IgE binding proteins and uses thereof
Provided herein are IgE-binding VHH domains, polypeptides, and proteins, and methods of using such IgE-binding polypeptides and proteins to modulate the biological activity of IgE.
1. A VHH domain that binds IgE, comprising a complementarity determining region 1 (CDR1), a complementarity determining region 2 (CDR2), and a complementarity determining region 3 (CDR3) of a VHH that comprises the amino acid sequence of SEQ ID NO: 42.
2. The VHH domain of claim 1 , wherein the CDR1 comprises the amino acid sequence of SEQ ID NO: 3, the CDR2 comprises the amino acid sequence of SEQ ID NO: 48, and the CDR3 comprises the amino acid sequence of SEQ ID NO: 51, under the AbM definition.
3. The VHH domain of claim 1 , wherein the CDR1 comprises the amino acid sequence of SEQ ID NO: 54, the CDR2 comprises the amino acid sequence of SEQ ID NO: 59, and the CDR3 comprises the amino acid sequence of SEQ ID NO: 71, under the Chothia definition.
4. The VHH domain of claim 1 , wherein the CDR1 comprises the amino acid sequence of SEQ ID NO: 55, the CDR2 comprises the amino acid sequence of SEQ ID NO: 68, and the CDR3 comprises the amino acid sequence of SEQ ID NO: 72, under the Kabat definition.
5. The VHH domain of claim 1 , wherein the CDR1 comprises the amino acid sequence of SEQ ID NO: 56, the CDR2 comprises the amino acid sequence of SEQ ID NO: 69, and the CDR3 comprises the amino acid sequence of SEQ ID NO: 73, under the Contact definition.
6. The VHH domain of claim 1 , wherein the CDR1 comprises the amino acid sequence of SEQ ID NO: 57, the CDR2 comprises the amino acid sequence of SEQ ID NO: 70, and the CDR3 comprises the amino acid sequence of SEQ ID NO: 74, under the IMGT definition.
7. The VHH domain of claim 1 , comprising:
(a) a framework 1 region, wherein the framework 1 region comprises glutamate (E), aspartate (D), lysine (K), or arginine (R) at position 11 according to Kabat numbering, and/or
(b) a framework 4 region, wherein the framework 4 region comprises:
(i) glutamate (E), arginine (R), or aspartate (D) at position 112 according to Kabat numbering, and/or
(ii) leucine (L) at position 108 according to Kabat numbering.
8. The VHH domain of claim 1 , wherein the VHH domain is humanized.
9. The VHH domain of claim 1 , comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 42.
10. The VHH domain of claim 1 , comprising the amino acid sequence of SEQ ID NO: 42.
11. A polypeptide comprising the VHH domain of claim 1 .
12. The polypeptide of claim 11 , further comprising an Fc region.
13. The polypeptide of claim 12 , wherein the Fc region is a human IgG1 Fc region.
14. The polypeptide of claim 11 , comprising the amino acid sequence of SEQ ID NO: 86.
15. A composition comprising two or more multimerized polypeptides of claim 11 .
16. A pharmaceutical composition comprising:
(a) the polypeptide of claim 11 ; and
(b) a pharmaceutically acceptable carrier.
17. The polypeptide of claim 11 , comprising the amino acid sequence of SEQ ID NO: 93.
18. The polypeptide of claim 12 , wherein the Fc region is a human IgG1 Fc region comprising substitutions S267E and L328F, numbered according to the EU index as in Kabat.
19. A polypeptide comprising the VHH domain of claim 10 and an Fc region.
20. The polypeptide of claim 19 , wherein the Fc region is a human IgG1 Fc region comprising substitutions S267E and L328F, numbered according to the EU index as in Kabat.
21. A composition comprising two dimerized polypeptides of claim 12 .
22. A composition comprising two dimerized polypeptides of claim 14 .
23. A pharmaceutical composition comprising the polypeptide of claim 14 and a pharmaceutically acceptable carrier.
24. A pharmaceutical composition comprising the polypeptide of claim 17 and a pharmaceutically acceptable carrier.
25. A polypeptide comprising:
(a) a VHH domain comprising the amino acid sequence of SEQ ID NO: 42;
(b) a human IgG1 Fc region comprising substitutions S267E and L328F, numbered according to the EU index as in Kabat; and
(c) a polypeptide linker,
wherein the VHH domain is linked to the human IgG1 Fc region via the polypeptide linker.
26. A polypeptide consisting of the amino acid sequence of SEQ ID NO: 86.
27. A pharmaceutical composition comprising the polypeptide of claim 26 and a pharmaceutically acceptable carrier.
28. The pharmaceutical composition of claim 27 , the pharmaceutical composition further comprising a polypeptide consisting of the amino acid sequence of SEQ ID NO: 93.
29. A polypeptide consisting of the amino acid sequence of SEQ ID NO: 93.
30. A pharmaceutical composition comprising the polypeptide of claim 29 and a pharmaceutically acceptable carrier.