Bispecific Antibody Formulation pH and Ionic Strength Control
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Solution Overview
Problem
The development of stable pharmaceutical formulations for anti-IL-4/anti-IL-13 bispecific antibodies is challenging due to high viscosity, pH shifts, color changes, and the formation of visible and sub-visible particles, especially at high concentrations, and the antibodies' propensity for aggregation and low isoelectric point, which complicates their formulation in liquid form.
Innovation Solution
A stable formulation comprising an anti-IL-4/anti-IL-13 bispecific antibody with a buffering system maintaining pH 7 and low salt concentration, optionally including non-ionic surfactants, sugars, and stabilizing agents like polysorbate 80 and mannitol, which improves stability against aggregation and particle formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the antibody concentration is increased to about 100 mg/mL or greater for subcutaneous administration, then the therapeutic efficacy is improved, but the viscosity increases and the formulation becomes unstable
Solution Approach 1:
The patent applies parameter changes by adjusting the pH to approximately 7.0 and reducing salt concentration to lower ionic strength, which resolves the instability and high viscosity issues at 100 mg/mL antibody concentration, enabling stable liquid formulations at therapeutic doses
Solution Approach 2:
The patent uses composite materials by combining the antibody with specific excipients including buffering systems, non-ionic surfactants, sugars, and stabilizing agents to create a stable formulation that maintains low viscosity and prevents aggregation at high concentrations
2Quantity of substance
If the antibody concentration is increased to about 100 mg/mL or greater for subcutaneous administration, then the therapeutic efficacy is improved, but visible and sub-visible particles form
Solution Approach 1:
The patent applies parameter changes by optimizing pH to approximately 7.0 and reducing ionic strength through low salt concentration, which prevents antibody aggregation and eliminates visible and sub-visible particle formation at 100 mg/mL concentration
Solution Approach 2:
The patent uses intermediary substances including non-ionic surfactants, sugars, and stabilizing agents that act as mediators to prevent antibody-antibody interactions leading to aggregation and particle formation, while maintaining solubility and stability
3Stability of the object's composition
If the salt concentration is reduced to lower ionic strength, then the stability is improved, but the buffering capacity is reduced
Solution Approach 1:
The patent applies parameter changes by using low concentrations of buffering agents (e.g., 5-20 mM phosphate buffer, 10-30 mM Tris buffer) that provide sufficient pH buffering capacity at pH 7.0 without contributing to high ionic strength, thus maintaining both stability and buffering reliability
Solution Approach 2:
The patent uses composite buffering systems combining multiple buffering agents in low concentrations to achieve adequate buffering capacity while maintaining low ionic strength, preventing the trade-off between stability and buffering reliability
Data Source
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AI summary
The present invention provides stable pharmaceutical antibody formulations, including lyophilized formulations, comprising an anti-IL-4/anti-IL-13 bispecific antibody and a buffering system, wherein the pH of the formulation is about pH 7, and wherein the formulation has a low salt concentration in order to reduce the ionic strength of the formulation. The formulations may, optionally, further comprise a non-ionic surfactant, a sugar, and/or a non-ionic stabilizing agent. The formulations can be used in the treatment of various diseases.