Fc Variants with Increased Affinity for FcyRIIC
The present invention relates to Fc variants having increased affinity for FcγRIIc, methods for their generation, Fc polypeptides comprising optimized Fc variants, and methods for using optimized Fc variants.
1 . An antibody or immunoadhesin comprising at least one engineered glycoform, at a position selected from the group consisting of: 221, 222, 223, 224, 225, 227, and 228, wherein said modification has greater affinity for an Fc gamma receptor relative to said parent antibody or immunoadhesin, and wherein numbering is according to the EU index.
2 . An antibody or immunoadhesin according to claim 1 , wherein said amino acid modification is selected from the group consisting of: 221K, 221Y, 222E, 222Y, 223E, 223K, 224E, 224Y, 225E, 225K, 225W, 227E, 227G, 227K, 227Y, 228E, 228G, 228K, and 228Y.
3 . An antibody or immunoadhesin according to claim 1 , further comprising at least one amino acid modification selected from the group consisting of 236, 239, 268, and 332.
4 . An antibody or immunoadhesin according to claim 4 , further comprising an amino acid modification at position 330.
5 . An antibody or immunoadhesin according to claim 1 , further comprising an amino acid modification at a position selected from the group consisting of: 298, 326, 333, and 334.
6 . An antibody or immunoadhesin according to claim 1 , wherein said engineered glycoform is a reduced level of fucose relative to a native human IgG.
7 . An antibody or immunoadhesin according to claim 6 , wherein said antibody or immunoadhesin has been produced in lec13 CHO cells or YB2/0 cells, and wherein said reduced fucose is relative to a native human IgG that has been produced in CHO cells.
8 . An antibody or immunoadhesin according to claim 6 , wherein said antibody or immunoadhesin has been produced in cells wherein a glycosylation enzyme has been modified, and wherein said reduced fucose is relative to a native human IgG that has been produced in CHO cells.
9 . An antibody or immunoadhesin according to claim 8 , wherein said glycosylation enzyme is a 1,6-fucosyltranserase (FUT8) or β1-4-N-acetylglucosaminyltransferase III (GnTIII).
10 . An antibody or immunoadhesin according to claim 1 , wherein said Fc gamma receptor is FcgRIIIa.
11 . An antibody or immunoadhesin according to claim 1 , wherein said antibody or immunoadhesin mediates greater antibody dependent cell-mediated cytotoxicity (ADCC) relative to said parent antibody or immunoadhesin.
12 . A nucleic acid encoding an antibody or immunoadhesin of claim 1 .
13 . An expression vector comprising the nucleic acid of claim 12 .
14 . A host cell comprising the nucleic acid of claim 12 .
15 . A host cell comprising the expression vector of claim 14 .
16 . A method of producing an antibody or immunoadhesin comprising culturing the host cell of claim 14 or 15 under conditions suitable for expression of said nucleic acid.
17 . The method according to claim 16 further comprising recovering said an antibody or immunoadhesin.
18 . A composition comprising an antibody or immunoadhesin according to claim 1 and a carrier.
19 . A method of treating a mammal in need of said treatment, comprising administering an antibody or immunoadhesin of claim 1.