Molecules with extended half-lives, compositions and uses thereof
AssigneeMedImmune, LLC
InventorsWilliam Dall'Acqua, Leslie S. Johnson, Elizabeth Sally Ward
Life of this patent
Estimating the term…
Abstract
The present invention provides molecules, including IgGs, non-IgG immunoglobulin, proteins and non-protein agents, that have increased in vivo half-lives due to the presence of an IgG constant domain, or a portion thereof that binds the FcRn, having one or more amino acid modifications that increase the affinity of the constant domain or fragment for FcRn. Such proteins and molecules with increased half-lives have the advantage that smaller amounts and or less frequent dosing is required in the therapeutic, prophylactic or diagnostic use of such molecules.
Claims31
A modified IgG comprising a human IgG constant domain comprising one or more amino acid substitutions relative to a wild-type human IgG constant domain at one or more of amino acid residues 251–256, 285–290, 308–314, 385–389 and 428–436, numbered according to the EU index as in Kabat, wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type human IgG constant domain, and wherein at least one of the amino acid substitutions is at amino acid residue 252, 254, 256, 309, 311, 433 or 434, and an amino acid substitution at amino acid residue 252 is a substitution with tyrosine, phenylalanine, tryptophan or threonine, an amino acid substitution at amino acid residue 254 is a substitution with threonine, an amino acid substitution at amino acid residue 256 is a substitution with serine, arginine, glutamine, glutamic acid, aspartic acid, or threonine, an amino acid substitution at amino acid residue 309 is a substitution with proline, an amino acid substitution at amino acid residue 311 is a substitution with serine, an amino acid substitution at amino acid residue 433 is a substitution with arginine, serine, isoleucine, proline, or glutamine, and an amino acid substitution at amino acid residue 434 is a substitution with histidine, phenylalanine, or tyrosine.
A modified IgG comprising a human IgG constant domain comprising amino acid substitutions relative to a wild-type human IgG constant domain at amino acid residues 252, 254 and 256, numbered according to the EU index as in Kabat, wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type human IgG constant domain, and wherein the amino acid substitution at amino acid residue 252 is a substitution with tyrosine, the amino acid substitution at amino acid residue 254 is a substitution with threonine, and the amino acid substitution at amino acid residue 256 is a substitution with glutamic acid.
A modified IgG comprising a human IgG constant domain comprising amino acid substitutions relative to a wild-type human IgG constant domain at amino acid residues 252, 254, 256, 433, 434 and 436, numbered according to the EU index as in Kabat, wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type human IgG constant domain, and wherein the amino acid substitution at amino acid residue 252 is a substitution with tyrosine, the amino acid substitution at amino acid residue 254 is a substitution with threonine, the amino acid substitution at amino acid residue 256 is glutamic acid, the amino acid substitution at amino acid residue 433 is a substitution with lysine, the amino acid substitution at amino acid residue 434 is a substitution with phenyalanine, and the amino acid substitution at amino acid residue 436 is a substitution with histidine.
A modified IgG comprising a non-human LgG constant domain comprising one or more amino acid substitutions relative to a wild-type non-human IgG constant domain at one or more amino acid residues 251–256, 285–290, 308–314, 385–389 and 428–436, numbered according to the EU index as in Kabat, wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type non-human IgG constant domain, and wherein at least one of the amino acid substitutions is at amino acid residue 252, 254, 256, 309, 311, 433 or 434, and an amino acid substitution at amino acid residue 252 is a substitution with tyrosine, phenylalanine, tryptophan or threonine, an amino acid substitution at amino acid residue 254 is a substitution with threonine, an amino acid substitution at amino acid residue 256 is a substitution with serine, arginine, glutamine, glutamic acid, aspartic acid, alanine, asparagine or threonine, an amino acid substitution at amino acid residue 309 is a substitution with proline, an amino acid substitution at amino acid residue 311 is a substitution with serine, an amino acid substitution at amino acid residue 433 is a substitution with arginine, serine, isoleucine, proline, or glutamine, and an amino acid substitution at amino acid residue 434 is a substitution with histidine, phenylalanine, or tyrosine.
Dependencies are inferred from the claim text.