Anti-Ang2 Antibody Formulation Stabilization
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Solution Overview
Problem
There is a need for novel pharmaceutical formulations of anti-Ang-2 antibodies that are stable and suitable for administration, as existing formulations face challenges with degradation, aggregation, and maintaining effective concentrations during storage and use.
Innovation Solution
A pharmaceutical formulation comprising a human IgG1 antibody specifically binding to Ang-2, formulated with a histidine buffer at 10 mM ± 1.5 mM and pH 6.0 ± 0.3, polysorbate 20 at 0.2% w/v ± 0.03%, and sucrose at 10% w/v ± 1.5%, which stabilizes the antibody and maintains its structural integrity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If therapeutic antibodies are formulated in liquid solution, then they are suitable for administration to patients, but they are prone to degradation, aggregation, or undesired chemical modifications during storage and use
Solution Approach 1:
The patent optimizes multiple formulation parameters including buffer composition (histidine, phosphate, or citrate at specific pH ranges), excipient concentrations (sucrose, trehalose, polysorbate 80), and antibody concentration to achieve a balance between stability and administerability. The specific parameter ranges are determined through systematic experimentation to prevent degradation while maintaining liquid formulation properties suitable for injection.
Solution Approach 2:
The formulation employs a composite system combining multiple excipients with specific functions: buffers (histidine/phosphate/citrate) for pH control, sugars (sucrose/trehalose) for structural stabilization, and surfactants (polysorbate 80) for aggregation prevention. This multi-component composite approach addresses various degradation mechanisms simultaneously while maintaining the antibody in a stable liquid state suitable for clinical administration.
2Reliability
If the concentration of excipients is increased to improve antibody stability, then degradation and aggregation are reduced, but the viscosity of the solution increases and the concentration of antibody that can be accommodated decreases
Solution Approach 1:
The patent establishes specific concentration ranges for each excipient to optimize the stability-viscosity trade-off. Histidine buffer at 10-50 mM, sucrose at 2-10%, trehalose at 2-10%, and polysorbate 80 at 0.01-0.5% are determined through systematic experimentation. These parameter optimizations ensure adequate stability protection while maintaining viscosity levels that allow high antibody concentrations to be accommodated without excessive thickness.
Solution Approach 2:
Different excipients are selected to address specific local stability needs: histidine buffer for pH-dependent stability, sucrose/trehalose for hydrophobic interface stabilization, and polysorbate 80 for surface-related aggregation prevention. This targeted approach allows each component to contribute optimally to stability without unnecessarily increasing overall viscosity, enabling higher antibody concentrations to be formulated.
3Reliability
If the pH of the buffer is adjusted to optimize antibody stability, then degradation is reduced, but the visual quality or appeal of the formulation may be affected
Solution Approach 1:
The patent specifies optimal pH ranges (histidine buffer pH 5.5-7.0, phosphate buffer pH 6.0-8.0, citrate buffer pH 3.0-6.0) that balance stability optimization with visual quality maintenance. These pH ranges are determined through experimentation to prevent both degradation and visible formulation defects such as precipitation or discoloration, ensuring the formulation remains visually acceptable while providing optimal stability protection.
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 ensures that at least 96% of the anti-Ang-2 antibody remains non-aggregated and un-degraded after storage at various temperatures, retaining its native form and binding affinity, making it suitable for clinical use.
Implementation Method 1
a histidine buffer at a concentration of 10 mM ± 1.5 mM and a pH of 6.0 ± 0.3
Implementation Method 2
polysorbate 20 at a concentration of 0.2% w/v ± 0.03% w/v
Implementation Method 3
sucrose at a concentration of 10% w/v ± 1.5% w/v
Data Source
AI summary
The present disclosure provides pharmaceutical formulations comprising an antibody that specifically binds to angiopoietin 2 (Ang-2). The formulations may contain, in addition to an anti-Ang-2 antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present disclosure exhibit a substantial degree of antibody stability after storage for several months and after being subjected to thermal and other physical stress.