Bispecific Antibody Formulation for Aggregate and Charge Control
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Solution Overview
Problem
Existing stable solution formulations for bispecific antibodies that bind to blood coagulation factors FIX and/or FIXa and FX do not effectively suppress aggregate formation and charge heterogeneity.
Innovation Solution
A solution formulation of pH 4.5 to 6.5 comprising 20 to 180 mg/mL bispecific antibody, 10 mM to 40 mM histidine/aspartate buffer, 0.2 to 1 mg/mL Poloxamer 188, and 100 mM to 300 mM arginine, which stabilizes the antibody by reducing aggregate formation and charge heterogeneity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional solution formulations (using histidine/arginine or histidine/aspartate buffer) are used for bisspecific antibodies, then the formulations can be prepared with high antibody concentration, but aggregate formation and charge heterogeneity are not effectively suppressed
Solution Approach 1:
The patent optimizes specific parameter ranges for multiple formulation components simultaneously: pH (4.5-6.5), histidine/aspartate buffer concentration (10-40 mM), Poloxamer 188 concentration (0.2-1 mg/mL), and arginine concentration (100-300 mM). This multi-parameter optimization resolves the contradiction by finding the specific parameter space where both high antibody concentration and suppression of aggregate formation are achieved.
Solution Approach 2:
The formulation uses a composite approach by combining multiple excipients (histidine/aspartate buffer, Poloxamer 188, and arginine) rather than relying on a single buffering system. This composite formulation strategy allows the components to work synergistically: the buffer maintains pH, Poloxamer 188 suppresses aggregation through steric stabilization, and arginine prevents charge heterogeneity, thereby achieving both high concentration and stability.
2Productivity
If high concentration of antibody is formulated (20 to 180 mg/mL), then the dosing volume can be reduced, but the solution stability and suppression of aggregate formation become challenging
Solution Approach 1:
Poloxamer 188 acts as an intermediary substance that mediates between the high concentration antibody molecules, preventing their direct interaction and aggregation. The surfactant adsorbs at the protein-protein interface and provides steric stabilization, allowing high antibody concentrations to be maintained without compromising solution stability or increasing aggregate formation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulation achieves stable antibody solutions with suppressed aggregate formation and charge heterogeneity, enhancing the stability and effectiveness of bispecific antibodies like Emicizumab (ACE910) for treating hemophilia A.
Implementation Method 1
10 mM to 40 mM histidine/aspartate buffer
Implementation Method 2
Poloxamer 188 at 0.2 to 1 mg/mL
Implementation Method 3
100 mM to 300 mM arginine
Data Source
AI summary
The present invention relates to stable antibody-containing solution formulations in which aggregate formation of Emicizumab (ACE910) which is a bispecific antibody functionally substituting for FVIII, is suppressed. Specifically, the present invention relates to the above-mentioned antibody-containing solution formulations of pH 4.5 to 6.5 that contain the aforementioned bispecific antibody at 20 to 180 mg/mL, 10 mM to 40 mM histidine-aspartate buffer, Poloxamer 188 at 0.2 to 1 mg/mL, and 100 mM to 300 mM arginine.