High Affinity PD-1 Mimic Polypeptides Block Tumor Immune Evasion
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Solution Overview
Problem
Current therapies fail to effectively block the interaction between PD-1 and its ligands PD-L1/PD-L2, which allows tumor cells and infected cells to evade immune detection, leading to inadequate immune responses against cancer and chronic infections.
Innovation Solution
Development of high affinity PD-1 mimic polypeptides that specifically bind to PD-L1/PD-L2, blocking their interaction with PD-1 and enhancing immune activation by increasing the affinity for PD-L1/PD-L2 relative to the wild-type PD-1 protein, thereby inhibiting immune suppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type PD-1 protein is used to block PD-L1 interaction, then immune suppression is reduced, but the affinity for PD-L1 is insufficient to effectively block the interaction
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues at the PD-1/PD-L1 interface to increase binding affinity. Specific mutations (e.g., L97Y, Q66P, N41V) were introduced to enhance the interaction strength between PD-1 mimic and PD-L1, transforming the wild-type PD-1 into a high-affinity binder that effectively blocks PD-L1-mediated immune suppression.
2Reliability
If full-length PD-1 protein is used, then natural binding function is maintained, but the transmembrane domain prevents optimal in vitro and in vivo blocking activity
Solution Approach 1:
The patent applies the extraction principle by removing the transmembrane domain from the full-length PD-1 protein to create a soluble PD-1 mimic. This extraction of the problematic transmembrane region allows the extracellular domain to function as a free-floating inhibitor that can more effectively bind and block PD-L1 interactions in both in vitro and in vivo settings without being anchored to cell membranes.
3Productivity
If current therapies are used to block PD-1/PD-L1 interaction, then immune response is enhanced, but the blocking is insufficient to prevent tumor cell evasion
Solution Approach 1:
The patent applies composite materials by creating a chimeric PD-1 mimic that combines elements from different sources and functionalities. The construct integrates the extracellular domain of human PD-1 with engineered amino acid mutations that confer high affinity for PD-L1, creating a composite molecule that overcomes the limitations of wild-type PD-1 and current therapeutic antibodies, resulting in enhanced tumor cell clearance.
Data Source
AI summary
High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.