Methods and compositions for inhibiting CD32B expressing cells in IgG4-related diseases
Inventors
Zack, Debra • Stone, John H. • Pillai, Shiv • Foster, Paul
Assignees
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Publication Number
US-12509518-B2
Publication Date
2025-12-30
Expiration Date
Abstract
The present disclosure relates to immunoglobulins that bind FcγRIIb+ B cells and coengage CD19 on the cell's surface and an FcγRIIb on the cell's surface, methods for their generation, and methods for using the immunoglobulins for the treatment of an IgG4-related disease.
Core Innovation
The invention describes engineered Fc-containing immunoglobulins that coengage CD19 on B cells and FcγRIIb through an Fc region variant with enhanced FcγRIIb affinity. The document describes Fc variants defined using Kabat EU-indexed Fc substitutions, including 267E/328F and related variants, together with CD19-binding sequences referenced through SEQ ID NO:35-40 for Fc-independent binding.
The disclosure further includes therapeutic methods for IgG4-related disease (IgG4-RD). The methods include reducing IgG4-RD symptoms and an IgG4-RD responder index (IgG4-RD RI), with pharmacodynamic effects described as reductions in total B cells, plasmablasts, and CD4+SLAMF7+ CTL cell numbers, together with receptor occupancy and downstream signaling-related measurements referenced in the document.
The invention also includes formulation and administration concepts for the antibody, including intravenous (IV) and subcutaneous (SC) formulations, and excipient composition concepts such as acetate buffer, proline, and polysorbate. The document describes an anti-CD19 antibody variant used in an open-label IgG4-RD study, including an S267E/L328F Fc variant and heavy/light chain definition by SEQ ID.
Claims Coverage
The partial content includes two independent claims. Across these claims, the inventive coverage focuses on a subcutaneous formulation that combines a defined anti-CD19 antibody with specific acetate buffer and proline, optionally including polysorbate-80, within defined concentration ranges.
Subcutaneous anti-CD19 formulation with defined heavy and light chains
A formulation for subcutaneous administration comprising an anti-CD19 antibody at a concentration of 100-250 mg/ml, an acetate buffer and proline, wherein the anti-CD19 antibody comprises a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 7.
Subcutaneous formulation with specified excipient concentration ranges and defined antibody chains
A formulation for subcutaneous administration comprising 100-250 mg/ml of an anti-CD19 antibody, 1-2.5 mg/mL sodium acetate, 1-2.5 mg/mL acetic acid, 20-40 mg/mL proline, and 0.05-0.2 mg/mL polysorbate-80, wherein the anti-CD19 antibody comprises a light chain comprising SEQ ID NO: 7, and a heavy chain comprising SEQ ID NO: 9.
The independent claims define subcutaneous formulations containing an anti-CD19 antibody defined by SEQ ID NO: 9 (heavy chain) and SEQ ID NO: 7 (light chain). The formulation coverage is grounded in acetate buffer and proline inclusion and, in claim 11, additionally specifies sodium acetate, acetic acid, and polysorbate-80 within stated concentration ranges.
Stated Advantages
Reducing IgG4-RD symptoms.
Reducing an IgG4-RD responder index (IgG4-RD RI).
Reducing total B cells.
Reducing plasmablasts.
Reducing CD4+SLAMF7+ CTL cell numbers.
Treatment of IgG4-related disease (IgG4-RD).
Inhibition of B-cell activation and antibody production via coengagement of FcγRIIb and CD19 on B cells.
Reduction of pharmacodynamic markers including B cells, plasmablasts, CD4+SLAMF7+ CTLs, and CD19 receptor occupancy.
Rapid but reversible B-cell inhibition as reported in the open-label IgG4-RD study.
Documented Applications
Therapeutic methods for IgG4-related disease (IgG4-RD), including reducing IgG4-RD symptoms and IgG4-RD responder index (IgG4-RD RI), with described pharmacodynamic effects on B cells, plasmablasts, and CD4+SLAMF7+ CTL cells.
Clinical use for treating IgG4-related disease (IgG4-RD), including an open-label IgG4-RD study using an anti-CD19 antibody variant.
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