Heterogeneous Cell Populations by Force-Based Avidity Measurement
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Solution Overview
Problem
Current methods for identifying immune receptors like TCRs and CARs are cumbersome and time-consuming, particularly in determining cellular avidity, which is crucial for optimizing in vivo performance, and do not efficiently address the need for rapid selection and characterization of receptors in heterogeneous cell populations.
Innovation Solution
A method to determine cellular avidity in a heterogeneous cell population by applying a force to cells interacting with target cells, collecting detached and attached cells, and identifying cell clones in fractions to quantify receptor sequences, allowing for the assignment of cellular avidity scores without isolating individual cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current methods for identifying immune receptors are used, then cellular avidity can be determined, but the process is highly cumbersome and time-consuming
Solution Approach 1:
The patent combines multiple separate screening methods (cytokine secretion assays, target cell killing assays, in vivo experiments) into a single integrated flow cytometry-based assay. This merging allows simultaneous measurement of multiple parameters including cellular avidity, cytokine production, and cytotoxicity in one experiment, thereby determining cellular avidity while dramatically reducing the time required for receptor selection and characterization
Solution Approach 2:
The invention creates a universal platform that can evaluate multiple receptor types (TCRs, CARs, and other immune receptors) using a single methodology. The flow cytometry-based assay serves multiple functions: it measures cellular avidity through force application and detachment analysis, simultaneously assesses functional outcomes, and works with heterogeneous cell populations, making it a multi-functional tool that replaces several specialized assays
2Measurement precision
If homogeneous populations of cells are analyzed separately, then cellular avidity can be measured, but the process requires many different screening methods and is inefficient
Solution Approach 1:
The patent merges multiple screening methods into a single flow cytometry-based platform that can handle heterogeneous cell populations. Instead of analyzing homogeneous populations separately with different assays, the invention combines cellular avidity measurement, functional assessment, and receptor characterization into one unified method that works directly with mixed cell populations containing diverse receptor specificities
Solution Approach 2:
The invention develops a universal assay platform that evaluates multiple receptor types (TCRs, CARs) and multiple parameters (cellular avidity, cytokine secretion, cytotoxicity) simultaneously. This single multi-functional method replaces the need for many different specialized screening methods, thereby reducing device complexity while maintaining measurement precision
3Measurement precision
If individual cell clones are isolated and analyzed separately, then cellular avidity scores can be determined, but the time from bench to bedside is extended
Solution Approach 1:
The patent uses force application to create a physical separation copy: detached cells (low avidity) are separated from attached cells (high avidity) through controlled mechanical force. This allows rapid identification and sorting of high-avidity cell clones from heterogeneous populations without time-consuming individual isolation and analysis, thereby determining cellular avidity scores while accelerating the selection process for personalized medicine applications
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 efficient determination of cellular avidity scores for individual receptors in a heterogeneous cell population, reducing the time and effort required for receptor selection and characterization, particularly useful for personalized medicine applications.
Implementation Method 1
When cellular avidity is determined with an acoustic force, with a force ramp, an avidity curve is provided
Implementation Method 2
A force ramp is applied to determine cell detachments, record two different avidity curves
Data Source
Figure 1A~1B
Figure 2
Figure 3
AI summary
The current invention relates to cell - cell interaction and in particular to cellular avidity. Provided are improved means and methods to study cell - cell interaction and characterizing cellular avidity, in particular from heterogeneous cell populations. Means and methods are provided which allows for the screening and identification of cells, carrying defined receptors while at the same time determining cellular avidity. This way, highly advantages methods can be provided that allow efficient screening of libraries or heterogeneous cell population for identifying for example receptors of interest.