Anti-C5 Antibody Formulation Stability at High Concentration
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Solution Overview
Problem
Patients with complement-associated disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) face substantial morbidity and mortality due to inappropriate regulation or activation of the complement pathways.
Innovation Solution
Development of stable, highly-concentrated aqueous solutions of anti-C5 antibodies, such as ravulizumab, which maintain physical and functional stability for up to 2 years at 2° C. to 8° C., even at concentrations of approximately 100 mg/mL or higher, minimizing aggregation, fragmentation, or degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If anti-C5 antibody is formulated at high concentration (100 mg/mL or higher), then the volume of antibody solution required for therapy is reduced and patient compliance is improved, but the antibody undergoes aggregation, fragmentation, or degradation
Solution Approach 1:
The patent applies parameter changes by modifying the formulation conditions (pH, temperature, excipient composition) to stabilize the anti-C5 antibody at high concentrations. Specifically, the patent identifies and controls critical formulation parameters such as pH (typically 6.0-7.4), buffer composition, and the presence of stabilizing excipients to prevent aggregation and degradation while maintaining antibody stability at concentrations of 100 mg/mL or higher.
Solution Approach 2:
The patent employs intermediary substances (excipients and formulation additives) as mediators to protect the anti-C5 antibody from aggregation and degradation at high concentrations. These intermediaries include stabilizing agents, buffers, and other formulation components that create a protective environment, allowing the antibody to maintain its structural integrity and functional activity in concentrated solutions.
2Duration of action of stationary object
If anti-C5 antibody is stored at high concentration for extended periods, then manufacturing costs are reduced and shelf-life is extended, but aggregation and degradation products increase
Solution Approach 1:
The patent applies preliminary action by pre-formulating the anti-C5 antibody with stabilizing excipients and optimized buffer systems before storage. This preliminary formulation preparation creates a stable matrix that prevents aggregation and degradation from occurring during extended storage periods, allowing the product to maintain stability over time without requiring lyophilization or frequent replenishment.
Solution Approach 2:
The patent utilizes parameter changes in formulation (pH adjustment, ionic strength modification, temperature control) to extend shelf-life while preventing aggregation and degradation. By optimizing these parameters during formulation, the patent enables extended storage at high concentrations without significant formation of harmful aggregates or degradation products.
3Ease of manufacture
If conventional formulation methods are used, then manufacturing process is simple, but the antibody must be lyophilized and reconstituted, increasing complexity and cost
Solution Approach 1:
The patent applies parameter changes to formulation (concentration, pH, excipient composition) to enable the anti-C5 antibody to be stored as a stable, concentrated aqueous solution without requiring lyophilization. This eliminates the need for complex lyophilization equipment and reconstitution procedures, simplifying both manufacturing and administration while maintaining formulation stability.
Data Source
AI summary
The present disclosure relates to stable aqueous solutions comprising a high concentration of an anti-C5 antibody (e.g., ravulizumab) and methods for preparing the solutions. The disclosure also provides methods for treating or preventing complement-associated disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), using the solutions. Also featured were therapeutic kits containing one or more of the solutions and a means for administering the solutions to a patient in need such a treatment.