Anti-C5 Antibody Formulation Stability at High Concentration
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Solution Overview
Problem
Current formulations of anti-C5 antibodies are not stable at high concentrations, leading to aggregation, fragmentation, and degradation, which limits their therapeutic efficacy and convenience in administration for complement-associated disorders.
Innovation Solution
Development of stable, highly-concentrated aqueous solutions of anti-C5 antibodies, such as eculizumab, using specific buffering agents like histidine and glycine, and carbohydrate excipients like sorbitol and mannitol, which maintain the antibody in a predominantly monomeric form for extended periods without detectable aggregation or degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If anti-C5 antibodies are formulated at high concentrations, then therapeutic efficacy and administration flexibility are improved, but formulation stability deteriorates due to aggregation, fragmentation, and degradation
Solution Approach 1:
The patent applies parameter changes by systematically optimizing formulation conditions including pH (adjusted to specific ranges using buffers like histidine or glycine), ionic strength, temperature, and the presence of excipients. These parameter modifications enable the antibody to remain stable at high concentrations (100-500 mg/mL) by preventing aggregation and degradation mechanisms that would otherwise occur under concentrated conditions.
Solution Approach 2:
The patent introduces intermediary substances including buffering agents (histidine, glycine), carbohydrate excipients (sorbitol, mannitol), and surfactants that act as mediators between the antibody molecules. These intermediaries prevent direct unfavorable interactions between antibody molecules at high concentrations, thereby maintaining monomeric form and preventing aggregation while enabling the desired high concentration formulation.
2Productivity
If high concentration formulations are developed, then storage and manufacturing costs are reduced, but formulation complexity increases due to stability requirements
Solution Approach 1:
The patent simplifies manufacturing by establishing specific parameter ranges for formulation components (buffer concentrations, excipient ratios, pH ranges) that ensure stability. By defining these parameters clearly, the formulation process becomes more controllable and scalable, reducing manufacturing complexity despite the high concentration requirements.
Solution Approach 2:
The patent employs readily available, inexpensive excipients and buffering agents that can be easily sourced and handled. These simple, well-characterized materials reduce formulation complexity while enabling high concentration stability, making the manufacturing process more efficient and cost-effective.
Data Source
AI summary
The present disclosure relates to, inter alia, stable aqueous solutions comprising a high concentration of an antibody that binds to human complement component C5 and methods for preparing the solutions. The disclosure also provides methods for treating or preventing complement-associated disorders (for example, age-related macular degeneration or rheumatoid arthritis) using the solutions. Also featured are therapeutic kits containing one or more of the solutions and a means for administering the solutions to a patient in need such a treatment.