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Publication Number
US-10053517-B2
Publication Date
2018-08-21
Expiration Date
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 provides an antibody having an immunoglobulin heavy chain constant region with CH2 and CH3 regions, each of which is of IgG or IgA isotype, and Cμ3 and Cμ4 regions. The antibody is arranged from the N- to C-terminus to combine an IgG/IgA constant region framework with Cμ3/Cμ4 regions derived from IgM, and is directed to a surface-bound target protein where aggregation induces signal transduction through a receptor.
The hybrid constant regions retain IgG/IgA functional properties while also retaining IgM-like multimerization through Cμ3/Cμ4 disulfide interactions. The resulting antibodies form pentamers and hexamers to create multivalent architectures, and the multimeric complexes drive receptor aggregation and signal transduction, producing immunological outcomes such as apoptosis and growth arrest.
The described framework is applied to receptor signaling settings including TNF receptor superfamily members and B-cell receptor cross-linking. Examples include apoptosis or cytostasis associated with targets such as DR5, CD30, and FAS (CD95), and B-cell receptor cross-linking via CD79a/CD79b that leads to apoptosis or growth arrest. The partial content also describes Fc-related properties such as pH-dependent FcRn binding for IgG, protein A binding, protein G binding, ADCC via CD16, CDC, opsonization, and IgA Fc-alpha receptor (CD89) binding.
Claims Coverage
The partial content identifies one independent claim (clm-00001). This independent claim covers an antibody architecture defined by a specific hybrid heavy-chain constant-region order and a functional requirement that target aggregation induces receptor signal transduction; the dependents shown further specify example mechanisms, quantitative potency and activation thresholds, formats, and multispecific complex assembly.
Hybrid IgG/IgA CH2-CH3 with IgM Cμ3/Cμ4 heavy-chain architecture
An antibody comprising an immunoglobulin heavy chain constant region with CH2 and CH3 regions, each of which is of IgG or IgA isotype, and Cμ3 and Cμ4 regions, in order from N- to C-terminus.
Aggregation-triggered receptor signal transduction on a surface-bound target
The antibody is to a surface-bound target protein in which aggregation of the target protein induces signal transduction through a receptor.
B-cell receptor cross-linking via CD79a/CD79b inducing apoptosis or growth arrest
An antibody that binds to a CD79b receptor subunit complexed with a CD79a receptor subunit, inducing cross-linking of molecules of the B-cell receptor and apoptosis or growth arrest of the cell.
Apoptosis potency threshold
An antibody that induces apoptosis with an EC50 of less than 10 ng/ml.
Activation-associated receptor and cytokine thresholds
An antibody whose activation increases expression of CD23, CD54 and/or CD95 by at least five-fold compared with a control antibody lacking the Cμ3 and Cμ4 regions, or alternatively increases IL-2 expression by at least 50% compared with the control antibody or fusion protein that does not increase IL-2 expression.
Single-chain antibody format with single-chain Fv linked to heavy-chain constant region
A single-chain antibody protein including a single-chain Fv linked to the heavy chain constant region.
Multispecific antibody complex assembly via Cμ3/Cμ4-mediated expression and isolation
A multispecific complex of antibodies produced and isolated by transfecting a cell with vectors encoding multiple antibodies of different specificities, expressing and assembling them via the Cμ3 and Cμ4 regions, and isolating the resulting complex from the cell culture.
Across the independent claim and the dependents reflected in the partial content, the core coverage is directed to a hybrid heavy-chain constant region combining IgG/IgA CH2/CH3 with IgM Cμ3/Cμ4 in a defined N- to C- order, where binding and aggregation of a surface-bound target induces receptor signal transduction. The dependent coverage further narrows to B-cell receptor cross-linking through CD79a/CD79b, apoptosis with an EC50 threshold, expression and cytokine activation thresholds, single-chain Fv formats, and production and isolation of multispecific antibody complexes assembled via Cμ3/Cμ4.
Stated Advantages
Retains IgG/IgA functional properties while also retaining IgM-like multimerization through Cμ3/Cμ4 multimerization.
Enables formation of pentameric and hexameric multimeric complexes to drive receptor signaling through aggregation.
Provides Fc-related functions including pH-dependent FcRn binding for IgG, protein A binding, protein G binding, ADCC, CDC, and opsonization.
Provides IgA Fc-alpha receptor (CD89) binding.
Induces apoptosis or growth arrest via receptor signal transduction, including settings involving TNF receptor superfamily members and B-cell receptor cross-linking.
Documented Applications
Cancer treatment via antitumor and immune-activation efficacy described for antibodies and multimeric complexes, including examples such as systemic xenograft survival benefit and cytostasis or apoptosis associated with targets including CD30, DR5, and DR4.
Immunological disorder treatment described as use of the antibody framework.
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