Immune Cell Clonotype Identification via Full-Length Receptor Sequencing
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Solution Overview
Problem
Current methods for characterizing adaptive immune cell responses, such as those post-vaccination or post-treatment, are limited by their inability to efficiently differentiate adaptive immune cell clonotypes in a high-throughput fashion, particularly in understanding antigen specificity and phenotype changes, which is crucial for antibody discovery and engineering.
Innovation Solution
A method and system for grouping immune cells within an immune cell receptor sequence dataset by comparing full-length sequences, identifying clonotypes based on shared mutations and antigen specificity, using multi-modal single cell technologies like microfluidic droplet-based techniques, and processing units with comparison and identification engines.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If multi-modal single cell technologies are used to characterize adaptive immune cell responses, then measurement precision and ability to differentiate clonotypes is improved, but device complexity and cost increase
Solution Approach 1:
The system segments the complex immune cell characterization task into distinct functional modules: single cell isolation, multi-parameter detection, receptor sequencing, and clonotype grouping. Each module handles specific aspects of analysis, making the overall complex system manageable and systematically approachable
Solution Approach 2:
The platform integrates multiple functional capabilities into a single universal system that can perform flow cytometry, mass cytometry, single cell RNA sequencing, and protein sequencing simultaneously on the same cells, eliminating the need for separate specialized instruments for each measurement type
2Productivity
If traditional flow cytometry and mass cytometry are used, then ease of operation is maintained, but productivity and throughput are limited
Solution Approach 1:
The system merges multiple measurement modalities (flow cytometry, mass cytometry, sequencing) into a single integrated platform that processes thousands of cells simultaneously, combining the operational simplicity of traditional methods with the high throughput of modern sequencing technologies
Solution Approach 2:
The system transitions from two-dimensional measurement approaches (flow/mass cytometry measuring 10-50 parameters) to high-dimensional analysis by incorporating single cell receptor sequencing, enabling characterization of clonotypes and antigen specificity that were previously inaccessible
3Measurement precision
If bulk DNA and RNA-based sequencing assays are used, then ease of manufacture is improved, but measurement precision for single cell clonotypes deteriorates
Solution Approach 1:
The system performs preliminary single cell isolation and barcoding before sequencing, establishing unique identifiers for each cell early in the process. This preliminary action enables subsequent high-precision clonotype analysis while maintaining manufacturability through standardized single-cell preparation protocols
4Productivity
If plate-based assays are used, then ease of operation is maintained, but productivity and high-throughput capability deteriorate
Solution Approach 1:
The system replaces manual plate-based mechanical operations with automated microfluidic droplet-based processing, where cells are encapsulated in droplets and processed in parallel through automated sequencing instruments, dramatically increasing throughput while reducing manual labor
Data Source
AI summary
A method for grouping immune cells within an immune cell receptor sequence dataset, is disclosed. An immune cell receptor sequence dataset is obtained from a sample. The dataset includes a plurality of full-length immune cell receptor sequences. Each full-length immune cell receptor sequence can comprise of at least one heavy chain region sequence and one light chain region sequence. Each immune cell receptor sequence is associated with an individual immune cell in the sample. The immune cell receptor sequences associated with a first immune cell and a second immune cell from the sample is compared using a comparison protocol. The first immune cell and the second immune cell are identified as members of the same clonotype if one or more immune cell receptor sequence comparison criteria is met.