Variant PD-1 Polypeptides Binding Affinity Stability Trade-off
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Solution Overview
Problem
Current therapeutic options for modulating the immune response in cancer and immunological diseases are limited by the need for improved binding affinity and specificity of PD-1 proteins to their cognate binding partners, such as PD-L1, which is essential for effective immune modulation.
Innovation Solution
Development of variant PD-1 polypeptides with specific amino acid modifications at various positions, including those at positions 8, 9, 11, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28, 31, 33, 34, 35, 36, 37, 40, 41, 42, 43, 51, 52, 59, 64, 66, 75, 80, 81, 85, 86, 89, 90, 91, 93, 94, 100, 106, 113, 114, 116, 129, 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, which enhance binding affinity to PD-L1 compared to unmodified PD-1 proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Force
If amino acid modifications are introduced to enhance binding affinity, then binding affinity to PD-L1 is improved, but protein structure stability may be compromised
Solution Approach 1:
The patent applies local quality by introducing amino acid modifications at specific positions (e.g., positions 8, 9, 11, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28, 31, 33, 34, 35, 36, 37, 40, 41, 42, 43, 51, 52, 59, 64, 66, 75, 80, 81, 85, 86, 89, 90, 91, 93, 94, 100, 106, 113, 114, 116, 129, 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144) within the PD-1 polypeptide structure. These localized modifications enhance binding affinity to PD-L1 while preserving the overall structural stability of the protein through careful selection of modification sites and types.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid residues at specific positions in the PD-1 polypeptide. Through controlled substitution of amino acids at defined positions, the binding affinity parameter is optimized while maintaining structural integrity. This approach allows precise tuning of the protein's binding characteristics without compromising its fundamental stability.
2Reliability
If multiple amino acid positions are modified to improve binding affinity, then immune modulation efficacy is enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the PD-1 polypeptide into specific modification zones at defined positions. Rather than randomly modifying the entire structure, the invention focuses on specific segments (positions 8-43, 51-52, 59-66, 75, 80-86, 89-94, 100, 106, 113-116, 129-144) where modifications yield the greatest binding affinity improvement. This segmented approach simplifies manufacturing by providing clear, discrete modification targets.
Solution Approach 2:
The patent uses parameter changes to systematically optimize binding affinity through controlled amino acid substitutions at specific positions. By defining exact modification parameters (position and residue type), the invention enhances immune modulation efficacy while maintaining manufacturability through standardized, reproducible modification protocols.
Data Source
AI summary
Provided herein are immunomodulatory proteins comprising variant PD-1 polypeptides, nucleic acids encoding such proteins and engineered cells expressing 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.