Artificial Protein Design for Programmable Immunogenicity
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Solution Overview
Problem
Existing methods for determining lymphocyte receptor sequences are prone to high false positives and negatives, and existing vaccine immunogens are susceptible to antigenic drift, necessitating improved methods for identifying specific lymphocyte receptor sequences and creating artificial proteins that can prime desired immune responses.
Innovation Solution
A method involving sorting antigens into unique reaction mixtures, expanding activated T cells, and using error-correcting codes and decoding algorithms to accurately determine T cell receptor sequences, followed by sequencing and detecting specific antigens recognized by these receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If existing methods are used to determine lymphocyte receptor sequences, then the process can be completed, but high false positives and false negatives occur reducing accuracy
Solution Approach 1:
The patent segments the determination process into distinct phases: (1) pooling multiple antigens with unique identifiers into reaction mixtures, (2) expanding activated T cells that recognize specific antigens, (3) sequencing T cell receptors from expanded clones, and (4) using decoding algorithms to map receptor sequences back to specific antigens. This segmentation allows for systematic error correction and verification at each stage, reducing false positives and negatives.
Solution Approach 2:
The patent implements feedback through decoding algorithms that analyze the relationship between T cell receptor sequences and antigen pool compositions. The system uses the known structure of antigen pools (which antigens are present in which pools) to verify and correct identification results, providing a feedback mechanism that reduces errors in sequence determination.
2Adaptability or versatility
If natural protein targets are used as vaccine immunogens, then the immune response can be primed, but antigenic drift occurs allowing variants to escape surveillance
Solution Approach 1:
The patent applies preliminary action by using the identified lymphocyte receptor sequences (particularly T cell receptors) to design artificial proteins before they are used as vaccines. The artificial proteins are computationally designed to incorporate epitopes that are predicted to be recognized by the identified receptors, ensuring that the vaccine will prime the desired immune response. This preliminary design step allows optimization for immunogenicity before the vaccine is administered, addressing the adaptability requirement.
Solution Approach 2:
The patent changes the parameters of the protein structure by creating artificial proteins with modified sequences that maintain immunogenicity while resisting antigenic drift. The artificial proteins are designed to preserve critical epitope regions that are recognized by the identified lymphocyte receptors, while other regions can be optimized for stability. This allows the vaccine to maintain its ability to prime immune responses while reducing susceptibility to drift.
3Productivity
If pool-based detection formats are used to discover lymphocyte receptors, then throughput is increased, but accuracy decreases due to false positives and negatives
Solution Approach 1:
The patent segments the large-scale pool-based detection into manageable units by organizing antigens into structured pools with unique identifiers. Each pool contains a defined subset of antigens, and the system processes multiple pools in parallel. This segmentation maintains high throughput while enabling systematic analysis of results through decoding algorithms that can identify specific antigen-receptor interactions even within the context of pooled samples.
Solution Approach 2:
The patent introduces an intermediary decoding layer that mediates between the pooled detection results and the final identification of specific lymphocyte-receptor interactions. The decoding algorithms act as intermediaries that process the complex data from pool-based detection, using the known pool structures to resolve which specific antigens are recognized by which T cell receptors. This intermediary step enables accurate identification while maintaining the throughput benefits of pooling.
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 significantly reduces false positives and negatives in identifying lymphocyte receptor sequences and enables the creation of artificial proteins that can effectively prime desired immune responses, overcoming antigenic drift.
Implementation Method 1
contacting each reaction mixture with a biological sample comprising a plurality of T cells, providing a condition for a first activated T cell in at least one reaction mixture of the plurality of reaction mixtures to expand in number
Implementation Method 2
providing a condition for a first activated T cell in at least one reaction mixture of the plurality of reaction mixtures to expand in number such that a plurality of T cell clones is formed
Implementation Method 3
sequencing nucleic acids of the second activated T cell to obtain the T cell receptor chain sequence
Data Source
AI summary
Described herein is a method for generating an artificial protein, comprising: training an immunogenicity conditioner to predict one or more lymphocyte receptor sequences that recognize one or more target molecules; using a gradient computed using one or more parameters of the immunogenicity conditioner to guide a generative process of protein design, wherein the gradient is computed to guide the design of the artificial protein such that the artificial protein is recognized by a target set of the one or more of lymphocyte receptor sequences; testing the recognition of the resulting artificial protein by one or more of the lymphocyte receptor sequences using an experimental assay.