De novo design of potent and selective interleukin mimetics
De novo designed polypeptides that bind to IL-2 receptor βγ c heterodimer (IL-2Rβγ c ), IL-4 receptor αγ c heterodimer (IL-4Rαγ c ), or IL-13 receptor α subunit (IL-13Rα) are disclosed, as are methods for using and designing the polypeptides.
1. A non-naturally occurring polypeptide that binds to IL-2 receptor βγc heterodimer (IL-2Rβγc) and comprises an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:181, wherein the polypeptide further comprises a targeting domain.
2. The polypeptide of claim 1 wherein the targeting domain binds to a cell surface protein marker on the surface of a tumor cell, a tumor vascular component cell, or a tumor microenvironment cell.
3. The polypeptide of claim 1 wherein the targeting domain binds to an immune cell surface protein marker.
4. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence at least 85% identical to the amino acid sequence set forth in SEQ ID NO:181.
5. The polypeptide of claim 4 wherein the targeting domain binds to a cell surface protein marker on the surface of a tumor cell, a tumor vascular component cell, or a tumor microenvironment cell.
6. The polypeptide of claim 4 wherein the targeting domain binds to an immune cell surface protein marker.
7. The polypeptide of claim 4 wherein the targeting domain is an antibody.
8. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:181.
9. The polypeptide of claim 8 wherein the targeting domain binds to a cell surface protein marker on the surface of a tumor cell, a tumor vascular component cell, or a tumor microenvironment cell.
10. The polypeptide of claim 8 wherein the targeting domain binds to an immune cell surface protein marker.
11. The polypeptide of claim 8 wherein the targeting domain is an antibody.
12. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence at least 93% identical to the amino acid sequence set forth in SEQ ID NO:181.
13. The polypeptide of claim 12 wherein the targeting domain binds to a cell surface protein marker on the surface of a tumor cell, a tumor vascular component cell, or a tumor microenvironment cell.
14. The polypeptide of claim 12 wherein the targeting domain binds to an immune cell surface protein marker.
15. The polypeptide of claim 12 wherein the targeting domain is an antibody.
16. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:181.
17. The polypeptide of claim 16 wherein the targeting domain binds to a cell surface protein marker on the surface of a tumor cell, a tumor vascular component cell, or a tumor microenvironment cell.
18. The polypeptide of claim 16 wherein the targeting domain binds to an immune cell surface protein marker.
19. The polypeptide of claim 16 wherein the targeting domain is an antibody.
20. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence at least 97% identical to the amino acid sequence set forth in SEQ ID NO:181.
21. The polypeptide of claim 20 wherein the targeting domain binds to a cell surface protein marker on the surface of a tumor cell, a tumor vascular component cell, or a tumor microenvironment cell.
22. The polypeptide of claim 20 wherein the targeting domain binds to an immune cell surface protein marker.
23. The polypeptide of claim 20 wherein the targeting domain is an antibody.
24. The polypeptide of claim 1 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:181.
25. The polypeptide of claim 24 wherein the targeting domain binds to a cell surface protein marker on the surface of a tumor cell, a tumor vascular component cell, or a tumor microenvironment cell.
26. The polypeptide of claim 24 wherein the targeting domain binds to an immune cell surface protein marker.
27. A non-naturally occurring polypeptide that binds to IL-2 receptor βγc heterodimer (IL-2Rβγc) and comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:181, wherein the polypeptide is linked to a stabilization compound selected from polyethylene glycol or albumin.
28. A non-naturally occurring polypeptide that binds to IL-2 receptor βγc heterodimer (IL-2Rβγc) and comprises an amino acid sequence at least 85% identical to the amino acid sequence set forth in SEQ ID NO:181.
29. The polypeptide of claim 28 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:181.
30. The polypeptide of claim 28 , wherein (i) the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 181, except that the N-terminal proline and the C-terminal serine of SEQ ID NO:181 are absent and the amino acid sequence CNSN (SEQ ID NO:260) is present at the N-terminus of SEQ ID NO: 181 and the amino acid sequence NFQC (SEQ ID NO:261) is present at the C terminus of SEQ ID NO:181; (ii) the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 181, except for a tyrosine at position 8 and a glutamic acid at position 33 of SEQ ID NO:181; or (iii) the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 181, except for a cysteine at position 50, 53, or 82 of SEQ ID NO:181.