CD80 Variant Proteins for Selective PD-L1 Immune Checkpoint Binding
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Solution Overview
Problem
Existing therapeutics for modulating immune responses at the immunological synapse are limited in their ability to effectively intervene in the complex interactions between antigen-presenting cells and lymphocytes, particularly in altering the affinity and selectivity of CD80 binding to PD-L1, CD28, and CTLA-4, which is crucial for regulating immune responses in cancer and immunological diseases.
Innovation Solution
Development of CD80 variant polypeptides with specific amino acid modifications that enhance binding affinity and selectivity to PD-L1, while potentially reducing binding to CD28 and CTLA-4, allowing for targeted modulation of immune responses through altered binding properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If wild-type CD80 is used to modulate immune response, then it can bind to multiple receptors (CD28, CTLA-4, PD-L1), but it lacks selectivity and cannot preferentially target specific immune pathways
Solution Approach 1:
The patent applies local quality by introducing specific amino acid modifications at particular positions (e.g., Y87L, Y87W, Y87F substitutions in the IgV domain) to alter the binding properties of CD80 at specific locations. These localized changes enable the protein to selectively bind PD-L1 with high affinity while reducing binding to other receptors like CD28 and CTLA-4, thus achieving pathway-specific immunomodulation without compromising overall binding reliability
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences at key positions in the CD80 protein structure. By changing parameters such as hydrophobicity, charge, and steric properties at specific residues (e.g., positions 87, 91, 92, 93), the invention achieves differential binding affinities for various receptors, enabling selective targeting of PD-L1 while maintaining controlled interactions with other immune checkpoints
2Adaptability or versatility
If CD80 binds strongly to multiple receptors, then broad immune modulation is achieved, but the ability to selectively activate or inhibit specific immune pathways is reduced
Solution Approach 1:
The patent makes different parts of the CD80 protein have different binding properties through localized amino acid modifications. Specifically, residues in the IgV domain (such as Y87, Y91, Y92, Y93) are modified to create high affinity for PD-L1 while reducing affinity for CD28 and CTLA-4. This local differentiation enables the single protein to selectively engage different immune pathways with appropriate binding strengths, achieving pathway-specific immunomodulation
Solution Approach 2:
The patent creates dynamic binding properties by designing CD80 variants that can differentially interact with various receptors based on physiological conditions. The amino acid modifications (e.g., Y87L, Y87W substitutions) enable the protein to exhibit context-dependent binding behavior, preferentially engaging PD-L1 in tumor microenvironments while maintaining reduced interactions with other receptors, thus dynamically regulating immune responses in a pathway-selective manner
3Measurement precision
If existing CD80 therapeutics are used, then immune response modulation is achieved, but the precision in targeting specific immune synapse interactions is insufficient
Solution Approach 1:
The patent achieves precise binding affinity control through localized amino acid substitutions at specific positions in the CD80 IgV domain. By modifying individual residues (e.g., Y87L, Y87W, Y91F, Y92F, Y93F) rather than making extensive structural changes, the invention achieves high precision in binding affinity for PD-L1 versus other receptors. This approach maintains relatively simple protein structure while achieving precise immunomodulatory effects through targeted residue modifications
Solution Approach 2:
The patent achieves precise binding affinity control by systematically varying amino acid parameters at key positions. Through controlled changes in residue properties (hydrophobicity, charge, size) at specific locations in the IgV domain, the invention achieves differential binding affinities with precision. This parameter-based approach allows fine-tuning of immune synapse interactions without requiring complex structural modifications, maintaining protein simplicity while achieving high binding precision
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.