T Cell Receptor Multimers for High-Avidity pMHC Binding
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Solution Overview
Problem
Existing T cell therapies for cancer treatment, such as TIL, engineered TCR, and CAR T cell therapy, face limitations in efficacy, safety, and tolerability, necessitating improved agents and methods for determining TCR-pMHC interactions and modulating T cell responses.
Innovation Solution
Development of TCR multimers comprising a TCR moiety linked to a multimerization moiety from IgM or IgA, forming multivalent and soluble molecules with high avidity for pMHC complexes, potentially incorporating effector moieties for therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing T cell therapies (TIL, engineered TCR, CAR T cell therapy) are used for cancer treatment, then therapeutic effect is achieved, but limitations in efficacy, safety, and tolerability occur
Solution Approach 1:
The T cell therapy approach is segmented into modular components: a TCR moiety for antigen recognition, a multimerization moiety for forming multivalent structures, and optional effector moieties for therapeutic action. This segmentation allows independent optimization of each component's function and safety profile.
Solution Approach 2:
The invention creates composite therapeutic molecules by fusing the TCR moiety with the multimerization moiety from IgM or IgA. This composite structure combines the antigen-specificity of TCRs with the multivalent binding capability of immunoglobulins, achieving enhanced efficacy while maintaining safety through controlled multimerization.
2Measurement precision
If monovalent TCR molecules are used, then antigen specificity is maintained, but binding avidity to pMHC complexes is insufficient
Solution Approach 1:
Multiple TCR moieties are merged into a single multimeric structure through the multimerization moiety, creating molecules with multiple antigen-binding sites. This merging increases the overall binding avidity to pMHC complexes while each individual TCR moiety maintains its specific antigen recognition capability.
Solution Approach 2:
The binding interaction is enhanced by transitioning from monovalent (single binding site) to multivalent (multiple binding sites) architecture. This dimensional change in binding capacity allows simultaneous engagement of multiple pMHC complexes, dramatically increasing avidity while preserving specificity.
3Power
If TCR multimers are designed for high avidity binding, then therapeutic potency is enhanced, but molecular complexity increases
Solution Approach 1:
The multimerization moiety from IgM or IgA serves multiple functions: it enables multivalent binding to increase potency, provides a well-characterized structural framework, and offers established expression and purification protocols. This universality reduces the practical complexity despite the enhanced molecular functionality.
Solution Approach 2:
The valency parameter of the TCR molecule is changed from 1 to multiple binding sites through the multimerization moiety. This parameter change directly increases therapeutic potency while the modular design allows systematic control of the complexity level by selecting different multimerization domains.
4Productivity
If adoptive T cell transfer or CAR-based therapy is used, then cancer treatment effect is achieved, but safety and tolerability limitations occur
Solution Approach 1:
The TCR multimer acts as an intermediary therapeutic agent that bridges antigen recognition and T cell activation without requiring direct engineering of patient T cells. This intermediary approach maintains the therapeutic effect while reducing the safety and tolerability issues associated with cellular therapies.
Data Source
AI summary
T cell receptor (TCR) multimers are provided in which a binding moiety from a T cell receptor variable region is attached to a multimerization moiety from IgM or IgA to thereby create a multivalent TCR multimer composition. The TCR multimers can be used, for example, to determine the binding specificity of the TCR-derived binding moiety, such as for particular MHC-peptide complexes. The multimers can also be used, for example, to modulate an immune response in a subject by administering the multimer to the subject. Methods of making the TCR multimers are also provided.