Conditionally Active Proteins for Senescent Cell Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapeutics targeting senescent cells can have undesirable side effects due to non-specific binding to proteins also present on other cell types, leading to unintended consequences.
Innovation Solution
Development of conditionally active proteins that selectively bind to senescent cells by evolving DNA encoding parent proteins using evolutionary techniques, subjecting mutant proteins to assays under senescent and normal physiological conditions to select proteins with enhanced activity specifically in senescent cell environments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutics are used to target senescent cells, then therapeutic effect is achieved, but non-specific binding to proteins on other cell types causes undesirable side effects
Solution Approach 1:
The patent applies local quality by engineering proteins with conditionally active properties that differ between senescent and non-senescent cells. The proteins are designed to be inactive under normal physiological conditions but become active specifically in the acidic microenvironment of senescent cells, thereby achieving selective targeting without affecting other cell types.
Solution Approach 2:
The patent utilizes parameter changes by exploiting the pH difference between the senescent cell microenvironment (acidic) and normal physiological conditions (neutral). The conditionally active proteins are engineered to undergo conformational changes or activation only under acidic conditions, allowing selective binding to senescent cells while avoiding non-specific binding to other cells.
2Reliability
If proteins are designed to bind specifically to senescent cells, then selectivity is improved, but binding activity under normal physiological conditions decreases
Solution Approach 1:
The patent applies dynamics by designing proteins that can dynamically change their binding activity based on environmental conditions. The conditionally active proteins remain inactive under normal physiological conditions but become active when encountering the acidic microenvironment of senescent cells, allowing the protein to adapt its binding properties to the specific context.
Solution Approach 2:
The patent uses parameter changes to control protein binding activity through pH-dependent activation. The proteins are engineered with structural features that prevent binding under neutral pH conditions but enable binding when exposed to acidic conditions, thereby achieving conditionally active behavior that enhances selectivity without permanently reducing overall binding capacity.
Data Source
AI summary
Methods of generating conditionally active proteins that target senescent cells and which are conditionally active in an extracellular environment of a senescent cell. The methods include methods using libraries of evolved proteins and assays employing physiological concentrations of components of bodily fluids. Also disclosed are conditionally active proteins for killing or removing senescent cells, antibodies and antibody fragments, conjugates and pharmaceutical compositions employing these conditionally active proteins and methods for treatment of age-related diseases, conditions or disorders using same. The conditionally active proteins may be further evolved, conjugated to other molecules, masked, reduced in activity by attaching a cleavable moiety.