Immunoglobulin constant region Fc receptor binding agents
Inventors
Strome, Scott E. • Schulze, Dan H. • Block, David S. • Olsen, Henrik
Assignees
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Publication Number
US-10941191-B2
Publication Date
2021-03-09
Expiration Date
Abstract
IVIG replacement compounds are derived from recombinant and/or biochemical creation of immunologically active biomimetic(s). These replacement compounds are then screened in vitro to assess each replacement compound's efficiency at modulating immune function. Particular replacement compounds are selected for further in vivo validation and dosage/administration optimization. Finally, the replacement compounds are used to treat a wide range of diseases, including inflammatory and autoimmune diseases.
Core Innovation
The invention provides immunologically active biomimetic compositions, including recombinantly produced biomimetic compositions comprising one or more Fc-based constructs, for binding human low affinity Fcγ receptors (FcγR) on effector cells. The biomimetic compositions include two or more or three or more human IgG3 Fc domains that are capable of binding a human low affinity FcγR and that bind two or more human low affinity FcγRs. The compositions do not comprise either an antigen binding domain or a non-immunoglobulin protein.
The biomimetic compositions are configured to engage low affinity FcγR receptors such as FcγRIIA, FcγRIIB, FcγRIIIA, and FcγRIIIB, thereby modulating immune responses on effector cells. The document describes targeting FcγR engagement using immunologically active biomimetics/stradomers and Fcγ receptor binding to influence immune effector functions, including antigen presentation by dendritic cells, and immune cell activities associated with monocytes, macrophages, dendritic cells, osteoclasts, and NK/B-cell functions.
The disclosed approach includes fixed Fc compositions, including Fc reagent bound to substrates/implants, and immobilized or soluble Fc-based biomimetics to recapitulate IVIG-like dendritic cell phenotypes, including changes associated with CD86 and CD1a. The document also describes FcγRIIIa engagement and reports that certain aggregated biomimetics and multimeric constructs can be more potent than IVIG, while maintaining a biomimetic composition framework based on human IgG3 Fc domains without antigen binding domains.
Claims Coverage
The independent claims cover a method of binding human low affinity Fcγ receptors on effector cells by administering recombinantly produced Fc-domain biomimetic compositions with multivalent human IgG3 Fc domains. The coverage is organized around two inventive feature sets distinguished primarily by the minimum number of IgG3 Fc domains (two or more versus three or more) and the shared multivalent binding requirement to two or more FcγRs, while excluding antigen binding domains and non-immunoglobulin proteins.
Multivalent IgG3 Fc biomimetic for FcγR binding without antigen-binding domain
Administering a recombinantly produced biomimetic composition comprising two or more human IgG3 Fc domains, each capable of binding a human low affinity FcγR, wherein the composition binds to two or more human low affinity FcγRs, and wherein the biomimetic composition does not comprise either an antigen binding domain or a non-immunoglobulin protein; the human low affinity FcγR is an FcγRIIA, an FcγRIIB, an FcγRIIIA, or an FcγRIIIB receptor.
Three-or-more IgG3 Fc biomimetic for FcγR binding without antigen-binding domain
Administering a recombinantly produced biomimetic composition comprising three or more human IgG3 Fc domains, each comprising an IgG3 CH2 and an IgG3 CH3 domain and capable of binding a human low affinity FcγR, wherein the biomimetic composition binds to two or more human low affinity FcγRs, and wherein the biomimetic composition does not comprise either an antigen binding domain or a non-immunoglobulin protein; the human low affinity FcγR is an FcγRIIA, an FcγRIIB, an FcγRIIIA, or an FcγRIIIB receptor.
Across the independent claims, the key inventive coverage is the administration of recombinantly produced biomimetic compositions built from human IgG3 Fc domains arranged to bind multiple human low affinity FcγRs (FcγRIIA, FcγRIIB, FcγRIIIA, or FcγRIIIB) on effector cells, while excluding antigen binding domains and non-immunoglobulin proteins. The claims differentiate the multivalent architecture mainly by requiring two-or-more versus three-or-more IgG3 Fc domains, and the second independent claim further requires inclusion of IgG3 CH2 and IgG3 CH3 within each Fc domain.
Stated Advantages
Can recapitulate IVIG-like dendritic cell phenotypes (including changes associated with CD86 and CD1a).
Can engage FcγRIIIa.
Certain multimeric or heat-aggregated biomimetics can be more potent than IVIG.
Can modulate immune responses by targeting Fcγ receptors and thereby influence immune effector functions, including antigen presentation.
Documented Applications
Binding human low affinity Fcγ receptors on effector cells by administering Fc-based biomimetic compositions (including FcγR-targeted stradomer/biomimetic approaches) to modulate immune responses and immune effector functions.
Treatment context for inflammatory disease, autoimmune disease, or rheumatic disease using IVIG (as stated in dependent claim context).
In vivo ITP models and dosing concepts for stradomer therapies are described.
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