Variant PD-L1 Proteins for Selective PD-1 and CD80 Binding
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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 PD-1 and CD80 to effectively regulate immune cell interactions.
Innovation Solution
Development of variant PD-L1 polypeptides with specific amino acid modifications at defined positions, enhancing binding affinity and selectivity to PD-1 and CD80 ectodomains, and optionally linked to multimerization and IgSF domains for modulating immune cell responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type PD-L1 is used as the immunomodulatory protein, then the protein structure is simple and easy to produce, but the binding affinity and selectivity for PD-1 and CD80 are insufficient
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid modifications at defined positions (e.g., positions 6, 10, 11, 14, 15, 16, 17, 18, 19, 20, 22, 23, 26, 27, 28, 33, 35, 36, 40, 41, 43, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 64, 65, 68, 71, 72, 73, 74, 75, 78, 79, 83, 85, 87, 89, 90, 93, 97, 98, 99, 101, 102, 103, 104, 106, 110, 111, 112, 113, 117, 119, 120, 121, 124, 129, 130, 131, 134, 137, 138, 144, 148, 149, 150, 155, 158, 160, 163, 165, 167, 170, 171, 173, 175, 176, 177, 179, 180, 183, 185, 188, 189, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 206, 207, 213, or 221) to the PD-L1 protein sequence. These modifications systematically alter the protein's binding parameters to enhance affinity for PD-1 and CD80 while maintaining production feasibility.
2Reliability
If wild-type PD-L1 is used, then the protein structure is simple, but the binding selectivity for PD-1 and CD80 is insufficient
Solution Approach 1:
The patent applies local quality by making specific amino acid modifications at defined positions within the PD-L1 protein sequence. Rather than altering the entire protein structure, the invention introduces targeted changes at specific locations (positions 6, 10, 11, 14, 15, 16, 17, 18, 19, 20, 22, 23, 26, 27, 28, 33, 35, 36, 40, 41, 43, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 64, 65, 68, 71, 72, 73, 74, 75, 78, 79, 83, 85, 87, 89, 90, 93, 97, 98, 99, 101, 102, 103, 104, 106, 110, 111, 112, 113, 117, 119, 120, 121, 124, 129, 130, 131, 134, 137, 138, 144, 148, 149, 150, 155, 158, 160, 163, 165, 167, 170, 171, 173, 175, 176, 177, 179, 180, 183, 185, 188, 189, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 206, 207, 213, or 221) to locally enhance binding selectivity for PD-1 and CD80 while preserving the overall protein structure and functionality.
3Reliability
If existing therapeutics are used to modulate immune response, then the approach is straightforward, but the immune modulation effectiveness is inadequate
Solution Approach 1:
The patent applies universality by designing a variant PD-L1 protein that can simultaneously bind to multiple targets (PD-1 and CD80) with enhanced affinity and selectivity. This multi-functional capability allows a single protein variant to modulate multiple immune pathways, thereby improving overall immune modulation effectiveness compared to existing single-target therapeutics, while maintaining a relatively simple protein structure.
Data Source
AI summary
Provided herein are immunomodulatory proteins comprising variant PD-L1 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.