Anti-TNFα Antibody Formulations for High-Concentration Stability
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Solution Overview
Problem
Existing anti-TNFα antibody formulations are unstable at high concentrations, leading to aggregation and require frequent dosing, which complicates administration and increases patient burden.
Innovation Solution
A stable formulation of anti-TNFα antibodies with specific amino acid substitutions and additives, such as M428L and N434S in the Fc region, along with components like histidine buffer, sucrose, sorbitol, and polysorbate 80, maintains high concentrations (e.g., 50-200 mg/mL) with minimal high molecular weight species and allows for less frequent dosing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If anti-TNFα antibody formulation is concentrated to reduce dosing frequency, then dosing frequency decreases, but formulation stability deteriorates due to aggregation
Solution Approach 1:
The patent applies parameter changes by modifying the Fc region amino acid sequence (specifically M428L and N434S substitutions) to alter the antibody's physical-chemical properties, enabling stable formulation at high concentrations (50-200 mg/mL) without aggregation, thus resolving the contradiction between concentration and stability
Solution Approach 2:
The patent uses composite formulation strategies combining the engineered antibody with specific excipients (histidine buffer, sucrose, sorbitol, polysorbate 80) to create a stable high-concentration formulation that prevents aggregation and maintains protein integrity, allowing both high concentration and stability
2Duration of action of moving object
If Fc region is engineered to increase binding affinity to FcRn, then serum half-life increases, but manufacturing complexity increases
Solution Approach 1:
The patent implements parameter changes by introducing specific amino acid substitutions (M428L and N434S) in the Fc region to enhance FcRn binding affinity, which extends serum half-life while maintaining manageable manufacturing complexity through defined mutagenesis steps
Data Source
AI summary
Antibodies, fragments thereof and fusion proteins that specifically bind to TNFα, are described, as well as stable formulations comprising such antibodies. Such antibodies, fusion proteins and fragments thereof are useful for the treatment and diagnosis of various autoimmune diseases.