P2X7 Receptor Binders Reducing Antibody Binding
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Solution Overview
Problem
Current P2X7 receptor binders face challenges in reducing binding with pre-existing antibodies, particularly in the presence of C-terminal extensions, which limits their therapeutic efficacy in treating conditions like neurodegenerative diseases and pain management.
Innovation Solution
Development of biparatopic anti-P2X7 receptor polypeptides comprising 3c23 and 1c81-based building blocks with specific mutations and C-terminal extensions, such as alanine or glycine, to minimize binding with pre-existing antibodies, thereby enhancing their therapeutic potential.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If C-terminal extensions are added to P2X7 receptor binders, then binding affinity and therapeutic efficacy are improved, but binding with pre-existing antibodies increases causing immune system interference
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations at defined positions (e.g., position 89: T, V, or L; position 11: V or L; position 110: K or Q; position 112: K or Q) to modify the binding characteristics of the P2X7 receptor binders. These mutations alter the epitope structure to maintain therapeutic binding affinity while reducing recognition by pre-existing antibodies in the immune system.
Solution Approach 2:
The patent applies local quality by making specific localized changes at particular positions in the polypeptide sequence rather than altering the entire structure. The C-terminal extensions and specific mutations are introduced at precise locations (positions 11, 89, 110, 112) to achieve the desired balance between maintaining target binding and avoiding immune recognition.
2Object-affected harmful factors
If mutations are introduced at specific positions to reduce antibody binding, then immune system interference is minimized, but structural stability may be compromised
Solution Approach 1:
The patent introduces specific amino acid substitutions at carefully selected positions that are known to maintain structural integrity. The mutations at positions 11, 89, 110, and 112 are chosen from amino acids that preserve the local structural context while altering the epitope characteristics to reduce antibody binding.
Solution Approach 2:
The patent employs a modular approach where the variable domain can be quickly mutated and optimized without requiring complete redesign. The standardized mutation scheme allows for rapid generation of variants that are optimized for reducing antibody binding while maintaining functional stability.
Data Source
AI summary
The present invention relates to amino acid sequences and polypeptides binding to the P2X7 receptor. In particular, the present invention relates to improved heavy-chain immunoglobulin single variable domains (also referred to herein as “ISV's” or “ISVD's”) binding to the P2X7 receptor, as well as to proteins, polypeptides and other constructs, compounds, molecules or 5 chemical entities that comprise such ISVD's.