Targeted engineered interferon and uses thereof
View Patent ↗The present invention relates, in part, to chimeric proteins comprising consensus interferon, or a variant thereof, and their use as therapeutic agents.
1. A chimeric protein comprising:
(a) a variant consensus interferon comprising: the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 comprising one or more mutations that confer reduced affinity for interferon-α/β receptor (IFNAR), wherein the one or more mutations confer reduced affinity or activity that is restorable by attachment to one or more targeting moieties; and
(b) the one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest; and
wherein the variant consensus interferon and the one or more targeting moieties are optionally connected with one or more linkers.
2. The chimeric protein of claim 1 , wherein the variant consensus interferon is pegylated.
3. The chimeric protein of claim 1 , wherein the targeting moiety is directed against a tumor cell or an immune cell.
4. The chimeric protein of claim 1 , wherein the targeting moiety comprises a recognition domain that is a full-length antibody, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a shark heavy-chain-only antibody (VNAR), a microprotein (e.g. cysteine knot protein, knottin), a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab′, a F(ab′) 2 , a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecule.
5. The chimeric protein of claim 1 , wherein the recognition domain is a single-domain antibody.
6. The chimeric protein of claim 5 , wherein the recognition domain is a V HH , humanized V HH , or camelized V HH .
7. The chimeric protein of claim 1 , comprising two or more targeting moieties.
8. The chimeric protein of claim 1 , further comprising one or more additional modified signaling agents.
9. The chimeric protein of claim 8 , wherein the additional modified signaling agent comprises one or more mutations conferring reduced affinity or activity for a receptor relative to an unmutated signaling agent.
10. The chimeric protein of claim 9 , wherein the one or more mutations in the additional modified signaling agent allow for attenuation of activity.
11. The chimeric protein of claim 9 , wherein the one or more mutations in the additional modified signaling agent confer reduced affinity or activity that is restorable by attachment to one or more targeting moiety.
12. The chimeric protein of claim 1 , wherein the chimeric protein comprises two signaling agents or two targeting moieties or two of both.
13. The chimeric protein of claim 1 , wherein the chimeric protein comprises three signaling agents or three targeting moieties or three of both.
14. The chimeric protein of claim 1 , wherein the one or more mutations are at amino acid positions 33, 145, 146, 149, 150, and 154 with reference to SEQ ID NO: 2.
15. The chimeric protein of claim 14 , wherein the one or more mutations are selected from R33A, R145X 1 , A146X 2 , M149A, R150A, and L154A, wherein X 1 is selected from A, S, T, Y, L, and I, and wherein X 2 is selected from G, H, Y, K, and D.
16. A method for treating cancer or hepatitis, comprising administering an effective amount of the chimeric protein of claim 1 to a patient in need thereof.