Stable liquid pharmaceutical formulation of anti-influenza virus antibody
Inventors
LEE, Joon Won • HAN, Won Yong • KIM, Su Jung • OH, Jun Seok • Kim, So Young • Kim, Kwang Woo • SHIN, Yeon Kyeong
Assignees
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Publication Number
US-12065482-B2
Publication Date
2024-08-20
Expiration Date
Abstract
A stable liquid pharmaceutical preparation of an anti-influenza virus antibody and, more specifically, a stable liquid pharmaceutical preparation that comprises: (A) an anti-influenza virus antibody or a mixture of two or more different types of anti-influenza virus antibodies; (B) a surfactant; (C) a sugar or a sugar derivative; and (D) an amino acid. The stable liquid pharmaceutical preparation for an anti-influenza virus antibody disclosed herein has excellent storage stability at low temperature (5° C.), room temperature (25° C.), and high temperature (40° C.) and excellent long-term (12 months) storage stability, and may be administered intravenously, intramuscularly, transdermally, subcutaneously, intraperitoneally, topically, or in combinations thereof.
Core Innovation
The invention provides a stable liquid pharmaceutical formulation for anti-influenza virus antibodies in water. The formulation comprises an antibody, or a mixture of two or more different anti-influenza virus (A) antibodies, together with polysorbate 80, sorbitol, and histidine, and has a pH of 6. The formulation includes defined compositional ranges for antibody concentration, surfactant, sugar, and histidine.
The formulation is defined as 25 to 50 mg/mL of a mixture of two or more different anti-influenza virus (A) antibodies, 0.02 to 0.1% (w/v) polysorbate 80, 1.0 to 5% (w/v) sorbitol, and 5 to 15 mM histidine, wherein the pharmaceutical formulation has a pH of 6. The antibody mixture includes specific antibodies characterized by light-chain variable regions with CDR1, CDR2, and CDR3 regions identified by SEQ ID NOs: 1, 2, 3 and heavy-chain variable regions identified by SEQ ID NOs: 4, 5, 6, or by CDR1, CDR2, and CDR3 regions identified by SEQ ID NOs: 7, 8, 9 and heavy-chain CDR1, CDR2, and CDR3 regions identified by SEQ ID NOs: 10, 11, 12.
The described approach addresses stability of anti-influenza virus antibody formulations by using histidine and sorbitol in combination with polysorbate 80 and a defined pH. Stability is evaluated using appearance, pH, sterility, antibody concentration, intact IgG, intact HC+LC, monomer content, and HA binding affinity, and long-term storage at 5/25/40°C up to 12 months is reported. Histidine/sorbitol-containing formulations exhibit superior stability compared with alternative buffers or sodium chloride.
Claims Coverage
The independent claim defines a stable liquid pharmaceutical formulation comprising specified amounts of antibody mixture components, polysorbate 80, sorbitol, and histidine at pH 6, with anti-influenza virus antibodies characterized by particular light- and heavy-chain CDR regions identified by SEQ ID NOs. The claim set includes 7 inventive features across dependent claims, refining antibody targeting, mixture ratio, stability or quality thresholds, administration routes, and container format.
Stable liquid formulation with specified components at pH 6
A stable liquid pharmaceutical formulation comprising 25 to 50 mg/mL of a mixture of two or more different anti-influenza virus (A) antibodies, 0.02 to 0.1% (w/v) polysorbate 80 surfactant, 1.0 to 5% (w/v) sorbitol sugar, and 5 to 15 mM histidine, wherein the pharmaceutical formulation has a pH of 6.
Two antibody CDR-defined anti-influenza antibodies
The mixture of two or more different anti-influenza virus (A) antibodies comprises (i) an antibody with a light-chain variable region comprising CDR1, CDR2, and CDR3 regions of SEQ ID NO: 1, 2, and 3 and a heavy-chain variable region comprising CDR1, CDR2, and CDR3 regions of SEQ ID NO: 4, 5, and 6; and (ii) an antibody with a light-chain variable region comprising CDR1, CDR2, and CDR3 regions of SEQ ID NO: 7, 8, and 9 and a heavy-chain variable region comprising CDR1, CDR2, and CDR3 regions of SEQ ID NO: 10, 11, and 12.
Hemagglutinin epitope binding by HA1/HA2 residues
The anti-influenza virus antibody binds to a specific epitope on influenza A virus hemagglutinin (HA), wherein the epitope includes defined amino-acid residues on HA1 and HA2 polypeptides.
Defined ratio range for two antibodies
The formulation includes a mixture of two different anti-influenza virus antibodies in a ratio ranging from 9:1 to 1:9.
Monomer purity threshold after storage
The formulation has an antibody monomer purity of at least 95% measured after 6 weeks of storage at 40±2°C.
Administration routes selected from specified set
The formulation is configured for administration by one or more routes selected from intravenous, intramuscular, transdermal, subcutaneous, intraperitoneal, topical, or combinations thereof.
Pre-filled syringe container
A pre-filled syringe is provided that is filled with the stable liquid pharmaceutical formulation described in claim 1.
Overall, the claim coverage centers on a pH 6 stable liquid formulation containing polysorbate 80, sorbitol, and histidine, together with anti-influenza virus (A) antibodies defined by CDR sequences. Dependent claims further specify hemagglutinin epitope binding, constrain the antibody ratio and monomer purity after storage, and define administration routes and pre-filled syringe packaging.
Stated Advantages
Superior stability for histidine/sorbitol-containing formulations versus alternative buffers or sodium chloride.
Documented Applications
Administration of the stable liquid pharmaceutical formulation by one or more routes selected from intravenous, intramuscular, transdermal, subcutaneous, intraperitoneal, topical, or combinations thereof.
Packaging and delivery using a pre-filled syringe filled with the stable liquid pharmaceutical formulation.
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