Affinity-Tuned IgSF Proteins for Multi-Partner Immune Synapse Modulation

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Solution Overview

Problem

Current biologics for modulating immune response, such as soluble receptors and antibodies, lack the ability to simultaneously agonize or antagonize multiple protein interactions at the immunological synapse, and fail to maintain the spatial and temporal requirements of the immune synapse, limiting their therapeutic efficacy.

Innovation Solution

Development of immunomodulatory proteins with altered binding affinities and non-competitive binding capabilities to multiple cognate binding partners, specifically engineered IgSF domains with amino acid substitutions, allowing simultaneous modulation of immune responses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If soluble receptors or antibodies are used to modulate immune response, then immune response modulation capability is achieved, but the ability to simultaneously agonize or antagonize multiple protein interactions at the immunological synapse is lost

Engineering Contradiction:

Improveability to modulate multiple protein interactionsVSAvoidmaintenance of spatial and temporal requirements of immunological synapse

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The immunomodulatory protein is divided into multiple independent IgSF domains, each capable of binding to different cognate binding partners. This segmentation allows the protein to simultaneously interact with multiple targets at the immunological synapse while maintaining the spatial and temporal requirements through its modular architecture.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The immunomodulatory protein is designed with multiple IgSF domains that can bind to different cognate binding partners, enabling a single protein to perform multiple functions: simultaneously agonizing or antagonizing different protein interactions at the immunological synapse, thereby achieving versatile immune response modulation.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Reliability

If wild-type IgSF domains are used, then natural immune interaction is maintained, but binding affinity to cognate binding partners is insufficient for effective immunomodulation

Engineering Contradiction:

Improvebinding affinity to cognate binding partnersVSAvoidability to bind multiple binding partners simultaneously

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The binding affinity parameters of the IgSF domains are modified through amino acid substitutions at specific positions. These parameter changes enhance the binding affinity to cognate binding partners while maintaining the ability to bind multiple partners simultaneously through the multi-domain architecture.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The immunomodulatory protein is constructed as a composite of multiple IgSF domains, each with optimized binding characteristics. This composite structure combines the advantages of high binding affinity (through amino acid substitutions) with the versatility to bind multiple cognate binding partners simultaneously.

Inventive Principle:

Principle #40Composite materials

3Device complexity

If a single binding site is used in the protein, then structural simplicity is maintained, but the ability to interact with multiple binding partners at the immunological synapse is compromised

Engineering Contradiction:

Improveprotein structure complexityVSAvoidsimultaneous binding to multiple binding partners

Core Design Contradiction:

Device complexityVSAdaptability or versatility

Solution Approach 1:

The protein structure is segmented into multiple independent IgSF domains, each with its own binding site. This segmentation increases the number of binding sites without creating excessive structural complexity, as each domain is a modular unit that can be independently optimized for binding to different partners.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The protein architecture transitions from a single binding site to multiple binding sites arranged in a multi-dimensional domain structure. This dimensional expansion allows simultaneous interaction with multiple binding partners at the immunological synapse while maintaining manageable structural complexity through modular domain organization.

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

These proteins effectively modulate immune activity by enhancing or suppressing immune responses, providing a more nuanced therapeutic approach to conditions like cancer and immunological diseases by maintaining the spatial and temporal requirements of the immunological synapse.

Implementation Method 1

the at least one affinity modified IgSF domain specifically binds non-competitively to the at least two cognate binding partners

Methodology Applied

Scientific EffectNon-competitive binding:

Data Source

PatentUS12486312B2Immunomodulatory proteins with tunable affinities

Publication Date: 2025.12.02 ALPINE IMMUNE SCIENCES INC

AI summary

Provided are immunomodulatory proteins 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.