Buffered Bevacizumab Formulation Stabilization
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Solution Overview
Problem
Bevacizumab antibodies, such as those marketed under the brand Avastin, tend to aggregate during storage, leading to reduced potency due to covalent aggregate formation in the antigen-binding domain, which diminishes their effectiveness in binding to vascular endothelial growth factor (VEGF).
Innovation Solution
A buffered formulation of bevacizumab is developed, comprising specific concentrations of citrate phosphate, trehalose or sucrose, and polysorbate 20, with a pH range of 5.6 to 6.1, which stabilizes the antibody, reducing aggregation and maintaining its VEGF binding activity over extended storage periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bevacizumab is stored under conventional conditions, then the antibody remains stable initially, but aggregates form over time reducing potency
Solution Approach 1:
The patent applies parameter changes by optimizing the pH to a specific range of 5.6-6.1 and adjusting buffer composition (citrate phosphate, sodium phosphate) along with stabilizer concentrations (trehalose 50-150 mg/mL, polysorbate 20 0.02-0.1%) to minimize aggregate formation and maintain antibody stability during long-term storage
Solution Approach 2:
The patent uses buffer components and stabilizers as intermediary substances that mediate between the antibody and storage conditions. Specifically, citrate phosphate and sodium phosphate buffers along with trehalose and polysorbate 20 act as protective intermediaries that prevent direct harmful interactions leading to aggregation
2Stability of the object's composition
If the formulation uses higher stabilizer concentrations to prevent aggregation, then colloidal stability improves, but formulation complexity increases
Solution Approach 1:
The patent optimizes stabilizer concentrations within specific ranges (trehalose 50-150 mg/mL, polysorbate 20 0.02-0.1%) rather than using excessive amounts, achieving colloidal stability while maintaining formulation simplicity through parameter optimization
3Quantity of substance
If the antibody concentration is increased to improve therapeutic efficacy, then potency per volume increases, but aggregation tendency increases
Solution Approach 1:
The patent enables higher antibody concentrations to be maintained in solution by changing the pH parameter to 5.6-6.1 and optimizing buffer and stabilizer concentrations, which suppresses aggregation even at elevated antibody levels, thereby achieving both high potency and stability
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 buffered formulation significantly enhances the thermal and colloidal stability of bevacizumab, ensuring minimal aggregation and maintaining therapeutic efficacy for at least 18 months when stored under refrigerated conditions, thereby improving the long-term storage and administration of the antibody.
Implementation Method 1
The invention features buffered formulations for storage of bevacizumab... the formulation has a pH of 5.6 to 5.8... the buffer may comprise citrate phosphate or sodium acetate
Implementation Method 2
the formulation may also comprise a stabilizer that comprises a sugar such as trehalose or sucrose... enhances the thermal stability and colloidal stability of the antibody
Implementation Method 3
the formulation may also comprise a mild surfactant such as polysorbate 20... reducing aggregation and maintaining its VEGF binding activity
Data Source
Figure 1
Figure 2A
Figure 2A(i)
AI summary
The invention provides buffered aqueous formulations of bevacizumab. The formulations comprise a citrate phosphate buffer comprising trehalose or sucrose, and polysorbate 20. The formulations have an acidic pH of from about 5.8 to about 6.0, and enhance the conformational and colloidal stability of the bevacizumab molecule. Levels of potency-reducing reversible aggregates and covalent dimers in the citrate phosphate buffer were low, and this buffer further offered protection against storage stress, but did not modify or alter any key biophysical descriptor of the antibody.