Heterodimeric human IgG1 polypeptides with isoelectric point modifications

Inventors

Moore, Gregory L. • Lazar, Gregory

Assignees

Xencor Inc

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 antibody-drug conjugates and engineered antibody properties, including enzyme-cleavable and pH-/redox-/self-immolative cleavable linkers, as well as linker stability criteria for extracellular stability. It also discusses drug loading characteristics, including attachment-site number and how increased drug loading can impact aggregation and toxicity, together with analytical characterization and cytotoxicity/cell viability/apoptosis assays.

In parallel, the patent addresses glycoengineering for engineered glycoforms, including afucosylation to increase ADCC via FcγRIIIa, and describes approaches for generating glycoforms and altering glycosylation sites or removal. The document further frames broad target/antibody usage for antibody engineering and ADC-related constructs.

The core invention described in the provided content focuses on engineering antibody constant domains to lower isoelectric point (pI) by charge-swapping and isotypic substitutions. Example variants based on an anti-VEGF IgG1 (bevacizumab) CH1/CK region substitutions are reported to yield lower calculated pI while preserving VEGF binding, and in vivo pharmacokinetics in huFcRn mice are described as showing extended half-life that correlates with pI. The patent also describes combining low-pI engineering with FcRn-binding-improving Fc mutations, including N434S, to increase half-life, and using low-pI isotype designs with altered effector function and purification advantages for resolving near-identical antibody heterodimers/bispecifics through ion exchange and isoelectric focusing.

Claims Coverage

The partial content includes one independent claim directed to a specific variant human IgG1 Fc region with defined amino acid substitutions and a sequence identity threshold. The claim scope is therefore centered on the defined L351K and T366K substitutions in EU numbering and high sequence identity to a reference sequence.

Overall, the claim coverage in the provided content is limited to compositions containing a variant human IgG1 Fc region with the specified L351K and T366K substitutions (EU numbering) and at least 95% sequence identity to SEQ ID NO: 2. No additional independent-claim inventive features are provided beyond these requirements.

Stated Advantages

Documented Applications

No documented applications found