High-Concentration Anti-Aβ Antibody Formulations for Low Aggregation
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Solution Overview
Problem
Developing high concentration anti-Aβ protofibril antibody formulations faces challenges such as protein-protein aggregation, fragmentation, and viscosity issues, which complicate manufacturing and administration, and require high excipient concentrations for stability.
Innovation Solution
Formulations containing 80-300 mg/mL of anti-Aβ protofibril antibody BAN2401 (lecanemab) with optimized excipients like arginine, polysorbate 80, and histidine buffers maintain low aggregation and fragmentation rates, ensuring stability and suitability for intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high concentration antibody formulations (80-300 mg/mL) are used, then productivity and dosage efficiency are improved, but protein-protein aggregation and fragmentation increase
Solution Approach 1:
The patent applies parameter changes by optimizing the pH of the formulation to a specific range (5.0-6.5, preferably 5.5-6.5) and controlling the concentration of stabilizing excipients. This resolves the contradiction by finding the optimal pH parameter that maintains protein stability at high concentrations while avoiding aggregation and fragmentation that would compromise reliability.
Solution Approach 2:
The patent uses stabilizing excipients (intermediaries) such as polysorbate 80, polysorbate 20, hydroxypropyl-beta-cyclodextrin, and mannitol to mediate between the high antibody concentration and protein stability. These excipients act as protective intermediaries that prevent protein-protein interactions leading to aggregation, thereby maintaining reliability at high productivity-enhancing concentrations.
2Productivity
If high concentration antibody formulations are used, then manufacturing efficiency is improved, but viscosity increases complicating administration
Solution Approach 1:
The patent employs parameter changes by optimizing pH and excipient concentrations to control the physical properties of the high-concentration formulation. By maintaining pH in the 5.0-6.5 range and using specific stabilizers, the formulation achieves acceptable viscosity levels that allow efficient manufacturing while remaining suitable for intravenous administration despite the high antibody concentration.
3Duration of action of stationary object
If high concentration antibody formulations are used, then shelf life is extended, but aggregation increases requiring higher excipient concentrations
Solution Approach 1:
The patent uses stabilizing excipients as intermediaries to prevent aggregation during long-term storage. These excipients (polysorbates, cyclodextrins, sugars) act as protective agents that maintain protein stability over extended shelf life without requiring excessively high concentrations, thereby extending duration while controlling harmful aggregation effects.
Solution Approach 2:
The patent applies parameter changes by optimizing pH to 5.0-6.5 and carefully controlling excipient concentrations to achieve the right balance between shelf life extension and aggregation prevention. This optimal parameter set allows long-term stability without requiring excessive excipients that would increase formulation complexity.
4Reliability
If high excipient concentrations are used to stabilize high concentration antibodies, then protein stability is improved, but formulation complexity and cost increase
Solution Approach 1:
The patent resolves this contradiction through parameter optimization, specifically setting pH in the 5.0-6.5 range and using moderate concentrations of stabilizing excipients. This optimal parameter selection achieves adequate protein stability without requiring excessively high excipient levels, thereby maintaining formulation simplicity and reducing cost while preserving reliability.
Data Source
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AI summary
Provided herein are aqueous pharmaceutical formulations comprising high concentrations of an isolated anti-Aß protofibril antibody or a fragment thereof that binds to human Aß protofibrils, such as BAN2401, arginine, polysorbate 80, and a pharmaceutically acceptable buffer.