Variant CD155 Proteins for Selective TIGIT and CD226 Modulation
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Solution Overview
Problem
Existing therapeutics for modulating immune responses at the immunological synapse (IS) are inadequate, necessitating improved immunomodulatory proteins with enhanced binding affinity and selectivity for proteins like TIGIT, CD226, or CD96.
Innovation Solution
Development of variant CD155 polypeptides with specific amino acid modifications that alter binding to the ectodomains of TIGIT, CD226, or CD96, including soluble and transmembrane forms, to modulate immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If current therapeutics are used to modulate immune response, then immune modulation is achieved, but the ability to effectively target the immunological synapse and simultaneously interact with multiple protein targets is inadequate
Solution Approach 1:
The patent combines multiple functional domains into a single chimeric protein that can simultaneously interact with multiple targets (CD155, TIGIT, CD226, PD-1, PD-L1) within the immunological synapse, resolving the contradiction by merging multiple interaction capabilities into one molecule rather than requiring separate therapeutics for each target
Solution Approach 2:
The chimeric immunomodulatory protein is designed with multi-functionality to perform several roles simultaneously: binding to CD155 on APCs, interacting with TIGIT/CD226 on T cells, and potentially engaging PD-1/PD-L1 pathways, thereby achieving versatile target interaction while maintaining reliable immunological synapse targeting through a single agent
2Adaptability or versatility
If drug combinations are used to modulate immune response, then multiple targets can be addressed, but maintaining desired blood concentrations becomes difficult
Solution Approach 1:
By merging multiple therapeutic functions into a single chimeric protein molecule, the patent eliminates the need for complex drug combination regimens and their associated concentration management challenges, while still achieving coverage of multiple protein targets through domains within the single molecule
Solution Approach 2:
The universal design of the chimeric protein allows it to replace multiple separate drugs, simplifying the therapeutic regimen from a complex multi-drug protocol requiring coordinated concentration management to a single agent with built-in multi-target capability
3Measurement precision
If variant CD155 polypeptides with altered binding affinity are developed, then binding selectivity for TIGIT, CD226 or CD96 is improved, but the complexity of the polypeptide structure increases
Solution Approach 1:
The patent applies local quality by introducing specific amino acid modifications at particular positions within the CD155 polypeptide structure to alter binding affinity and selectivity for specific targets (TIGIT, CD226, CD96), rather than redesigning the entire protein, thus achieving improved selectivity with minimal structural complexity increase
Solution Approach 2:
The patent changes specific parameters of the CD155 polypeptide (amino acid sequence at specific positions) to modulate binding characteristics, allowing fine-tuning of selectivity and affinity for different targets while maintaining the overall structural framework and minimizing complexity increases
Data Source
AI summary
Provided herein are immunomodulatory proteins comprising variant CD155 and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.