Variant CD80 Immunomodulatory Proteins for Selective Immune Synapse Binding
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Solution Overview
Problem
Existing therapeutics for modulating the immune response at the immunological synapse (IS) are inadequate, necessitating improved immunomodulatory proteins that can alter binding interactions between antigen-presenting cells and lymphocytes.
Innovation Solution
Development of variant CD80 polypeptides with specific amino acid modifications in the IgV and IgC domains, enhancing binding affinity and selectivity to CD28, PD-L1, or CTLA-4, which can be expressed as soluble or transmembrane proteins to modulate immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapeutics are used to modulate immune response at the immunological synapse, then immune modulation is achieved, but the binding affinity and selectivity are inadequate
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid residues at specific positions (1-200) in the CD80 polypeptide sequence. These point mutations alter the binding interface properties, thereby changing the affinity and selectivity parameters for interactions with CD28, PD-L1, and CTLA-4, directly resolving the inadequate binding affinity issue
Solution Approach 2:
The invention applies local quality by introducing specific amino acid modifications at particular locations within the CD80 structure, particularly in the IgV and IgC domains that are responsible for ligand binding. This localized modification approach enhances binding properties at the interaction interface without altering the overall protein structure, thereby improving immunomodulatory effectiveness
2Reliability
If amino acid modifications are introduced in CD80 to enhance binding affinity, then binding specificity is improved, but protein structure complexity increases
Solution Approach 1:
The patent maintains structural simplicity by implementing parameter changes through point mutations rather than large-scale structural modifications. By changing individual amino acid properties (charge, hydrophobicity, size) at specific positions, the invention achieves enhanced binding specificity while preserving the overall CD80 fold and domain architecture
Solution Approach 2:
The invention applies local quality by confining modifications to specific binding interface regions (IgV and IgC domains) rather than throughout the entire protein. This localized approach allows enhancement of binding specificity at the interaction interface while leaving the rest of the protein structure unchanged, thereby minimizing overall structural complexity
Data Source
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AI summary
Provided herein are variant CD80 polypeptides, immunomodulatory proteins comprising variant CD80 polypeptides, 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.