Anti-α4β7 Antibody Formulation for Stability and Low Aggregation
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Solution Overview
Problem
Existing formulations for anti-α4β7 antibodies are unstable, prone to degradation, and lack suitable dosages and dosing schedules for effective treatment of inflammatory bowel diseases, particularly Crohn's disease and ulcerative colitis, leading to immunogenicity and short shelf life.
Innovation Solution
A stable liquid pharmaceutical formulation comprising anti-α4β7 antibody, an antioxidant or chelator, and at least one free amino acid, with specific excipients like citrate, EDTA, histidine, and surfactants, maintains stability and reduces aggregate formation, allowing for subcutaneous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional formulations are used for anti-α4β7 antibodies, then the formulation can be prepared and stored, but the antibody suffers from chemical and physical instability leading to degradation, aggregation, and short shelf life
Solution Approach 1:
The formulation uses specific pH buffering (pH 5.0-7.5) with amino acids like histidine, arginine, or glycine to control the chemical environment. This parameter control prevents deamidation, isomerization, and other chemical degradation pathways while maintaining antibody stability over extended storage periods
Solution Approach 2:
Excipients such as surfactants (polysorbate 20, polysorbate 80, poloxamer 188) act as intermediaries that protect the antibody from aggregation and adsorption to container surfaces. These mediators maintain the colloidal stability and physical integrity of the antibody during storage and administration
2Reliability
If the formulation includes excipients to maintain stability, then chemical and physical degradation is reduced, but the formulation complexity increases and immunogenicity risk may increase
Solution Approach 1:
The selected excipients serve multiple functions simultaneously: amino acids buffer pH and prevent deamidation, surfactants prevent aggregation and adsorption, and antioxidants prevent oxidation. This multi-functionality reduces the number of separate components needed while achieving comprehensive stability protection
Solution Approach 2:
The formulation uses site-specific protection strategies where different excipients target specific degradation pathways at different locations within the formulation system, such as antioxidants protecting against oxidation at the protein surface while surfactants protect against aggregation in the bulk solution
3Ease of operation
If the formulation is designed for subcutaneous administration with extended release, then patient convenience and compliance improve, but achieving steady therapeutically effective blood levels over extended periods becomes more difficult
Solution Approach 1:
The formulation is designed with dynamic release characteristics that adapt to physiological conditions, allowing controlled absorption from the subcutaneous site into the bloodstream. The excipient composition modulates the release rate to maintain steady therapeutic levels over extended periods while enabling convenient less-frequent dosing
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 achieves less than 1% aggregate formation after 12 months at room temperature, ensuring steady therapeutically effective blood levels over an extended period with minimal immunogenicity and reduced corticosteroid use.
Implementation Method 1
Chemical instability is manifested in, for example, deamidation, isomerization, hydrolysis, oxidation, fragmentation, glycan beta elimination or disulfide exchange
Implementation Method 2
Chemical instability is manifested in, for example, deamidation, isomerization, hydrolysis, oxidation, fragmentation, glycan beta elimination or disulfide exchange
Data Source
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AI summary
Antibody formulations are described comprising a mixture of an anti-α4β7 antibody, an antioxidant or chelator, and at least one free amino acid. The disclosed formulations may have improved stability, reduced aggregate formation, or both. The present invention further provides a safe dosing regimen of these antibody formulations that is easy to follow, and which results in a therapeutically effective amount of the anti-a4β7 antibody in vivo.