CTLA-4 Variant Proteins With Higher ICOSL and CD80/CD86 Binding

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Existing therapeutics for modulating the immunological synapse (IS) interactions are inadequate, necessitating improved immunomodulatory proteins that enhance binding affinity to ICOSL, CD80, and/or CD86.

Innovation Solution

Development of variant CTLA-4 polypeptides with specific amino acid modifications that increase binding affinity to the ectodomain of ICOSL, CD80, and/or CD86 compared to unmodified CTLA-4.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapeutics are used to modulate immune response at the immunological synapse, then immune modulation is achieved, but binding affinity to ICOSL, CD80, and CD86 is insufficient

Engineering Contradiction:

Improvebinding affinityVSAvoidineffectiveness in targeting autoimmune and inflammatory conditions

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by introducing specific amino acid modifications at defined positions in the CTLA-4 polypeptide sequence. These modifications alter the binding interface properties to enhance affinity for ICOSL, CD80, and CD86, directly resolving the insufficient binding affinity issue while maintaining the immunomodulatory function.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention applies local quality by making targeted amino acid substitutions at specific positions (e.g., G29W, L63P, Q82R) within the CTLA-4 polypeptide. These localized modifications improve binding affinity at the interaction interface without altering the overall structure or function of the protein, thereby enhancing effectiveness while maintaining reliability.

Inventive Principle:

Principle #3Local quality

2Reliability

If amino acid modifications are introduced to increase binding affinity, then affinity to ICOSL, CD80, and CD86 is enhanced, but protein structure complexity increases

Engineering Contradiction:

Improvebinding affinityVSAvoidamino acid modification complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent systematically applies parameter changes through defined amino acid substitutions at specific positions in the CTLA-4 sequence. By changing only select residues rather than the entire protein structure, the invention achieves enhanced binding affinity while minimizing structural complexity increases.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses local quality by implementing targeted amino acid modifications only at specific binding interface positions. This localized approach enhances affinity for ICOSL, CD80, and CD86 without requiring complex global structural changes, thereby resolving the contradiction between improved reliability and reduced complexity.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12612446B2CTLA-4 variant immunomodulatory proteins and uses thereof

Publication Date: 2026.04.28 ALPINE IMMUNE SCIENCES INC

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.