Modified immunoglobulin Fc regions
Provided are proteins comprising a variant IgG Fc region, wherein the proteins exhibit significantly reduced binding to human FcγRI when compared with a reference protein comprising the amino acid substitutions L234A/L235A/P329G. Also provided are compositions, methods of treatment and methods to reduce Fc-induced effector functions in a parent protein.
1. A protein comprising a variant IgG Fc region or a variant Cγ2 domain, wherein the variant IgG Fc region or variant Cγ2 domain comprises a combination of amino acids selected from the group consisting of: 234G/235S/236R, 234S/235T/236R, 234S/235V/236R, 234T/235Q/236R, and 234T/235T/236R, wherein the amino acid numbering is according to the EU index as in Kabat, and wherein the binding of the protein to human FcγRI, when measured by surface plasmon resonance, is less than 50% of the binding of a reference protein comprising an Fc region comprising the amino acid sequence of SEQ ID NO: 2.
2. A conjugate comprising the protein of claim 1 which is covalently attached to another substance.
3. A composition comprising the protein of claim 1 .
4. The protein of claim 1 , wherein reduced effector function of the protein: (a) reduces the likelihood of adverse clinical effects; (b) increases the likelihood of beneficial clinical effects; or (c) facilitates the use of higher doses, more frequent doses or more doses when compared with a reference protein.
5. A test system or kit comprising the protein of claim 1 .
6. The protein of claim 1 , wherein the protein is an antibody.
7. The protein of claim 1 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
8. The protein of claim 6 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
9. The protein of claim 1 , wherein the variant IgG Fc region or variant Cγ2 domain comprises a combination of amino acids comprising 234G/235S/236R, wherein the amino acid numbering is according to the EU index as in Kabat.
10. The protein of claim 9 , wherein the protein is an antibody.
11. The protein of claim 9 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
12. The protein of claim 10 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
13. The protein of claim 1 , wherein the variant IgG Fc region or variant Cγ2 domain comprises a combination of amino acids comprising 234S/235T/236R, wherein the amino acid numbering is according to the EU index as in Kabat.
14. The protein of claim 13 , wherein the protein is an antibody.
15. The protein of claim 13 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
16. The protein of claim 14 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
17. The protein of claim 1 , wherein the variant IgG Fc region or variant Cγ2 domain comprises a combination of amino acids comprising 234S/235V/236R, wherein the amino acid numbering is according to the EU index as in Kabat.
18. The protein of claim 17 , wherein the protein is an antibody.
19. The protein of claim 17 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
20. The protein of claim 18 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
21. The protein of claim 1 , wherein the variant IgG Fc region or variant Cγ2 domain comprises a combination of amino acids comprising 234T/235Q/236R, wherein the amino acid numbering is according to the EU index as in Kabat.
22. The protein of claim 21 , wherein the protein is an antibody.
23. The protein of claim 21 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
24. The protein of claim 22 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
25. The protein of claim 1 , wherein the variant IgG Fc region or variant Cγ2 domain comprises a combination of amino acids comprising 234T/235T/236R, wherein the amino acid numbering is according to the EU index as in Kabat.
26. The protein of claim 25 , wherein the protein is an antibody.
27. The protein of claim 25 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.
28. The protein of claim 26 , wherein the variant Fc region or variant Cγ2 domain is or is derived from human IgG1, human IgG2, human IgG3 or human IgG4.