IL-15 mutants having antagonist activity
The present invention relates to the identification of an epitope in human Interleukin-15 (IL-15) that is responsible for binding to the interleukin-15 receptor α-chain. Two IL-15 regions are involved in the formation of this epitope: the first region ( 44 LLELQVISL 52 , peptide 1) corresponds to a sequence located in the B helix and the second ( 64 ENLII 68 , peptide 2 or 64 ENLIIL 69 , peptide 2a) to a sequence located in helix C. Muteins displaying agonist or antagonist properties are described, and may be useful as therapeutic agents.
1. An IL-15 mutein or fragment thereof, said IL-15 mutein or fragment thereof being characterized in that it has a sequence that is directly derived from human mature wild-type IL-15 by one amino acid substitution of residue 64, 65, 68 or 69, this residue numbering corresponding to the human mature wild-type IL-15, wherein said IL-15 mutein or fragment thereof comprises the mutated 64-69 region, binds to IL-15 Ralpha and is an IL-15 antagonist or an IL-15 partial antagonist.
2. The IL-15 mutein or fragment thereof according to claim 1 , characterized in that said one substitution is a substitution of E64 by K.
3. The IL-15 mutein or fragment thereof according to claim 1 , characterized in that said one substitution is a substitution of residue N65 by K.
4. The IL-15 mutein or fragment thereof according to claim 1 , characterized in that said one substitution is a substitution of residue 168 by D.
5. The IL-15 mutein or fragment thereof according to claim 1 , characterized in that said one substitution is a substitution of residue L69 by R.
6. A pharmaceutical composition comprising the IL-15 mutein or fragment thereof according to claim 1 , and at least one of a pharmaceutically acceptable vehicle, a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, or a pharmaceutically acceptable adjuvant.