Modified adenoviruses
AssigneeUniversity College Cardiff Consultants Limited
InventorsAlan Parker, Hanni Uusi-Kerttula
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Abstract
The invention concerns a modified oncolytic adenovirus of serotype Ad5; a pharmaceutical composition comprising same; and a method of treating cancer using same wherein said modified adenovirus comprises at least one point mutation(s) in the hexon hypervariable region 7 (HVR7 mutation) to prevent virus binding with coagulation factor 10 (FX); at least one point mutation(s) in the fiber knob region AB loop (KO1 mutation) to prevent virus binding with the coxsackie and adenovirus receptor (CAR); and at least one point mutation(s) in the penton integrin binding motif Arg-Gly-Asp (RGD) to prevent virus binding with αvβ3/αvβ5 integrin.
Claims26
A viable modified Ad5 serotype adenovirus having mutations comprising
- a) I421G, T423N, E424S, E450Q and L426Y mutations in the hexon hypervariable region 7 (HVR7 mutation);
- b) S408E and P409A mutations in the fiber knob region AB loop (KO1 mutation);
- c) D342E mutation in the penton integrin binding motif Arg-Gly-Asp (RGD mutation);
- and
- d) a tumor-cell targeting mutation;
- whereby:
- the HVR7 mutation, KO1 mutation, and RGD mutation prevent virus binding with FX, CAR, and αvβ3/αvβ5 integrin, respectively, and reduce off-target sequestration of the modified Ad5 serotype adenovirus to the liver and spleen, and the adenovirus is viable.
A method (i) for preventing an Ad5 serotype adenovirus from binding with coagulation factor 10 (FX), coxsackie and adenovirus receptor (CAR) and αvβ3/αvβ5 integrin, and (ii) for reducing off-target sequestration of the Ad5 serotype adenovirus to the liver and spleen, and (iii) for having the Ad5 serotype adenovirus target tumor cells,
- said method comprising:
- modifying the Ad5 serotype adenovirus, whereby the Ad5 serotype adenovirus comprises:
- a) mutation in the hexon hypervariable region 7 (HVR7 mutation);
- b) mutation in the fiber knob region AB loop (KO1 mutation);
- and
- c) mutation in the penton integrin binding motif Arg-Gly-Asp (RGD mutation);
- and
- d) a tumor-cell targeting mutation;
- wherein:
- the HVR7 mutation comprises I421G, T423N, E424S, E450Q and L426Y;
- the KO1 mutation comprises S408E and P409A;
- and
- the RGD mutation comprises D342E;
- whereby the Ad5 serotype adenovirus is prevented from binding with FX, CAR, and αvβ3/αvβ5 integrin, and exhibits reduced off-target sequestration to the liver and spleen, and
- whereby:
- the adenovirus targets tumor cells;
- and
- the adenovirus is viable.
A modified Ad5 serotype adenovirus having mutations comprising mutations that prevent the modified Ad5 serotype binding with coagulation factor 10 (FX), the coxsackie and adenovirus receptor (CAR), and αvβ3/αvβ5 integrin, and that reduce off-target sequestration of the modified Ad5 serotype adenovirus to the liver and spleen, said mutations comprising:
- a) I421G, T423N, E424S, E450Q and L426Y mutations in the hexon hypervariable region 7 (HVR7 mutation);
- b) S408E and P409A mutations in the fiber knob region AB loop (KO1 mutation);
- and
- c) D342E mutation in the penton integrin binding motif Arg-Gly-Asp (RGD mutation);
- whereby:
- the HVR7 mutation, KO1 mutation, and RGD mutation prevent virus binding with FX, CAR, and αvβ3/αvβ5 integrin, respectively, and reduce off-target sequestration of the modified Ad5 serotype adenovirus to the liver and spleen.
A method for preventing an Ad5 serotype adenovirus from binding with coagulation factor 10 (FX), coxsackie and adenovirus receptor (CAR) and αvβ3/αvβ5 integrin, and for reducing off-target sequestration of the Ad5 serotype adenovirus to the liver and spleen,
- said method comprising:
- modifying the Ad5 serotype adenovirus, whereby the Ad5 serotype adenovirus comprises:
- a) mutation in the hexon hypervariable region 7 (HVR7 mutation);
- b) mutation in the fiber knob region AB loop (KO1 mutation);
- and
- c) mutation in the penton integrin binding motif Arg-Gly-Asp (RGD mutation);
- and
- wherein:
- the HVR7 mutation comprises I421G, T423N, E424S, E450Q and L426Y;
- the KO1 mutation comprises S408E and P409A;
- and
- the RGD mutation comprises D342E;
- whereby
- the Ad5 serotype adenovirus is prevented from binding with FX, CAR, and αvβ3/αvβ5 integrin, and exhibits reduced off-target sequestration to the liver and spleen.
Dependencies are inferred from the claim text.