-2 mutein of claim 1 , wherein said position 88 is substituted with isoleucine.
4. The IL-2 mutein of claim 1 , wherein said position 88 is substituted with glycine.
5. An isolated polynucleotide comprising a DNA sequence that encodes the human IL-2 mutein of claim 1 .
6. An expression vector comprising the polynucleotide of claim 5 .
7. An isolated prokaryotic host cell transformed with the polynucleotide of claim 5 .
8. An isolated eukaryotic host cell transformed with the polynucleotide of claim 5 .
9. A pharmaceutical composition comprising a human IL-2 mutein of claim 1 in combination with a pharmaceutically acceptable carrier.
10. A method of treating a mammal afflicted with a cancerous lung tumor by administering a therapeutically effective amount of the IL-2 mutein of claim 1 , whereby the lung tumor burden is reduced.