Multimeric T-Cell Polypeptides for Epitope-Specific Immune Modulation
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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, leading to unsuitable immune responses.
Innovation Solution
Development of variant immunomodulatory polypeptides and fusion polypeptides that engage T cell receptors with epitope-specific MHC complexes, incorporating reduced-affinity modulatory domains to target and modulate T cells with enhanced specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional costimulatory proteins are used for T cell modulation, then T cell activation or inhibition can be achieved, but specificity is reduced and off-target effects occur
Solution Approach 1:
The patent segments the T cell modulation function into two distinct components: an epitope-specific binding domain that provides target cell specificity, and a costimulatory domain that provides modulation effectiveness. This segmentation allows each component to perform its specialized function independently, resolving the contradiction between specificity and effectiveness.
Solution Approach 2:
The patent creates composite polypeptide structures by fusing epitope-specific binding domains (such as peptide-MHC complexes or TCR fragments) with costimulatory domains (such as CD28, CD40L, or cytokine domains). This composite structure combines the specificity of the binding domain with the modulatory power of the costimulatory domain, simultaneously achieving both high specificity and reliable T cell modulation.
2Power
If high-affinity costimulatory proteins are used, then strong T cell activation occurs, but off-target effects increase and immune responses become unsuitable
Solution Approach 1:
The patent applies local quality by making the costimulatory activity localized to specific target cells through the epitope-specific binding domain. The costimulatory domain only exerts its high-affinity effect on cells that present the specific epitope, creating localized high-power activation precisely where needed while avoiding off-target effects on non-target cells.
Solution Approach 2:
The epitope-specific binding domain acts as an intermediary that bridges the costimulatory domain to the target T cells. It selectively delivers the high-power costimulatory signal only to T cells that recognize the specific epitope-MHC complex, preventing direct widespread activation and thereby reducing off-target harmful effects.
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.