Hybrid constant regions

Inventors

Tso, J. Yun • Tsurushita, Naoya

Assignees

JN Biosciences LLC

Abstract

The invention provides hybrid constant regions and antibodies or fusion proteins incorporating the same. The hybrid constant regions include at least CH2 and CH3 regions of an IgG or IgA constant region and Cμ3 and Cμ4 regions of a Cμ constant region. The hybrids retain properties of both component constant regions. The hybrids retain the ability of a Cμ constant region to form multivalent complexes, e.g., pentameric or hexameric structures. IgG hybrids also retain IgG properties including pH-dependent FcRn binding, which is associated with a relatively long in vivo half-life, and specific binding to protein G, which facilitates purification. Depending on the isotype and subtype, the nature of the antigen and presence of additional IgG CH1 and hinge domains, IgG hybrids may also retain properties of specific binding to protein A, and effector functions ADCC, CDC and opsonization. IgA hybrids retain the property of IgA of binding to an Fc-alpha receptor CD89.

Core Innovation

The invention relates to an antibody that includes an immunoglobulin heavy chain constant region with CH2 and CH3 regions of IgG or IgA isotype arranged in order from N- to C-terminus, together with Cμ3 and Cμ4 regions. The antibody is complexed in a multimeric form via the Cμ3 and Cμ4 regions and specifically binds to a TNF receptor superfamily member expressed from a cell.

The antibody complex induces trimerization of the receptor and intracellular signal transduction via the receptor. The disclosed architecture ties the Cμ3/Cμ4-mediated multimerization to receptor clustering and downstream signaling, while retaining Fc functional properties in IgG/IgA hybrid constant-region designs.

The document describes functional outcomes including apoptosis, growth arrest, cytostasis, immune activation, and multivalent signaling through binding to TNF receptor superfamily members. It lists receptors including CD79a, CD30, DR5, DR4, CD40, OX40, and 4-1BB, among others, and describes multimeric and multivalent forms and further therapeutic and diagnostic uses.

Claims Coverage

The claim set is anchored by one independent claim defining a multimeric IgG/IgA constant-region antibody architecture that induces receptor trimerization and intracellular signal transduction on a TNF receptor superfamily member. Dependent claims refine this by specifying receptor selection, constraining constant-region composition, adding functional outcome constraints such as apoptosis potency and expression changes, and including a therapeutic use via administration to a cancer patient.

Overall, the claims cover an antibody with IgG/IgA CH2/CH3 plus Cμ3/Cμ4 that forms multimeric complexes to specifically bind TNF receptor superfamily members, thereby inducing receptor trimerization and intracellular signal transduction. Dependent claim refinements narrow the receptor targets, constrain human constant-region components, and add quantitative functional constraints such as apoptosis EC50 and activation-associated expression changes, and they include a cancer treatment method via administration.

Stated Advantages

Documented Applications