Anti-IL-6 Antibody Formulation for Aggregate Suppression
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Solution Overview
Problem
Existing antibody formulations, particularly those containing high concentrations of anti-IL-6 receptor antibodies like SA237, face issues with aggregate formation and insoluble particle generation during long-term storage, which can lead to reduced bioactivity and stability, especially in subcutaneous administration scenarios.
Innovation Solution
The use of arginine as an isotonic agent, aspartic acid or glutamic acid as a counterion species in a histidine buffer, and Poloxamer 188 at specific concentrations, along with a pH range of 5.5 to 6.6, effectively suppresses aggregate formation and insoluble particle generation in antibody solutions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Volume of moving object
If the antibody concentration is increased to 100-200 mg/mL for subcutaneous administration, then the volume for injection is reduced, but aggregate formation and insoluble particle generation increase during storage
Solution Approach 1:
The patent applies parameter changes by optimizing the pH to a specific range of 5.5-6.6 and using arginine at concentrations of 5-300 mM to stabilize the high-concentration antibody formulation. These parameter adjustments prevent aggregate formation while maintaining the required high antibody concentration for subcutaneous administration.
Solution Approach 2:
The patent uses arginine as an intermediary substance that mediates between the high antibody concentration and the formulation stability. Arginine acts as a stabilizing agent that prevents aggregate formation, allowing the formulation to maintain both high concentration and stability during storage.
2Reliability
If basic amino acids like arginine are used as stabilizers, then aggregate formation is suppressed, but counterion selection becomes critical to maintain stability
Solution Approach 1:
The patent applies parameter changes by specifying a narrow pH range of 5.5-6.6 and particular counterion selections (aspartic acid or glutamic acid) to work synergistically with arginine. These precise parameter specifications optimize aggregate suppression while managing formulation complexity through defined compositional parameters.
3Duration of action of stationary object
If the formulation is stored for long periods, then bioactivity may be maintained, but deamidation of asparagine residues occurs causing loss of bioactivity
Solution Approach 1:
The patent applies parameter changes by controlling the pH within the specific range of 5.5-6.6, which optimizes both long-term storage stability and prevention of deamidation. This pH optimization allows the formulation to maintain bioactivity over extended storage periods while suppressing degradation reactions.
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 formulation maintains high stability, with aggregate levels below 2.0% and insoluble particle generation below 25% over extended periods, ensuring the bioactivity and integrity of the antibody, suitable for subcutaneous administration.
Implementation Method 1
arginine as an isotonic agent... effectively suppresses aggregate formation and insoluble particle generation in antibody solutions
Implementation Method 2
Poloxamer 188 at specific concentrations... effectively suppresses aggregate formation and insoluble particle generation in antibody solutions
Implementation Method 3
aspartic acid or glutamic acid as a counterion species in a histidine buffer... maintains high stability
Data Source
AI summary
In one non-limiting embodiment, the present disclosure is an antibody-containing formulation comprising an anti-IL-6 receptor antibody as an active ingredient, and contains histidine-aspartate buffer or histidine-glutamate buffer, Poloxamer 188, and arginine, and has a pH of 5.5 to 6.6. In one non-limiting embodiment, the present disclosure is a method of stabilizing an antibody-containing solution, a method of suppressing antibody association (e.g., dimerization), and a method of suppressing the generation of insoluble particles, wherein L-aspartic acid or L-glutamic acid, and optionally, Poloxamer 188 are added.