Heterodimeric human IgG1 polypeptides with isoelectric point modifications
Inventors
Moore, Gregory L. • Lazar, Gregory
Assignees
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Publication Number
US-12617872-B2
Publication Date
2026-05-05
Expiration Date
Abstract
The invention relates generally to compositions and methods for purifying the desired species from a mixture of desired heterodimer and contaminating homodimer immunoglobulin variants by modifying the isoelectric point(s) of the individual chains.
Core Innovation
The patent describes IgG1-based heterodimeric antibody and fusion proteins purified from heterodimer/homodimer mixtures by engineering isoelectric point differences between monomers. It presents a concept of generating pI-separated heterodimers via constant-region charge engineering so that the heterodimer can be purified from mixtures containing homodimers using charge-based methods such as IEF and ion exchange purification context described in the document.
The invention uses a modular design in which variant heavy and/or variant light chain constant regions are engineered through amino acid substitutions at constant-domain positions referenced using EU numbering. It provides overarching constant-region charge engineering ranges and includes extensive lists of constant-region mutation positions, including substitution sets, to achieve specified charge and pI differences between monomers for heterodimer purification.
The patent further describes optional approaches connected to heterodimer formation and molecule properties, including discussion of isotype importation to reduce immunogenicity and optional steric knobs-into-holes Fc variants to increase heterodimer formation. It also discusses optional FcRn/Fc engineering to further improve half-life and effector function, and it includes sequence-formula-style descriptions for variant heavy-chain and variant light-chain constant domains using SEQ IDs.
Claims Coverage
1 independent claim is provided. The claim is focused on a specific variant human IgG1 heavy chain constant region sequence feature and a sequence identity threshold relative to a defined reference sequence.
Engineered variant human igg1 heavy chain constant region with defined substitutions
A composition comprising a variant human IgG1 heavy chain constant region comprising the amino acid substitutions L351K and T366K, wherein numbering is according to the EU index, and wherein the variant human IgG1 heavy chain constant region has at least 95% sequence identity to SEQ ID NO: 2.
The provided independent claim is directed to a composition that includes a variant human IgG1 heavy chain constant region defined by EU-numbered substitutions L351K and T366K, together with a sequence identity requirement to SEQ ID NO: 2.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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