Chemically Induced Proximity Systems for Controlled TAA Expression
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Solution Overview
Problem
Current assays for assessing the risk of 'on-target, off-tumor' effects in cancer immunotherapy are inadequate, relying on multiple cell lines with varying genetic backgrounds, leading to unreliable data interpretation and high clinical trial failure rates.
Innovation Solution
Development of chemically induced proximity (CIP) systems using membrane-permeable small-molecule inducers to control dimerization between proteins, allowing independent expression of multiple proteins of interest through constructs with distinct binding and effector domains, enabling precise control over protein expression levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If multiple cell lines with varied antigen expression levels are used for risk assessment, then a broader range of TAA expression levels can be assessed, but the genetic background differences between cell lines introduce confounding variables that compromise data interpretation reliability
Solution Approach 1:
The invention segments the assessment system into individual cell lines, each engineered to express a specific TAA at a controlled level using inducible proximity systems. This allows independent control of each cell line's antigen expression, eliminating the confounding effect of genetic background differences while maintaining the ability to assess multiple expression levels.
Solution Approach 2:
The invention uses chemically induced proximity systems to dynamically control and change the expression level of TAAs in cell lines. By adjusting inducer concentration, the same cell line can be modified to express different levels of the same TAA, providing precise control over the assessment parameter without introducing genetic variability.
2Adaptability or versatility
If multiple cell lines are used to assess multiantigen targeting formats, then more comprehensive coverage of TAA expression can be achieved, but the complexity of managing and comparing data across multiple cell lines with different genetic backgrounds increases
Solution Approach 1:
The system segments the multiantigen assessment into separate, standardized cell line modules, each expressing a single TAA at a defined level. This modular approach simplifies data management by creating uniform, comparable datasets across different antigens, as each cell line follows the same construction protocol and control mechanism.
Solution Approach 2:
The inducible proximity system serves as a universal platform that can control expression of any TAA in any cell line. This standardized system provides consistent control mechanisms across all assessment experiments, reducing the complexity of comparing data from different antigen expressions by using the same control framework.
3Reliability
If pre-clinical screening is performed to assess on-target off-tumor effects, then the risk of off-tumor effects can be evaluated, but the cost and time required for clinical trials remains high due to lack of reliable predictive data
Solution Approach 1:
The invention enables comprehensive risk assessment to be performed in advance using controlled cell line models with precise TAA expression levels. By conducting these assessments before clinical trials using the standardized proximity system, predictive data can be generated that accurately forecasts on-target off-tumor effects, allowing for earlier decision-making and reducing the time needed for clinical trial development.
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
Enables accurate assessment of drug candidates' ability to discriminate between high and low TAA expression, reducing the risk of off-tumor effects and lowering clinical trial failure rates by providing reliable pre-clinical screening.
Implementation Method 1
chemically induced proximity (CIP) systems use membrane-permeable, small-molecule inducers to control dimerization between proteins
Data Source
AI summary
The present invention relates to methods of screening the efficacy and safety of candidate therapies/immunotherapies/cell therapies using cells containing a first and optionally a second inducible system operable to express a first and optionally a second protein of interest to the desired levels. The invention further relates to inducible systems, especially to one or more chemically induced proximity systems comprising a first plant hormone inducible proximity system and a second plant hormone inducible proximity system, and to methods of controlling the expression of proteins of interest using the systems. The invention further relates to a method of making a cell comprising the systems, and to cells comprising the system.