Variant CD155 Proteins Modulating TIGIT and CD226 Binding
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Solution Overview
Problem
Current therapeutics for modulating the immune response in cancer and immunological diseases are inadequate in effectively targeting the immunological synapse, particularly in enhancing or inhibiting interactions between antigen-presenting cells and lymphocytes, due to limitations in simultaneously interacting with multiple protein targets and maintaining desired blood concentrations of drug combinations.
Innovation Solution
Development of variant CD155 polypeptides with altered binding affinity and selectivity for TIGIT, CD226, or CD96, which can be used as immunomodulatory proteins to modulate immune cell responses, either by increasing or decreasing IFN-gamma expression, and can be formulated as soluble or transmembrane proteins, or conjugated with other moieties to enhance therapeutic efficacy.
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 insufficient
Solution Approach 1:
The patent combines multiple functional domains into a single immunomodulatory protein construct. Specifically, it merges a variant IgSF domain (with modified binding affinity) with a transmembrane domain and signaling domain, creating a multifunctional protein that can simultaneously engage multiple targets at the immunological synapse, thereby resolving the contradiction between versatility and effectiveness.
Solution Approach 2:
The immunomodulatory protein is designed with universal applicability to interact with multiple protein targets (e.g., TIGIT, CD226, CD96) through its variant IgSF domain. This multi-functional design allows a single therapeutic agent to modulate multiple immune checkpoints simultaneously, improving both adaptability and reliability in targeting the immunological synapse.
2Adaptability or versatility
If drug combinations are used to modulate immune response, then multiple targets are addressed, but maintaining desired blood concentrations becomes difficult
Solution Approach 1:
The patent consolidates multiple therapeutic functions into a single molecular construct by fusing the variant IgSF domain with transmembrane and signaling domains. This unified approach eliminates the need for multiple separate drugs, simplifying pharmacokinetic management while maintaining coverage of multiple immune checkpoints.
Solution Approach 2:
The immunomodulatory protein functions as a composite molecular structure integrating multiple functional domains (IgSF variant, transmembrane domain, signaling domain) into one entity. This composite design allows simultaneous engagement of multiple targets through a single agent, avoiding the complexity of managing multiple drug concentrations.
3Measurement precision
If variant CD155 polypeptides with altered binding affinity are developed, then binding selectivity for TIGIT, CD226 or CD96 is improved, but protein structure complexity increases
Solution Approach 1:
The patent applies local quality modification by introducing specific amino acid substitutions only in the IgV domain of the CD155 protein, while keeping other domains (IgC domain, transmembrane domain) relatively unchanged. This localized modification approach achieves improved binding selectivity for specific targets (TIGIT, CD226, or CD96) without unnecessarily increasing overall protein structure complexity.
Solution Approach 2:
The patent achieves altered binding affinity through parameter changes in the amino acid sequence of the IgV domain. By modifying specific residues (e.g., substituting hydrophobic residues with polar or charged residues), the protein's binding characteristics are tuned to preferentially interact with desired targets, improving selectivity while maintaining structural feasibility.
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.