Variant ICOSL Polypeptides for Enhanced Binding Affinity

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Solution Overview

Problem

Current therapeutics for modulating the immune response in cancer and immunological diseases are inadequate, particularly in terms of effectively interacting with the immunological synapse and providing simultaneous or coordinated interactions with multiple protein targets, leading to a need for improved immunomodulatory proteins with enhanced binding affinity and selectivity.

Innovation Solution

Development of variant ICOS Ligand (ICOSL) polypeptides with specific amino acid substitutions and modifications that exhibit altered binding affinity and selectivity to ICOS, CD28, or CTLA-4, including increased or decreased binding capabilities, to modulate immune responses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapeutics are used to modulate immune response, then treatment is provided, but binding affinity and selectivity to multiple protein targets is insufficient

Engineering Contradiction:

Improvebinding affinityVSAvoidselectivity to multiple protein targets

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent creates immunomodulatory proteins that can simultaneously interact with multiple protein targets (ICOS, CD28, CTLA-4) through a single therapeutic molecule. The variant ICOSL polypeptides are designed to bind to multiple cognate binding partners, enabling one protein to perform multiple immunomodulatory functions that previously required separate therapeutics.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent employs amino acid substitutions and modifications in the ICOSL polypeptide sequence to alter binding characteristics. By changing specific amino acid parameters in the protein structure, the invention achieves enhanced binding affinity and modified selectivity profiles for different protein targets, directly addressing the insufficiency of current therapeutics.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If variant ICOSL polypeptides with multiple amino acid substitutions are developed, then binding affinity and selectivity are enhanced, but protein structure complexity increases

Engineering Contradiction:

Improvebinding affinityVSAvoidpolypeptide structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent introduces amino acid substitutions at specific localized positions within the ICOSL polypeptide sequence rather than throughout the entire structure. By making targeted local modifications at specific amino acid positions, the invention enhances binding affinity while minimizing overall structural complexity and maintaining producibility.

Inventive Principle:

Principle #3Local quality

3Reliability

If improved immunomodulatory proteins are designed for simultaneous interaction with multiple targets, then therapeutic effectiveness is enhanced, but manufacturing and characterization difficulty increases

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidproduction feasibility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent focuses modifications on specific functional domains (IgV and IgC domains) of the ICOSL polypeptide. By segmenting the protein into distinct functional regions and making targeted modifications to specific domains rather than the entire protein, the invention achieves enhanced therapeutic effectiveness while simplifying manufacturing and characterization processes.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20240409660A1ICOS ligand variant immunomodulatory proteins and uses thereof

Publication Date: 2024.12.12 ALPINE IMMUNE SCIENCES INC

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.