Engineered immunoglobulins with altered FcRn binding
The present invention relates to compositions and methods for antibody-mediated therapy. In particular, provided herein are engineered immunoglobulins with altered half-life.
1 . An immunoglobulin comprising a mutated IgG Fc region, wherein said mutated IgG Fc region comprises a human IgG Fc region modified to include:
(a) an arginine residue at amino acid position 311;
(b) a glutamic acid or an aspartic acid residue at amino acid position 428; and
(c) a trypton residue at amino acid position 434, wherein the numbering of amino acid residues is according to the EU index with reference to said wild-type IgG Fc region.
2 . The immunoglobulin of claim 1 , wherein said immunoglobulin has altered binding to FcRn as compared to a parent immunoglobulin comprising said human IgG Fc region without any mutation or modification.
3 . The immunoglobulin of claim 2 , wherein said parent immunoglobulin is selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and Fc fragments thereof.
4 . The immunoglobulin of claim 2 , wherein said parent immunoglobulin is IgG1 or IgG2 and said mutated IgG Fc region exhibits enhanced binding to complement factor C1q.
5 . The immunoglobulin of claim 1 , wherein said mutated IgG Fc region extends the serum half-life of the immunoglobulin as compared to said parent immunoglobulin.
6 . The immunoglobulin of claim 1 , wherein said immunoglobulin has an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 7, 8, 11, 12, 13, 14, 15, and 16.
7 . The immunoglobulin of claim 1 , wherein said immunoglobulin binds to a target selected from the group consisting of a cancer marker, a cytokine, an infectious disease marker, and a growth factor.
8 . An Fc fusion fragment comprising a mutated IgG Fc region of composed of a human IgG Fc region modified to include:
a. an arginine residue at amino acid position 311;
b. glutamic acid or an aspartic acid residue at amino acid position 428; and
c. a tryptophan residue at amino acid position 434,
wherein the numbering of amino acid residues is according to the EU index with reference to said wild-type IgG FC region.
9 . A fusion protein comprising the immunoglobulin recited in claim 1 fused to an immunogen.
10 . The fusion protein of claim 9 , wherein said immunogen is the extracellular portion of the human p75 TNF receptor.
11 . A fusion protein comprising the Fc fusion fragment of claim 8 fused to an immunogen.