Mutant CTLA-4 Proteins Enhancing Cross-Species Binding
Solution Overview
Problem
Current CTLA-4 proteins, particularly those derived from porcine sources, are unable to effectively bind to human CD80, limiting their immunosuppressive efficacy in xenotransplantation settings, and existing human CTLA-4 proteins have specific binding motifs that are not adaptable for porcine CD80 interaction.
Innovation Solution
Mutating the CTLA-4 proteins by altering specific amino acids at the binding motifs, such as changing methionine to leucine at position 97, creates mutant forms that enhance binding affinity to either human or porcine CD80, allowing for improved immunosuppressive function in xenotransplantation by specifically targeting and blocking antigen-presenting cells in both human and porcine contexts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If porcine CTLA-4 protein is used, then binding to porcine CD80 is achieved, but binding to human CD80 is lost
Solution Approach 1:
The patent applies local quality by making a specific amino acid substitution (Met97Leu) at the binding motif position 97 of human CTLA-4. This localized change at the critical binding interface confers the ability to bind porcine CD80 while preserving human CD80 binding, thereby resolving the contradiction between species-specific binding and cross-species adaptability.
Solution Approach 2:
The patent utilizes parameter changes by altering the amino acid sequence parameter at position 97 from Methionine to Leucine. This single amino acid substitution changes the binding characteristics of CTLA-4, enabling it to interact with both human and porcine CD80, thus resolving the contradiction between maintaining original binding specificity and gaining cross-species functionality.
2Reliability
If human CTLA-4 protein is used, then binding to human CD80 is achieved, but binding to porcine CD80 is lost
Solution Approach 1:
The patent applies local quality by introducing a specific amino acid substitution (Met97Leu) at the binding motif position 97 of human CTLA-4. This localized change at the critical binding interface confers the ability to bind porcine CD80 while preserving human CD80 binding, thereby resolving the contradiction between species-specific binding and cross-species adaptability.
Solution Approach 2:
The patent utilizes parameter changes by altering the amino acid sequence parameter at position 97 from Methionine to Leucine. This single amino acid substitution changes the binding characteristics of CTLA-4, enabling it to interact with both human and porcine CD80, thus resolving the contradiction between maintaining original binding specificity and gaining cross-species functionality.
3Adaptability or versatility
If amino acid substitution is made at binding motif, then cross-species binding is improved, but binding affinity to original target may decrease
Solution Approach 1:
The patent applies local quality by making a conservative amino acid substitution (Met97Leu) at the binding motif. Both Methionine and Leucine are hydrophobic amino acids with similar side chain properties, which minimizes disruption to the overall binding affinity while enabling cross-species recognition. This resolves the contradiction by maintaining binding strength while gaining versatility.
Solution Approach 2:
The patent utilizes parameter changes by performing a conservative substitution at position 97 that maintains hydrophobic character while altering species specificity. This approach preserves binding affinity to human CD80 while conferring ability to bind porcine CD80, thus resolving the contradiction between maintaining affinity and gaining adaptability.
Data Source
AI summary
Mutant forms of human CTLA4, and their use, e.g., in xenotransplantation.