Conditionally Active Proteins via Parameter Changes
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Solution Overview
Problem
Current methods struggle to develop proteins that are conditionally active, specifically inactive at wild-type physiological conditions but active at alternative conditions, with minimal side effects, as existing strategies often result in proteins that are either too active or inactive across all conditions.
Innovation Solution
A method involving the selection of a parent biological protein, evolution of its DNA using various techniques, expression of mutant proteins, and assays under different physiological conditions to identify conditionally active proteins that preferentially function in specific environments like synovial fluid while minimizing activity in other parts of the body.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a protein is engineered to be active at alternative physiological conditions, then activity at targeted conditions is improved, but activity at wild-type conditions increases causing side effects
Solution Approach 1:
The patent applies parameter changes by introducing mutations that alter the protein's response to physiological parameters such as pH, temperature, or ionic composition. The mutant protein is engineered to exhibit increased stability or activity specifically under alternative conditions (e.g., lower pH in endosomes) while maintaining reduced activity at wild-type conditions, thereby achieving conditional activation without unwanted side effects at normal physiological levels.
2Object-generated harmful factors
If a protein is engineered to be inactive at wild-type conditions, then side effects are reduced, but activity at alternative conditions may be insufficient
Solution Approach 1:
The patent uses parameter changes to create a switch-like behavior in the mutant protein. By selecting specific mutations, the protein's conformational state or binding affinity is modulated in response to changes in physiological parameters. This ensures that the protein remains inactive at wild-type conditions (reducing side effects) while becoming sufficiently active under alternative conditions (maintaining therapeutic efficacy).
Solution Approach 2:
The patent applies dynamics by engineering the protein to dynamically respond to changes in its physiological environment. The mutant protein can transition between active and inactive states based on external conditions such as pH changes during cellular uptake or temperature variations, ensuring that activity is activated only when and where needed, thus balancing reduced side effects with sufficient alternative condition activity.
3Reliability
If existing strategies are used to create conditionally active proteins, then conditional activity is achieved, but the proteins are either too active or inactive across all conditions
Solution Approach 1:
The patent refines activity control through parameter changes by systematically testing and selecting mutations that produce the desired conditional response. By adjusting the protein's sensitivity to specific physiological parameters, the invention achieves precise control over when and where the protein is active, avoiding the extremes of being too active or completely inactive across all conditions.
Data Source
AI summary
This disclosure relates to a method of generating conditionally active biologic proteins from wild type proteins, in particular therapeutic proteins, which are reversibly or irreversibly inactivated at some physiological conditions. For example, conditionally active biologic proteins are active in tumors, but virtually inactive at other body parts, or conditionally active antibodies capable of crossing blood-brain-barrier.