Fc variants with altered binding to FcRn
Inventors
CHAMBERLAIN, Aaron Keith • Desjarlais, John R. • Karki, Sher Bahadur • Lazar, Gregory Alan • Vielmetter, Jost • Yoder, Sean C.
Assignees
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Publication Number
US-12215165-B2
Publication Date
2025-02-04
Expiration Date
Abstract
The present application relates to optimized IgG immunoglobulin variants, engineering methods for their generation, and their application, particularly for therapeutic purposes.
Core Innovation
The document describes Fc engineering of a wildtype human IgG Fc polypeptide to modulate binding to the neonatal Fc receptor (FcRn) and thereby alter IgG serum half-life. The engineering focuses on increasing FcRn binding at acidic pH while maintaining release at neutral pH, with the objective of prolonged retention. Fcγ receptor interactions are discussed, including ADCC, ADCP, and CDC effector functions mediated by Fcγ receptors such as FcγRI/CD64, FcγRII/CD32, and FcγRIII/CD16, including FcγRIIIb and FcγRIIb.
A central theme in the document is to modify the Fc variant such that FcRn binding is enhanced at pH 6.0 and not increased at neutral pH 7.4. The document also describes an alternative direction in which FcRn affinity is decreased to enable faster clearance, including use in diagnostics and radiotherapeutics. The described residue-numbering framework is based on EU numbering and includes engineered regions and Fc variants intended to shift pH-dependent FcRn interaction behavior.
The document reports evaluation approaches and example Fc variants with substantially altered FcRn binding, using surface plasmon resonance (SPR) and AlphaScreen competition/direct binding assays. Examples include an Fc variant with increased FcRn binding such as N434Y, as well as combinations of variants yielding much larger effects. The document further describes specific loop or insertion/deletion engineering, including a variant with insertion {circumflex over ( )}281S that increases binding at pH 6.0 without increased binding at pH 7.0, and variants such as N286# deletion and insertion {circumflex over ( )}254N that change binding in the opposite directions.
Claims Coverage
The provided independent claims (clm-00001 through clm-00006) all share a single defining inventive element: an Fc variant, or related polypeptide/protein/nucleic-acid-encoded form, of a wildtype human IgG Fc polypeptide that comprises a serine residue at position 434 using EU numbering. Each claim varies only the claimed subject matter type while keeping the positional serine feature constant.
Serine at position 434 in EU numbering Fc variant composition
A composition comprising an Fc variant of a wildtype human IgG Fc polypeptide, wherein the Fc variant comprises a serine residue at position 434, with numbering according to EU numbering.
Serine at position 434 in EU numbering variant Fc domain composition
A composition comprising a variant Fc domain as compared to a wildtype human IgG Fc domain, wherein the variant Fc domain comprises a serine residue at position 434, with numbering according to EU numbering.
Serine at position 434 in EU numbering Fc variant IgG1 polypeptide
A polypeptide comprising an Fc variant of a wildtype human IgG1 Fc, wherein the Fc variant comprises a serine residue at position 434, with numbering according to EU numbering.
Nucleic acid-encoded Fc variant with serine at position 434 in EU numbering
A composition comprising an Fc variant polypeptide encoded by a nucleic acid encoding a variant of a wildtype human IgG Fc polypeptide, wherein the Fc variant comprises a serine residue at position 434, with numbering according to EU numbering.
Nucleic acid-encoded polypeptide with serine at position 434 in EU numbering
A polypeptide encoded by a nucleic acid encoding a polypeptide comprising an Fc variant of a wildtype human IgG Fc polypeptide, wherein the Fc variant comprises a serine residue at position 434, with numbering according to EU numbering.
Protein comprising Fc variant with serine at position 434 in EU numbering
A protein comprising an Fc variant of a wildtype human IgG Fc polypeptide, wherein the Fc variant comprises a serine residue at position 434, with numbering according to EU numbering.
Across the independent claims, the inventive coverage centers on Fc engineering where an Fc variant includes a serine residue at EU position 434, expressed through compositions, polypeptides, nucleic-acid-encoded polypeptides, and proteins.
Stated Advantages
Prolonged IgG retention is described as achievable by increasing FcRn binding at acidic pH without increased binding at neutral pH.
Faster clearance is described as achievable by decreasing FcRn affinity.
Altered pH-dependent FcRn binding is described and evaluated using SPR and AlphaScreen competition/direct binding assays.
Documented Applications
Diagnostics and radiotherapeutics are described as contexts where decreased FcRn affinity for faster clearance can be used.
Therapeutic antibodies and Fc fusion proteins are described in the context of therapeutic uses, including examples such as alemtuzumab, trastuzumab, and anti-CD30 AC10.
Pharmaceutical compositions are described, including compositions containing engineered Fc variants and nucleic-acid-encoded Fc variant polypeptides.
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