Conditionally Active Polypeptides for Tumor Targeting
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Solution Overview
Problem
There is a need for conditionally active polypeptides that exhibit higher activity in aberrant conditions while being less active or inactive under normal physiological conditions, to minimize side effects and enhance therapeutic efficacy by targeting specific environments such as tumor microenvironments.
Innovation Solution
The development of non-naturally occurring polypeptides with altered activity ratios in response to pH changes in the presence of specific species like histidine, histamine, or bicarbonate, allowing for increased activity at aberrant pH levels compared to normal physiological pH, achieved through evolutionary mutagenesis and selection processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polypeptides are designed to be active under normal physiological conditions, then therapeutic efficacy is achieved, but side effects occur due to activity in non-target tissues
Solution Approach 1:
The patent applies local quality by engineering polypeptides with pH-dependent activity profiles. The polypeptides are designed to exhibit high activity specifically in acidic environments (pH 5.0-6.5) characteristic of tumor microenvironments, while maintaining low activity at neutral physiological pH (7.2-7.4). This spatial differentiation of activity levels allows targeted therapeutic action at the disease site while minimizing exposure and side effects in healthy tissues.
Solution Approach 2:
The patent utilizes parameter changes by modifying the polypeptides' response to pH variations. Through directed evolution and rational design, the polypeptides are engineered to undergo conformational changes or activate catalytic functions specifically when exposed to acidic pH conditions. This parameter-based control mechanism enables the same polypeptide to exhibit contrasting activity levels under different pH conditions, achieving selective targeting.
2Reliability
If polypeptide dose is increased to enhance therapeutic effect, then efficacy improves, but normal tissue damage increases
Solution Approach 1:
By creating polypeptides with location-specific activity (high in acidic tumor microenvironments, low in neutral normal tissues), the invention allows administration of higher doses that achieve sufficient therapeutic concentration at the target site without proportionally increasing exposure and damage to healthy tissues. The localized activation principle decouples dose-efficacy from dose-toxicity relationships.
3Stability of the object's composition
If polypeptides are evolved for stability at higher temperatures, then thermal stability improves, but activity at lower temperatures decreases
Solution Approach 1:
The patent applies parameter changes by shifting the environmental parameter from temperature to pH as the controlling factor for activity modulation. Instead of optimizing for thermal stability which creates a trade-off with cold-temperature activity, the invention engineers polypeptides that respond to pH changes, allowing stable structure across a broad temperature range while achieving conditional activity through pH-dependent conformational changes or protonation events.
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
This approach enables polypeptides to be more active in targeted conditions, reducing normal tissue damage and allowing for higher doses or prolonged treatments with reduced side effects, thereby enhancing therapeutic efficacy.
Implementation Method 1
non-naturally occurring polypeptides with altered activity ratios in response to pH changes in the presence of specific species like histidine, histamine, or bicarbonate
Data Source
AI summary
A non-naturally occurring polypeptide or isolated polypeptide having a ratio of at least 1.3 of an activity in an assay at a first pH in the presence of at least one species having a molecular weight of less than 900 a.m.u. and a pKa up to 4 pH units away from said first pH, to an activity in an assay at a second pH in the presence of the same at least one species. The species has a pKa between said first pH and said second pH and can be a small molecule. Also disclosed are pharmaceutical formulations including the polypeptide and uses thereof. Methods of producing conditionally active polypeptides are also disclosed.