PD-L1 Variants Enhancing PD-1 Binding Affinity
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Solution Overview
Problem
Current PD-L1 variants have low binding affinity for PD-1 and are immunogenic, posing challenges for effective cancer treatment with minimal side effects.
Innovation Solution
Development of PD-L1 variants with specific amino acid substitutions, such as E169D and R195K, to enhance binding affinity for PD-1 while minimizing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-L1 variants are developed to inhibit PD-1 binding, then cancer treatment efficacy is improved, but immunogenicity increases
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions only at critical binding sites (positions 169 and 195) while maintaining the rest of the PD-L1 protein sequence identical to wild-type. This localized modification approach enhances PD-1 binding affinity specifically where needed, without introducing widespread immunogenicity across the entire protein structure.
Solution Approach 2:
The patent changes the amino acid sequence parameters at specific positions (E169D and R195K substitutions) to alter the binding affinity characteristics of PD-L1. By modifying these specific parameters while keeping other parameters unchanged, the invention achieves enhanced binding affinity without proportionally increasing immunogenicity.
2Reliability
If PD-L1 variants are created with multiple mutations to enhance binding affinity, then PD-1 binding affinity is improved, but immunogenicity increases
Solution Approach 1:
The patent applies partial action by introducing only the minimum necessary mutations (two specific amino acid substitutions at positions 169 and 195) to achieve enhanced binding affinity, rather than introducing multiple random mutations. This partial modification approach provides sufficient binding affinity enhancement while minimizing the creation of immunogenic epitopes.
Solution Approach 2:
The patent makes localized modifications only at the critical binding interface regions (positions 169 and 195 in the extracellular domain) while maintaining the rest of the protein sequence identical to wild-type PD-L1. This localized approach ensures that binding affinity is enhanced only where needed for PD-1 interaction, without creating widespread immunogenicity.
3Reliability
If antibody drugs are used to block PD-1/PD-L1 binding, then cancer treatment efficacy is improved, but side effects increase due to lack of specificity
Solution Approach 1:
Instead of using external antibody drugs to block PD-1/PD-L1 binding (which cause side effects by affecting healthy cells), the patent inverts the approach by creating modified PD-L1 variants that actively enhance binding to PD-1. This inversion transforms the mechanism from blocking binding to promoting binding, thereby achieving cancer treatment efficacy without the harmful side effects associated with antibody-based approaches.
Solution Approach 2:
The patent enables PD-L1 itself to perform the binding enhancement function through its own modified amino acid sequences, rather than relying on external antibody mediators. The modified PD-L1 variants self-promote PD-1 binding through their enhanced affinity, eliminating the need for external therapeutic agents that would otherwise cause off-target effects.
Data Source
AI summary
A PD-L1 mutant having improved binding affinity for PD-1 is disclosed. A method for preparing the PD-L1 variant and a method for screening the PD-L1 variant are also disclosed. The PD-L1 variant produced by substituting some amino acids in the sequence of wild-type PD-L1 with other optimal amino acids, achieving greatly improved affinity for PD-1. In addition, the possibility of immunogenicity can be reduced by the smallest possible number of the mutation sites.