Epitope-Specific T-Cell Modulatory Polypeptides for Precise Activation
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Solution Overview
Problem
Existing T cell modulation technologies lack specificity and efficiency in activating or inhibiting T cells, as they rely on non-epitope-specific costimulatory proteins that are expressed on all T cells or large subsets, leading to non-specific responses.
Innovation Solution
Development of T-cell modulatory multimeric polypeptides that engage the T cell receptor with an epitope-presenting peptide complex and include a variant immunomodulatory protein with reduced affinity for costimulatory receptors, mimicking the adaptive immune response to achieve epitope-specific targeting and modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-epitope-specific costimulatory proteins are used to activate T cells, then T cell activation is achieved, but specificity is lost and non-specific responses occur
Solution Approach 1:
The costimulatory protein is segmented into multiple domains: an epitope-specific binding domain that provides target cell recognition and a costimulatory domain that provides activation signal. This segmentation allows the molecule to perform both specific targeting and reliable activation functions simultaneously, resolving the contradiction between specificity and activation reliability.
Solution Approach 2:
The invention merges the epitope-specific binding function (typically from MHC-peptide complexes) with the costimulatory activation function into a single chimeric protein molecule. This merging creates a unified agent that can both specifically identify target cells and reliably activate T cells, eliminating the need for separate molecules and reducing non-specific activation.
2Adaptability or versatility
If costimulatory proteins expressed on all T cells are engaged, then broad T cell subset activation occurs, but precision of targeting is reduced
Solution Approach 1:
The costimulatory protein is engineered with localized epitope-specific binding domains at specific positions on the molecule, while maintaining the costimulatory domains in other regions. This local quality differentiation allows the protein to achieve both broad T cell subset coverage (through costimulatory engagement) and high targeting precision (through localized epitope recognition).
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
The multimeric polypeptides enhance T cell specificity and modulation, allowing for targeted activation or inhibition, improving the precision and effectiveness of immune responses.
Implementation Method 1
The multimeric polypeptide engages a TCR present on the surface of a target cell with an epitope-presenting peptide complex
Implementation Method 2
engagement of costimulatory proteins found on the APC with counterpart costimulatory proteins the T cells
Data Source
AI summary
The present disclosure provides variant immunomodulatory polypeptides, and fusion polypeptides comprising the variant immunomodulatory peptides. The present disclosure provides T-cell modulatory multimeric polypeptides, and compositions comprising same, where the T-cell modulatory multimeric polypeptides comprise a variant immunomodulatory polypeptide of the present disclosure. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the T-cell modulatory multimeric polypeptides, and host cells comprising the nucleic acids. The present disclosure provides methods of modulating the activity of a T cell; the methods comprise contacting the T cell with a T-cell modulatory multimeric polypeptide of the present disclosure.