Variant PD-L2 Polypeptides for Enhanced Binding Affinity
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Solution Overview
Problem
Current therapeutic modalities for modulating the immune response in cancer and immunological diseases are limited by their inability to effectively target and alter the interactions within the immunological synapse, particularly the binding affinity and selectivity of PD-L2 with its cognate partners PD-1 and RGMb.
Innovation Solution
Development of variant PD-L2 polypeptides with specific amino acid modifications that enhance binding affinity and selectivity to PD-1 and RGMb, including substitutions, insertions, and deletions at specific positions, which can be used as immunomodulatory proteins to modulate immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amino acid modifications are introduced to enhance binding affinity to PD-1, then binding affinity to PD-1 is improved, but binding selectivity between PD-1 and RGMb may deteriorate
Solution Approach 1:
The patent applies local quality by introducing specific amino acid modifications at particular positions (e.g., L33P, L33H, L33F, I36V) within the PD-L2 protein structure to enhance binding affinity to PD-1, while maintaining or preserving binding selectivity between PD-1 and RGMb through targeted local changes rather than global modifications
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences at specific positions to optimize binding characteristics, achieving enhanced affinity to PD-1 while maintaining selectivity through precise control of binding parameters
2Reliability
If amino acid modifications are introduced to enhance binding affinity to PD-1, then binding affinity to PD-1 is improved, but the complexity of protein structure increases
Solution Approach 1:
The patent reduces structural complexity by applying local quality modifications - introducing amino acid changes only at specific critical positions (e.g., L33, L36, I39, T47) rather than throughout the entire protein structure, thereby achieving enhanced binding affinity with minimal increase in overall complexity
3Adaptability or versatility
If amino acid substitutions are made to improve binding selectivity, then binding selectivity is improved, but the stability of the protein structure may deteriorate
Solution Approach 1:
The patent applies parameter changes by systematically evaluating amino acid substitutions at specific positions to optimize binding selectivity while monitoring and maintaining protein structure stability, achieving enhanced selectivity without compromising structural integrity
Data Source
AI summary
Provided herein are immunomodulatory proteins comprising variant PD-L2 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.