T-cell modulatory multimeric polypeptides with reduced-affinity domains
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Solution Overview
Problem
Current immunomodulatory therapies face challenges in selectively modulating T-cell responses due to non-specific binding affinities of immunomodulatory polypeptides to co-immunomodulatory polypeptides, leading to inadequate targeting and activation of specific T-cell subsets.
Innovation Solution
Development of T-cell modulatory multimeric polypeptides (TMMPs) with reduced binding affinity to cognate co-immunomodulatory polypeptides, comprising epitopes, MHC polypeptides, and immunomodulatory polypeptides, which selectively bind to T-cell receptors and co-immunomodulatory proteins on T-cells, enhancing specificity and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunomodulatory polypeptides are used to modulate T-cell responses, then T-cell activity can be regulated, but non-specific binding affinities lead to inadequate targeting and activation of specific T-cell subsets
Solution Approach 1:
The immunomodulatory polypeptide is divided into multiple domains including a TCR-binding domain, a costimulatory domain, and an immunomodulatory domain. Each domain performs a specific function, allowing the overall molecule to achieve high specificity through modular composition rather than requiring a single complex structure.
Solution Approach 2:
The patent creates composite polypeptide structures that combine different functional domains (TCR binding, costimulatory, immunomodulatory) into a single multimeric construct. This composite approach enables simultaneous engagement of multiple T-cell components, achieving high specificity without excessive structural complexity in any single domain.
2Reliability
If reduced binding affinity is introduced to enhance selectivity, then epitope-specific T-cell responses are improved, but binding strength to cognate co-immunomodulatory polypeptides is reduced
Solution Approach 1:
The patent applies local quality by creating variants of the immunomodulatory polypeptide with modified binding affinity properties in specific regions. The TCR-binding domain maintains high affinity for epitope-specific TCRs, while the costimulatory domain uses reduced-affinity variants that bind selectively to activated T-cells, achieving local optimization of binding properties.
Solution Approach 2:
The patent systematically varies binding affinity parameters by introducing mutations in the costimulatory domain that reduce affinity by specific fold-changes (2-fold, 5-fold, 10-fold, etc.). This parameter optimization allows tuning of the balance between selectivity and binding strength to achieve desired therapeutic effects.
Data Source
AI summary
The present disclosure provides T-cell modulatory multimeric polypeptides that comprise an immunomodulatory polypeptide that exhibits reduced binding affinity to a cognate co-immunomodulatory polypeptide. A T-cell modulatory multimeric polypeptide is useful for modulating the activity of a T cell, and for modulating an immune response in an individual.