Targeted human-interferon fusion proteins
This disclosure relates to a modified α-helical bundle cytokine, with reduced activity via an α-helical bundle cytokine receptor, wherein the α-helical bundle cytokine is specifically delivered to target cells. Preferably, the α-helical bundle cytokine is a mutant, more preferably it is a mutant interferon, with low affinity to the interferon receptor, wherein the mutant interferon is specifically delivered to target cells. The targeting is realized by fusion of the modified α-helical bundle cytokine to a targeting moiety, preferably an antibody. This disclosure relates further to the use of such targeted modified α-helical bundle cytokine to treat diseases. A preferred embodiment is the use of a targeted mutant interferon, to treat diseases, preferably viral diseases and tumors.
1. A composition comprising a targeting construct, wherein the targeting construct comprises:
a mutated human interferon alpha 2, the mutated human interferon alpha 2 having an R149A mutation and a reduced affinity for IFNAR2 as compared to the wild-type human interferon alpha 2; and
a targeting moiety, the targeting moiety comprising an antibody directed to CD20, wherein the targeting moiety restores the reduced affinity of the mutated human interferon alpha 2 for IFNAR2 on targeted cells.
2. The composition of claim 1 , wherein the antibody is a variable domain of a camelid heavy chain antibody (VHH).
3. A pharmaceutical composition comprising the targeting construct of claim 2 and a suitable excipient.
4. The composition of claim 2 , further comprising a linker, wherein the linker connects the mutated human interferon alpha 2 and the variable domain of the camelid heavy chain antibody (VHH).
5. A pharmaceutical composition comprising the targeting construct of claim 4 and a suitable excipient.
6. The composition of claim 1 , wherein the antibody is a single-chain antibody.
7. A pharmaceutical composition comprising the targeting construct of claim 6 and a suitable excipient.
8. The composition of claim 6 , further comprising a linker, wherein the linker connects the mutated human interferon alpha 2 and the single-chain antibody.
9. A pharmaceutical composition comprising the targeting construct of claim 8 and a suitable excipient.
10. The composition of claim 1 , further comprising a linker, wherein the linker connects the mutated human interferon alpha 2 and the targeting moiety.
11. A pharmaceutical composition comprising the targeting construct of claim 10 and a suitable excipient.
12. A pharmaceutical composition comprising the targeting construct of claim 1 and a suitable excipient.