ICOSL Variant Proteins for Selective ICOS and CD28 Binding

Solution Overview

Problem

Existing therapeutics for modulating the immune response through the immunological synapse (IS) are inadequate in terms of binding affinity and selectivity for ICOS or CD28, necessitating improved immunomodulatory proteins.

Innovation Solution

Development of variant ICOS Ligand (ICOSL) polypeptides with specific amino acid modifications, such as truncations, deletions, or substitutions, to enhance binding to ICOS or CD28, thereby improving immune response modulation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing therapeutics are used to modulate immune response through the immunological synapse, then immune modulation is achieved, but binding affinity and selectivity for ICOS or CD28 are inadequate

Engineering Contradiction:

Improvebinding affinityVSAvoidtherapeutic adequacy

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by modifying amino acid residues at specific positions (207 and 208) in the ICOSL polypeptide sequence. These parameter changes at the molecular level directly improve binding affinity to ICOS and CD28, resolving the contradiction between achieving adequate therapeutic effect and maintaining manufacturability of the protein structure.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention applies local quality by making targeted amino acid substitutions at specific local positions (207 and 208) within the ICOSL protein rather than modifying the entire structure. This localized modification approach improves binding affinity and selectivity while preserving the overall protein structure and manufacturability.

Inventive Principle:

Principle #3Local quality

2Reliability

If existing therapeutics are used to modulate immune response through the immunological synapse, then immune modulation is achieved, but selectivity for ICOS or CD28 is inadequate

Engineering Contradiction:

ImproveselectivityVSAvoidtherapeutic adequacy

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by modifying amino acid residues at specific positions (207 and 208) in the ICOSL polypeptide sequence. These parameter changes at the molecular level directly improve binding affinity to ICOS and CD28, resolving the contradiction between achieving adequate therapeutic effect and maintaining manufacturability of the protein structure.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention applies local quality by making targeted amino acid substitutions at specific local positions (207 and 208) within the ICOSL protein rather than modifying the entire structure. This localized modification approach improves binding affinity and selectivity while preserving the overall protein structure and manufacturability.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP3697810B1Variant ICOS ligand immunomodulatory proteins and related compositions and methods

Publication Date: 2025.12.03 ALPINE IMMUNE SCIENCES INC

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Figure 3A

AI summary

Provided herein are immunomodulatory proteins comprising ICOSL variants and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.