Multivalent regulatory T cell modulators
This disclosure provides compounds that contain an IL-2 receptor-binding moiety and an ST2-binding moiety. The methods described in the present disclosure provide for a method for treating a condition by administering to a subject in need thereof a therapeutically-effective amount of a compound containing an IL-2 receptor-binding moiety and an ST2-binding moiety.
1. A fusion protein comprising:
a) a human IL-2 protein domain wherein the human IL-2 protein domain comprises human IL-2 with a substitution selected from the group consisting of: T3A, N88R, N88G, D20H, C125S, Q126L, and Q126F, relative to the amino acid sequence of SEQ ID NO: 2;
b) an immunoglobulin Fc protein domain; and
c) an antibody specific for Interleukin 1 receptor-like 1 (ST2), or an antigen-binding fragment thereof.
2. The fusion protein of claim 1 , further comprising at least one peptide linker domain.
3. The fusion protein of claim 1 , wherein the immunoglobulin Fc protein domain comprises an amino acid sequence selected from the group consisting of the human IgG1 Fc variant of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 8 or SEQ ID NO: 9.
4. The fusion protein of claim 2 , wherein the peptide linker domain comprises the amino acid sequence of SEQ ID NO: 6.
5. The fusion protein of claim 1 , further comprising a first peptide linker domain and a second peptide linker domain.
6. The fusion protein of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 24.
7. A dimeric protein comprising the fusion protein of claim 1 .
8. A dimeric protein comprising a first fusion protein and a second fusion protein, wherein:
a. each fusion protein comprises an immunoglobulin (IgG) Fc protein domain and at least one additional protein domain selected from the group consisting of
i. a human IL-2 protein domain, wherein the human IL-2 protein domain comprises human IL-2 with a substitution selected from the group consisting of: T3A, N88R, N88G, D20H, C125S, Q126L, and Q126F, relative to the amino acid sequence of SEQ ID NO: 2; and
ii. an antibody specific for Interleukin 1 receptor-like 1 (ST2), or an antigen-binding fragment thereof; and
b. the dimeric protein comprises at least one of the human IL-2 protein domain and at least one of the antibody specific for ST2, or the antigen-binding fragment thereof.
9. The dimeric protein of claim 8 , wherein at least one of the fusion proteins further comprises at least one peptide linker domain.
10. The dimeric protein of claim 8 , wherein the immunoglobulin Fc protein domain comprises an amino acid sequence selected from the group consisting of the human IgG1 Fc variant of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 8 or SEQ ID NO: 9.
11. The dimeric protein of claim 9 , wherein the peptide linker domain comprises the amino acid sequence of SEQ ID NO: 6.
12. The dimeric protein of claim 8 , wherein
the first fusion protein comprises the amino acid sequence of SEQ ID NO: 28, the second fusion protein comprises the amino acid sequence of SEQ ID NO: 24, and the dimeric protein further comprises the amino acid sequence of SEQ ID NO: 29.
13. A pharmaceutical composition comprising the dimeric protein of claim 8 .