Modified parvovirus having enhanced anti-tumor efficacy
Described are parvovirus variants derived, e.g., from H-1PV, showing higher anti-tumor potential compared to the wild type parvovirus, wherein said variant is characterized by (a) an amino acid substitution, alteration or addition, preferably substitution at position Lys96 of NS-2 and/or position Leu103 of NS-2 (together with a amino acid substitution at position Tyr595 of NS-1 in the latter case), or (b) an in-frame deletion in the parvovirus genome, preferably a deletion resulting in a large amino acid deletion in both the central part (aa 96-133) of NS-2 and the C-terminal part (aa 587-624) of NS-1. The present invention also relates to the use of said parvovirus variants for cancer therapy.
1. A method for treating cancer, comprising the step of administering to a patient a parvovirus variant derived from parvovirus H-1 (H-1PV) or a related rodent parvovirus, wherein said variant (a) has an amino acid substitution at position Lys96 and/or position Leu103 of NS-2 in SEQ ID NO: 13, or (b) has an in-frame deletion consisting of from nucleotides 2022 to 2135 in SEQ ID NO: 11, resulting in the translation of an NS1 protein having a deletion of amino acids 587-624 in SEQ ID NO: 12 and an NS2 protein having a deletion of amino acids 96-133 in SEQ ID NO: 13.
2. The method of claim 1 , wherein Lys at position 96 of NS-2 is substituted by a hydrophilic polar amino acid, and/or Leu at position 103 of NS-2 is substituted by Pro.
3. The method of claim 1 , wherein Lys at position 96 of NS-2 is substituted by a Glu, and/or Leu at position 103 of NS-2 is substituted by a neutral nonpolar amino acid.
4. The method of claim 1 , wherein said variant is characterized by the following substitution(s):
(a) Lys96Glu of NS2; or
(b) Leu103Pro of NS2 and Tyr595H is of NS1.
5. The method of claim 1 , wherein said variant (b) has an in-frame deletion consisting of from nucleotides 2022 to 2135 in SEQ ID NO: 11, resulting in the translation of an NS1 protein having a deletion of amino acid residues 587-624 in SEQ ID NO: 12 and an NS2 protein having a deletion of amino acid residues 96-133 in SEQ ID NO: 13.
6. The method of claim 1 , wherein said related rodent parvovirus is LuIII, Mouse minute virus (MMV), Mouse parvovirus (MPV), Minute virus of Mice (MVM), Rat minute virus (RMV), Rat parvovirus (RPV), Rat virus (RV), or Kilham rat virus (KRV).
7. The method of claim 1 , wherein said cancer is pancreatic carcinoma.
8. The method of claim 1 , wherein the parvovirus is derived from H-1PV.
9. The method of claim 1 , wherein said cancer is pancreatic carcinoma, cervical carcinoma, hepatoma, or lymphoma.