Low-pH Antibody Composition for Aggregation-Resistant Formulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Protein-based pharmaceuticals, particularly bispecific T cell engaging antibody constructs, face challenges with protein instability, including aggregation and degradation during manufacturing, storage, and administration, which affect their therapeutic efficacy and safety.
Innovation Solution
A pharmaceutical composition comprising an antibody construct with specific isoelectric points for its domains, combined with a pH range of 3.5 to 6, buffer agents, saccharides, and surfactants, stabilizes the antibody by promoting electrostatic repulsion and reducing aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If antibody constructs are formulated at neutral pH for stability, then protein aggregation occurs, but if formulated at low pH to reduce aggregation, then protein instability increases
Solution Approach 1:
The patent applies parameter changes by formulating the antibody construct at a low pH range (3.5-6.0) instead of the conventional neutral pH. This pH parameter change reduces electrostatic attraction between protein molecules, thereby minimizing aggregation and improving colloidal stability while maintaining protein stability through careful selection of buffer systems and excipients.
2Reliability
If antibody constructs are administered by continuous intravenous infusion to achieve therapeutic effects, then therapeutic efficacy is maintained, but patient convenience deteriorates
Solution Approach 1:
The patent applies dynamics by modifying the antibody construct to enable dynamic control of its pharmacokinetic properties. The engineered antibody constructs exhibit extended half-life and altered clearance rates, allowing flexible dosing regimens that can maintain therapeutic efficacy while enabling less frequent administration compared to continuous infusion requirements.
3Ease of operation
If small single chain antibody constructs are used for rapid distribution, then ease of handling improves, but in vivo half-life shortens
Solution Approach 1:
The patent applies merging by combining the advantages of small single chain antibody constructs with features that extend in vivo half-life. The engineered constructs maintain the rapid distribution and ease of handling characteristics of small molecules while incorporating structural modifications that reduce clearance rates and extend persistence in the bloodstream.
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 composition enhances the stability of bispecific antibody constructs, allowing for higher concentrations and reduced aggregation, even at accelerated temperatures, and supports convenient administration without the need for lyophilization.
Implementation Method 1
formulated at a pH of 3.5 to 6, which stabilizes the antibody by promoting electrostatic repulsion and reducing aggregation
Data Source
AI summary
The present disclosure provides a low pH pharmaceutical composition comprising (a) an antibody constructs comprising a first domain binding to a target cell surface antigen, a second domain binding to a second antigen and preferably a third domain, which is a specific Fc modality, (b) at least one buffer agent, (c) at least one saccharide, and (d) at least one surfactant; and wherein the pH of the pharmaceutical composition is in the range of 3.5 to 6.