CTLA-4 Variant Proteins for Higher ICOSL, CD80, and CD86 Affinity
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Solution Overview
Problem
Existing therapeutics for modulating the immunological synapse (IS) interactions are inadequate, necessitating improved immunomodulatory proteins that enhance binding affinity to target proteins like ICOSL, CD80, and CD86.
Innovation Solution
Development of variant CTLA-4 polypeptides with specific amino acid modifications that increase binding affinity to the ectodomains of ICOSL, CD80, and CD86, including substitutions, deletions, or insertions at specific positions in the IgV domain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapeutics are used to modulate immunological synapse interactions, then immune response modulation is achieved, but binding affinity to target proteins (ICOSL, CD80, CD86) is insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid residues at specific positions (6, 10, 12, 14, 15, 16, 18, 19, 20, 22, 24, 26, 27, 28, 29, 30, 33, 35, 37, 38, 41, 42, 43, 45, 46, 47, 48, 53, 54, 55, 56, 58, 59, 61, 63, 64, 65, 67, 69, 71, 72, 73, 75, 76, 82, 85, 86, 87, 89, 91, 93, 95, 96, 97, 98, 99, 105, 106, 108, 110, 113, 115, 116, 117, 118, 119, 120, 121, 122) in the CTLA-4 IgV domain to enhance binding affinity to ICOSL, CD80, and CD86 while maintaining the overall protein structure
Solution Approach 2:
The patent applies local quality by making specific amino acid modifications at targeted positions within the IgV domain rather than throughout the entire protein structure. This allows localized enhancement of binding interfaces while preserving the overall fold and function of the CTLA-4 protein
2Reliability
If amino acid modifications are introduced to increase binding affinity, then therapeutic efficacy is improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent defines specific amino acid substitutions, deletions, or insertions at predetermined positions to achieve enhanced binding affinity. The modifications are precisely specified (e.g., position 6, 10, 12, etc.) to ensure consistent manufacturing while achieving the desired therapeutic effect
Solution Approach 2:
The patent creates variant CTLA-4 polypeptides that copy the wild-type sequence with specific modifications. This allows for standardized manufacturing processes where the modified sequences can be reliably reproduced through genetic engineering and protein expression systems
Data Source
AI summary
Provided herein are variant CTLA-4 polypeptides and immunomodulatory proteins and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of disease applications, including for treatment of autoimmune or inflammatory conditions. Compositions and methods for making and using such proteins are provided.