Antibody Formulation Oxidation Prevention
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Solution Overview
Problem
Protein pharmaceuticals face oxidative degradation issues due to exposure to hydrogen peroxide, light, and metal ions, leading to oxidation of susceptible amino acid residues like methionine and tryptophan, which can impact biological activity and stability during storage and handling.
Innovation Solution
The development of liquid formulations containing a compound, such as 5-hydroxy indole, that prevents oxidation of antibodies by being incorporated into the formulation, thereby maintaining the stability and biological activity of the protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If L-tryptophan is added to formulations to prevent oxidation of tryptophan residues, then oxidation of tryptophan is reduced, but L-tryptophan possesses strong absorbance in the UV region making it a primary target during photo-oxidation and can generate ROS that lead to methionine oxidation
Solution Approach 1:
The patent removes L-tryptophan from the formulation entirely and replaces it with alternative antioxidants such as L-methionine, L-cysteine, or synthetic compounds. This extraction eliminates the harmful photo-oxidation properties of L-tryptophan while maintaining oxidation protection through alternative means.
Solution Approach 2:
The patent introduces intermediary antioxidant compounds that do not possess strong UV absorbance and do not generate ROS. These intermediaries (such as L-methionine, L-cysteine, or synthetic antioxidants) serve as alternative protective agents that prevent oxidation without the harmful side effects of L-tryptophan.
2Reliability
If proteins are exposed to light during processing and storage, then photo-oxidation can occur generating ROS, but avoiding light exposure entirely is not always practical during handling and storage
Solution Approach 1:
The patent incorporates antioxidants into the formulation beforehand, creating a protective system that is already in place before light exposure occurs. This preliminary protection allows the protein to withstand normal light exposure during handling and storage without requiring special light-avoidance measures.
Solution Approach 2:
The patent converts the unavoidable light exposure condition into a non-problematic situation by using antioxidants that either do not absorb UV light or do not generate ROS. This transforms the potential harmful photo-oxidation process into a safe condition where light exposure no longer threatens protein stability.
3Stability of the object's composition
If standard excipients are used in protein formulations, then formulation stability is maintained, but some excipients can induce ROS-induced oxidation of the protein
Solution Approach 1:
The patent uses antioxidants that act as sacrificial protective agents, consuming the oxidation stress themselves to protect the protein. These antioxidants (such as L-methionine, L-cysteine, or synthetic compounds) serve as disposable protective elements that can be replenished or replaced in the formulation.
Solution Approach 2:
The patent changes the chemical parameters of the antioxidant components by selecting compounds with specific properties: they should not possess strong UV absorbance and should not generate ROS. This parameter selection ensures that the antioxidants provide protection without introducing harmful side effects.
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 use of these formulations effectively reduces protein oxidation, ensuring the stability and biological activity of antibodies during storage and handling, addressing the challenges posed by standard excipients like L-tryptophan which can induce ROS-induced oxidation.
Implementation Method 1
Oxidative degradation of amino acid residues is a commonly observed phenomenon in protein pharmaceuticals
Implementation Method 2
Light exposure can result in protein oxidation through the formation of reactive oxygen species (ROS) including singlet oxygen, hydrogen peroxide and superoxide
Data Source
Figure 1A~1B
Figure 2
Figure 3A~3B
AI summary
The invention provides formulations comprising a protein in combination with a compound that prevents oxidation of the protein. The invention also provides methods for making such formulations and methods of using such formulations. The invention further provides methods of screening for compounds that prevent oxidation of a protein in a protein composition and methods of preventing oxidation of a protein in a formulation.