Heterodimeric proteins

Inventors

Moore, Gregory • Bernett, Matthew • Rashid, Rumana • Desjarlais, John

Assignees

Xencor Inc

Abstract

In one aspect, the present invention provides heterodimeric antibodies comprising a first monomer comprising a first heavy chain constant domain comprising a first variant Fc domain and a first antigen binding domain and a second monomer comprising a second heavy chain constant domain comprising a second variant Fc domain and a second antigen binding domain. In an additional aspect the heterodimeric antibody comprises a first monomer comprising a heavy chain comprising a first Fc domain and a single chain Fv region (scFv) that binds a first antigen, wherein the scFv comprises a charged scFv linker. The heterodimeric antibody further comprises a second monomer comprising a first heavy chain comprising a second Fc domain and a first variable heavy chain and a first light chain.

Core Innovation

The invention relates to heterodimeric protein architectures, in particular heterodimeric antibody formats that include a heterodimeric Fc domain formed from two distinct Fc monomers. The approach uses engineered heterodimerization variants on two variant human IgG Fc domains to favor heterodimer formation over homodimers and to enable purification over homodimers.

The described heterodimerization engineering is based on heterodimerization variants such as knobb-and-holes, steric or charge-pair variants, and pI variants, including electrostatic steering and isoelectric focusing or ion exchange purification behavior used to distinguish heterodimers from homodimers. The partial content further describes scFv/counted constructs using charged scFv linkers for pI tuning and discusses skewing and selection effects that support monovalent versus bivalent co-engagement considerations.

The invention further discusses additional Fc variants relevant to biological function and persistence, including FcγR ablation or knockout and FcRn-related or persistence-related changes, together with selectable linker options and broad target antigen scope. The architectures are described for inclusion with various immunoglobulin components and fusion partners, while also addressing production, purification, and analytical quality control distinguishing heterodimeric versus homodimeric species.

Claims Coverage

The provided independent claim set includes one independent claim (clm-00001). It specifies a heterodimeric protein with a heterodimeric Fc domain made from a first variant human IgG Fc monomer and a second variant human IgG Fc monomer, each defined by particular EU-numbered amino acid substitutions; this is the core inventive coverage in the partial record.

In the provided partial content, claim coverage is centered on the structural definition of a heterodimeric Fc domain using two distinct variant human IgG Fc monomers with specified EU-numbered substitutions. Dependent claims further expand the architecture with fusion partners and provide additional nucleic acid and production or recovery aspects, but the independently claimed novelty is the defined heterodimeric Fc composition.

Stated Advantages

Documented Applications