Variant CD80 Polypeptides for Epitope-Specific T-Cell Modulation
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Solution Overview
Problem
Current immunomodulatory therapies face challenges in selectively modulating T-cell activity with high specificity and efficacy, particularly in targeting epitope-specific T cells for therapeutic applications such as cancer treatment or infection management.
Innovation Solution
Development of variant immunomodulatory polypeptides, including CD80 and multimeric polypeptides with reduced binding affinity to CD86 or CD28, which are designed to modulate T-cell activity by altering the immunological synapse formation, allowing for enhanced target cell specificity and therapeutic intervention.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type CD80 is used for T-cell modulation, then costimulatory signal is provided to T cells, but binding affinity to CD86 is too high causing non-specific activation
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues in the CD80 polypeptide sequence (specifically residues in the B7 binding domain) to alter binding affinity parameters. Variant CD80 polypeptides with reduced binding affinity to CD86 are generated through site-directed mutagenesis, allowing selective modulation of T-cell activation while maintaining epitope-specific recognition.
2Reliability
If costimulatory proteins are engaged with T cells, then T cell activation is enhanced, but specificity is reduced due to non-epitope specific binding
Solution Approach 1:
The patent applies local quality by creating heterogeneity in binding properties across different regions of the immunomodulatory polypeptide. The epitope-binding region maintains high affinity and specificity for MHC-peptide complexes, while the costimulatory region (CD80 domain) has reduced binding affinity to CD86, enabling spatially differentiated interaction characteristics that achieve both specificity and controlled costimulation.
3Reliability
If multimeric polypeptides are constructed with MHC and costimulatory domains, then T-cell targeting is improved, but structural complexity increases
Solution Approach 1:
The patent applies merging by fusing multiple functional domains into a single multimeric polypeptide construct. The polypeptide combines MHC class I or II molecules (for epitope presentation), variant CD80 costimulatory domain (for controlled costimulation), and optionally IgG Fc regions (for dimerization and enhanced stability). This integration achieves coordinated T-cell targeting and activation in a unified molecular architecture.
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.