CD80/CD86-Binding CTLA-4 Protein Compositions for Reduced irAEs

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Solution Overview

Problem

Current anti-CTLA-4 immunotherapy for cancer treatment is associated with severe immune-related adverse events (irAEs) such as skin rash, hepatitis, and colitis, necessitating a need for compositions that mitigate these side effects while preserving therapeutic efficacy.

Innovation Solution

Development of CTLA-4 proteins with modified or mutated amino acids to reduce binding to anti-CTLA-4 antibodies and retain binding to B7-1 and B7-2, along with anti-B7 antibodies that block these interactions, forming pharmaceutical compositions for immunotherapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If anti-CTLA-4 antibodies are used for cancer immunotherapy, then anti-tumor immunity is enhanced, but immune-related adverse events occur

Engineering Contradiction:

Improveanti-tumor immunityVSAvoidimmune-related adverse events

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention divides the CTLA-4 protein into two functional components: the extracellular domain (ECD) that binds B7-1 and B7-2 to modulate immune responses, and the transmembrane/domain region that anchors the protein. By expressing only the soluble ECD portion as a fusion protein with Fc region, the invention separates the therapeutic function from the autoimmunity-triggering components, achieving immune modulation without severe irAEs

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The soluble CTLA-4 fusion protein acts as an intermediary molecule that binds to B7-1 and B7-2 on antigen-presenting cells, blocking their interaction with CD28 and CTLA-4 receptors. This intermediary approach provides controlled immune modulation without requiring direct engagement of anti-CTLA-4 antibodies, thereby reducing autoimmune side effects while maintaining therapeutic efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If soluble CTLA-4 fusion proteins are used to mitigate irAE, then autoimmune side effects are reduced, but the therapeutic effect of anti-CTLA-4 mAbs is blocked

Engineering Contradiction:

Improveautoimmune side effectsVSAvoidcancer therapeutic effect

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The invention introduces specific amino acid mutations in the CTLA-4 ECD region that selectively alter antibody binding properties. The mutations are designed to reduce affinity for anti-CTLA-4 monoclonal antibodies while preserving high-affinity binding to B7-1 and B7-2 ligands. This local modification approach creates a variant protein with differentiated binding characteristics that resolve the contradiction between reducing irAE and maintaining therapeutic effect

Inventive Principle:

Principle #3Local quality

3Object-affected harmful factors

If CTLA-4 fusion proteins are administered, then they bind to anti-CTLA-4 mAbs and are cleared from circulation, but they cannot effectively mitigate irAE

Engineering Contradiction:

ImproveirAE mitigationVSAvoidcirculation half-life

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of stationary object

Solution Approach 1:

The invention extracts the critical B7-binding functional domain (extracellular domain) from the full-length CTLA-4 protein and fuses it to an Fc region to create a soluble fusion protein. This extracted domain configuration eliminates the transmembrane anchoring requirement and reduces susceptibility to antibody-mediated clearance, extending circulation half-life and improving efficacy in mitigating irAE

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUS12441780B2CD80 and CD86 binding protein compositions and uses thereof

Publication Date: 2025.10.14 ONCOC4 INC

AI summary

This invention relates to CTLA-4 protein compositions and their use in the mitigation of autoimmune adverse events associated with cancer immunotherapy.