Stable liquid formulation of fusion protein with IgG Fc domain

Inventors

Park, Soon Jae • Chung, Hye-Shin • Kim, Jin Hwan • Kim, Yong Mo • Kim, Jun Young

Assignees

Alteogen Inc

Abstract

A stable liquid formulation includes a fusion protein having an Fc domain of a human immunoglobulin G (IgG), in particular, a protein in which an Fc domain of a human immunoglobulin G (IgG) and a soluble extracellular domain of a vascular endothelial growth factor (VEGF) receptor are fused (e.g., aflibercept)). A composition for stabilizing a protein and a method for stabilizing a protein in which an Fc domain of an IgG and a soluble extracellular domain of a VEGF receptor are fused are disclosed. The present invention improves therapeutic effects on various ophthalmic diseases (e.g., retinal vein occlusion, diabetic macular edema, choroidal neovascularization and wet age-related macular degeneration, etc.) caused by abnormal angiogenesis, while pursuing stabilization of bioactivity through a stable liquid formulation suitable for intravitreal injection of an anti-VEGF-Fc fusion protein including aflibercept.

Core Innovation

The patent describes a stable liquid pharmaceutical formulation comprising a protein in which a soluble extracellular domain of a vascular endothelial growth factor (VEGF) receptor is fused to an Fc domain of a human immunoglobulin G (IgG). The formulation includes a buffer consisting of a histidine salt having pH ranging from 5.7 to 6.2, with histidine-HCl or histidine-acetate present at 10 mM to 50 mM, and the protein is present at 10 to 100 mg/ml in the liquid formulation.

The formulation further includes a sugar selected from sucrose, trehalose, mannitol, and glucose, with a concentration of more than 6% but not more than 10%. A surfactant is also included, selected from polysorbate 20 and polysorbate 80, at 0% to 0.1%. The soluble extracellular domain is defined to comprise the immunoglobulin-like domain 2 of the human Flt1 VEGF receptor-1 and the immunoglobulin-like domain 3 of the human Flk1 VEGF receptor-2.

The document reports that the specified formulation improves suppression of aflibercept aggregation, fragmentation, and isomerization/impurity formation under harsh conditions, including exposure at 40°C and shaking. It also reports enhanced long-term stability, including measured reductions of fragments/aggregates and stable chromatographic and HPLC peak behavior. The pharmaceutical formulation is intended for intravitreal injection and for treating ophthalmic diseases associated with abnormal angiogenesis, including retinal vein occlusion, diabetic macular edema, choroidal neovascularization, and wet age-related macular degeneration.

Claims Coverage

The partial content includes two independent claims that define liquid formulations with multiple quantitative and compositional limits. Across the independent claims, the core inventive features relate to a VEGF receptor-Fc fusion protein composition in a histidine salt buffer at defined pH and concentration, a sugar stabilizer window, a low-level polysorbate surfactant selection and level, defined protein amount, and a version specifically for aflibercept.

The independent claims are directed to a liquid formulation defined by a histidine salt buffer at pH 5.7 to 6.2 with histidine-HCl or histidine-acetate at 10 to 50 mM, together with a sugar stabilizer at more than 6% and up to 10% selected from sucrose, trehalose, mannitol, and glucose, and a low-level polysorbate surfactant at 0 to 0.1%. The formulation is further characterized by the specific VEGF receptor soluble extracellular domain fused to an IgG Fc domain and by a protein concentration of 10 to 100 mg/ml, including a version specifically requiring aflibercept at 10 to 100 mg/ml.

Stated Advantages

Documented Applications