Antibodies having altered effector function and methods for making the same
First Claim
1. A variant polypeptide of a parent polypeptide comprising an Fc region, wherein the Fc region of the variant polypeptide comprises a modified first amino acid residue at T299 of the Fc region according to the Kabat numbering system of IgG immunoglobulins, the modified first amino acid residue having a side chain chemistry selected from the group consisting of a side chain chemistry comprising a cysteine thiol, a side chain chemistry of sufficient steric bulk such that the polypeptide displays reduced effector function, and a side chain chemistry of sufficient electrostatic charge such that the polypeptide displays reduced effector function, and a second amino acid residue at N297 of the Fc region according to the Kabat numbering system of IgG immunoglobulins, the second amino acid having reduced glycosylation, wherein the variant polypeptide has reduced effector function as compared to the parent polypeptide.
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Abstract
The invention provides a method of producing aglycosylated Fc-containing polypeptides, such as antibodies, having desired effector function. The invention also provides aglycosylated antibodies produced according to the method as well as methods of using such antibodies as therapeutics.
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Citations
88 Claims
- 1. A variant polypeptide of a parent polypeptide comprising an Fc region, wherein the Fc region of the variant polypeptide comprises a modified first amino acid residue at T299 of the Fc region according to the Kabat numbering system of IgG immunoglobulins, the modified first amino acid residue having a side chain chemistry selected from the group consisting of a side chain chemistry comprising a cysteine thiol, a side chain chemistry of sufficient steric bulk such that the polypeptide displays reduced effector function, and a side chain chemistry of sufficient electrostatic charge such that the polypeptide displays reduced effector function, and a second amino acid residue at N297 of the Fc region according to the Kabat numbering system of IgG immunoglobulins, the second amino acid having reduced glycosylation, wherein the variant polypeptide has reduced effector function as compared to the parent polypeptide.
- 10. The variant polypeptide of 1, wherein the reduced effector function is reduced binding to a complement protein.
- 21. A variant polypeptide of a parent polypeptide comprising an IgG1 Fc region, wherein the Fc region of the variant polypeptide comprises an amino acid at position 299 which differs from the amino acid at position 299 of the parent polypeptide, wherein the amino acid at position 299 of the parent polypeptide is threonine and the amino acid at position 299 of the variant polypeptide is selected from the group consisting of alanine, asparagine, glycine, tyrosine, cysteine, histidine, glutamic acid, aspartic acid, lysine, arginine, isolucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine, and wherein the variant polypeptide comprises an amino acid at position 297 of the Fc region having reduced glycosylation and displays reduced effector function as compared to the parent polypeptide.
- 31. An antibody variant of a parent antibody, wherein the antibody variant comprises an Fc region comprising a replacement amino acid substituted for the threonine at position 299 of the Fc region according to the Kabat numbering system for IgG immunoglobulins, the substituted amino acid residue having a side chain chemistry selected from the group consisting of a side chain chemistry comprising a cysteine thiol, a side chain chemistry of sufficient steric bulk such that the polypeptide displays reduced effector function, and a side chain chemistry of sufficient electrostatic charge such that the polypeptide displays reduced effector function and a second amino acid residue at N297 of the Fc region according to the Kabat numbering system for IgG immunoglobulins, the second amino acid residue having reduced glycosylation as compared to the parent antibody.
- 33. A varaint antibody of a parent antibody comprising an IgG1 Fc region, wherein the Fc region of the variant antibody comprises an amino acid at position 299 which differs from the amino acid at position 299 of the parent antibody, wherein the amino acid threonine at position 299 of the parent antibody is threonine and the amino acid at position 299 of the variant antibody is selected from the group consisting of alanine, asparagine, glycine, tyrosine, cysteine, histidine, glutamic acid, aspartic acid, lysine, arginine, isolucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine, and wherein the variant antibody comprises an amino acid at position 297 of the Fc region having reduced glycosylation and displays reduced effector function as compared to the parent polypeptide.
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87. A variant polypeptide of a parent polypeptide comprising an IgG 1 Fc region, wherein the Fc region of the variant polypeptide comprises an amino acid at position 299 which differs from the amino acid at position 299 of the parent polypeptide, wherein the amino acid at position 299 of the parent polypeptide is threonine and the amino acid at position 299 of the variant polypeptide is an alanine, and wherein the variant polypeptide comprises an amino acid at position 297 of the Fc region having reduced glycosylation and displays reduced effector function as compared to the parent polypeptide.
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88. A variant polypeptide of a parent polypeptide comprising an IgG4 Fc region, wherein the Fc region of the variant polypeptide comprises an amino acid at position 299 which differs from the amino acid at position 299 of the parent polypeptide, wherein the amino acid at position 299 of the parent polypeptide is threonine and the amino acid at position 299 of the variant polypeptide is an alanine, and wherein the variant polypeptide comprises an amino acid at position 297 of the Fc region having reduced glycosylation and displays reduced effector function as compared to the parent polypeptide.
Specification