rLP2086 Antigen Formulation Balancing Detergent and Aluminum Stability
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Solution Overview
Problem
rLP2086 Subfamily B antigens in immunogenic compositions lose potency over time, leading to instability, particularly when high molar ratios of detergent to protein are used, while rLP2086 Subfamily A antigens are more sensitive to low detergent molar ratios without aluminum.
Innovation Solution
Formulations with a low molar ratio of detergent to protein and increased aluminum concentration stabilize both rLP2086 Subfamily A and B antigens, preventing aggregation even with agitation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If high molar ratios of detergent to protein are used, then protein aggregation is prevented, but Subfamily B antigens lose potency over time
Solution Approach 1:
The patent changes the formulation parameters by reducing the detergent-to-protein molar ratio from high levels to specifically 0.5:1 to 10:1 (optimally 1:1 to 5:1), and simultaneously increases aluminum concentration to 0.1-1.0 mg/mL (optimally 0.5 mg/mL). This parameter adjustment resolves the contradiction by finding an optimal balance point where sufficient detergent prevents aggregation while lower than conventional levels preserve antigen potency.
Solution Approach 2:
The patent creates a composite formulation system combining multiple stabilizing components: reduced detergent (Polysorbate 80), increased aluminum (as aluminum phosphate, hydroxide, sulfate, or alum), histidine buffer (10mM at pH 6.0), and succinate (5mM). The synergistic interaction of these components collectively stabilizes both Subfamily A and B antigens, where aluminum and buffer components compensate for the reduced detergent levels.
2Reliability
If low detergent molar ratios are used, then Subfamily B antigen potency is maintained, but Subfamily A antigens become sensitive and aggregate
Solution Approach 1:
The patent develops a universal formulation system that simultaneously stabilizes both Subfamily A and B antigens with different stability requirements. The multi-functional formulation includes: aluminum (which stabilizes both subfamilies), histidine buffer (provides pH buffering for both), succinate (additional stabilization), and optimized detergent levels (sufficient for A, acceptable for B). This universal system eliminates the need for subfamily-specific formulations.
Solution Approach 2:
The patent introduces aluminum as an intermediary stabilizing component that mediates between the conflicting requirements of Subfamily A and B antigens. Aluminum (at 0.1-1.0 mg/mL) acts as a bridge, providing sufficient stabilization for Subfamily A at low detergent levels while not interfering with Subfamily B potency. The aluminum forms protective complexes with both antigen types, enabling co-stabilization.
3Stability of the object's composition
If aluminum concentration is increased, then antigen aggregation is prevented, but formulation complexity increases
Solution Approach 1:
The patent merges multiple functions into the aluminum component: aggregation prevention, pH buffering (when used as aluminum phosphate or hydroxide), and antigen complex formation. By selecting aluminum phosphate, aluminum hydroxide, aluminum sulfate, or alum, the formulation achieves multiple stabilization goals with a single component, reducing overall formulation complexity despite the increased aluminum concentration (0.1-1.0 mg/mL).
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
Maintains the potency and stability of both rLP2086 Subfamily A and B antigens over extended periods, ensuring effective immunogenic response.
Implementation Method 1
Polysorbate 80, also known, as TWEEN 80, is a nonionic surfactant and emulsifier derived from sorbitol, and is frequently used in pharmaceutical formulations as an emulsifier, solubilizer and stabilizer.
Implementation Method 2
The immunogenic composition further comprises a multivalent cation. The multivalent cation is aluminum.
Implementation Method 3
In some embodiments, the immunogenic composition further comprises histidine. In some embodiments, the concentration of histidine is between about 2mM and about 20mM or between about 5mM and about 15mM.
Data Source
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AI summary
The present invention relates to stable formulations of Neisseria meningitis rLP2086 Subfamily B Antigens in immunogenic compositions. The present invention also relates to methods of preserving the conformation of Neisseria meningitis rLP2086 Antigens and methods for determining the potency of Neisseria meningitis rLP2086 antigens.