CTLA4 Protein Variants With CDR Loop Mutations for CD80 Binding
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Solution Overview
Problem
Current CTLA4-Ig fusion proteins for treating autoimmune diseases and transplant rejection are costly due to required high doses and may induce immunogenic responses, with existing variants not adequately addressing differential binding to CD80 and CD86 isoforms, leading to adverse effects.
Innovation Solution
Development of CTLA4 proteins with specific amino acid substitutions in their CDR-like loops to enhance binding affinity to CD80 and/or CD86, allowing for targeted immune modulation with improved stability and reduced immunogenicity, achieved through mutagenesis and screening to identify variants with increased or altered binding properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CTLA4-Ig fusion proteins are used to treat autoimmune diseases and transplant rejection, then therapeutic effect is achieved, but high doses are required leading to high cost and potential immunogenic responses
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions in the CDR-like loops of the CTLA4 protein to alter its binding affinity parameters. Specifically, mutations such as K28H, A29H, T51Y, M53F, M53Y, L58G, L61H, L61Y, K93M, and K93Q are introduced to optimize the protein's interaction with CD80 and CD86 ligands, thereby enhancing therapeutic efficacy at reduced doses
Solution Approach 2:
The patent applies local quality by making targeted modifications specifically in the CDR-like loops (complementarity-determining regions) of the CTLA4 protein, while maintaining the overall protein structure and function. This localized mutagenesis approach allows optimization of binding affinity in specific regions without compromising the global therapeutic activity of the fusion protein
2Reliability
If existing CTLA4-Ig fusion proteins are used, then immune modulation is achieved, but immunogenic responses are induced
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the CTLA4 protein, specifically in the CDR-like loops, to alter epitopic characteristics. These mutations (e.g., K28H, A29H, T51Y, M53F, M53Y, L58G, L61H, L61Y, K93M, K93Q) are designed to reduce immunogenicity while preserving or enhancing the protein's ability to modulate immune responses through CD80/CD86 binding
Solution Approach 2:
The patent applies copying by creating engineered variants of the CTLA4 protein that replicate its functional properties while modifying specific regions to reduce immunogenicity. The fusion protein structure is maintained, but specific amino acid copies in the CDR-like loops are replaced with alternative residues that achieve the same binding function with reduced immune recognition
3Reliability
If CTLA4-Ig fusion proteins are used to block CD80/CD86-CD28 interaction, then T-cell activation is inhibited, but differential binding to CD80 and CD86 isoforms is not adequately addressed
Solution Approach 1:
The patent applies local quality by introducing mutations specifically in the CDR-like loops that are known to interact with CD80 and CD86. By making localized changes in specific regions (e.g., positions 28, 29, 51, 53, 58, 61, 93), the protein achieves differential binding preferences for different isoforms, allowing tailored inhibition of T-cell activation pathways
Solution Approach 2:
The patent applies parameter changes by systematically modifying the binding affinity parameters of the CTLA4 protein for different ligands. The introduced mutations alter the protein's interaction characteristics with CD80 versus CD86, enabling selective blocking of specific costimulatory pathways depending on the disease model and therapeutic objective
Data Source
AI summary
The present disclosure relates to CTLA4 proteins and uses of such proteins, for example to treat diseases associated with the dysregulation of immune responses.