WT-1 Multimeric T-Cell Polypeptides for Selective Modulation
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Solution Overview
Problem
Existing T-cell modulatory technologies lack specificity and efficiency in modulating T-cell responses, particularly in activating or inhibiting T cells based on epitope-specific and costimulatory protein interactions, which are crucial for targeted immune responses.
Innovation Solution
Development of T-cell modulatory multimeric polypeptides (TMMPs) that combine a Wilms tumor-1 (WT-1) peptide epitope with a class I MHC polypeptide, an immunomodulatory polypeptide variant with reduced affinity for the IL-2 receptor, and an Ig Fc polypeptide, linked via disulfide bonds, enhancing selective binding to T cells with specific TCR and co-immunomodulatory polypeptides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If existing T-cell modulatory technologies are used, then T cell activation or inhibition can be achieved, but the specificity and efficiency in modulating T-cell responses based on epitope-specific and costimulatory protein interactions is insufficient
Solution Approach 1:
The patent combines multiple functional components into a single multimeric polypeptide structure: an MHC class I heavy chain polypeptide for epitope presentation, an immunomodulatory polypeptide (such as IL-2 variant) for costimulatory signaling, and an Ig Fc polypeptide for multimerization and extended half-life. This merging of functions into one integrated molecule enables simultaneous epitope-specific TCR binding and costimulatory protein engagement, resolving the contradiction between specificity and efficiency by ensuring both functions occur together in a coordinated manner.
Solution Approach 2:
The multimeric polypeptide functions as a composite biological construct where distinct polypeptide chains (MHC heavy chain, immunomodulatory polypeptide, Ig Fc) are covalently linked via disulfide bonds. Each component contributes specific properties: the MHC heavy chain provides epitope-specific binding, the immunomodulatory polypeptide provides costimulatory activity, and the Ig Fc provides multimerization capability and extended circulation half-life. This composite structure enables the system to achieve both high specificity through epitope-TCR matching and high efficiency through coordinated costimulatory signaling.
2Reliability
If T cells are activated through engagement of costimulatory proteins, then T cell activation is achieved, but the epitope-specific targeting capability is lost because costimulatory proteins are generally expressed on all T cells or large T cell subsets
Solution Approach 1:
The patent merges the epitope presentation function (MHC class I heavy chain) with the costimulatory function (immunomodulatory polypeptide) into a single multimeric molecule. This ensures that costimulatory signaling occurs only in the context of specific epitope-TCR binding events, thereby maintaining epitope-specific targeting while preserving activation capability. The physical coupling of these functions prevents off-target activation.
Solution Approach 2:
The immunomodulatory polypeptide is locally positioned on the multimeric structure in close proximity to the MHC-bound epitope, creating a localized functional unit. This local arrangement ensures that costimulatory signals are delivered precisely at the site of epitope-specific TCR engagement, enhancing targeting specificity while maintaining activation efficiency. The spatial organization creates a functional gradient where only T cells with matching TCRs receive both signals simultaneously.
3Measurement precision
If multimeric polypeptides are constructed with multiple polypeptide chains linked via disulfide bonds, then binding affinity and selectivity are enhanced, but the structural complexity increases
Solution Approach 1:
The Ig Fc polypeptide serves as an intermediary component that facilitates multimerization of the MHC-immunomodulatory polypeptide complex. The Ig Fc domain provides standardized interaction interfaces (Fc-Fc or Fc-antibody binding) that enable controlled assembly of multimeric structures without requiring complex direct interactions between the MHC and immunomodulatory components. This intermediary simplifies the overall structural organization while achieving high binding affinity through multivalency.
Solution Approach 2:
The patent extracts the multimerization function into a separate, dedicated Ig Fc component rather than attempting to create multimers through direct self-association of the MHC-immunomodulatory complex. This extraction of the multimerization function into a specialized domain simplifies the design and assembly process, allowing the core functional unit (MHC-immunomodulatory polypeptide) to remain relatively simple while achieving enhanced binding affinity through the Fc-mediated multimeric architecture.
Data Source
Figure 1A~1C
Figure 1D~1F
Figure 2A~2C
AI summary
The present disclosure provides T-cell modulatory multimeric polypeptides that comprise an immunomodulatory polypeptide and that comprise an epitope-presenting Wilms tumor peptide. 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.