Variant CD80 Fusion Proteins for Immune Checkpoint Modulation

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Solution Overview

Problem

Current therapeutics for modulating the immune response in cancer treatment are inadequate in effectively targeting the immunological synapse, particularly in enhancing T cell activation and overcoming immune checkpoint inhibition by tumor cells expressing PD-L1.

Innovation Solution

Development of variant CD80 fusion proteins with altered binding affinity to CD28, PD-L1, and CTLA-4, which are administered to patients in combination with immune checkpoint inhibitors or chemotherapeutic agents to disrupt inhibitory signaling and promote T cell activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapeutics are used to modulate immune response, then treatment is provided, but effective targeting of the immunological synapse and enhancement of T cell activation is insufficient

Engineering Contradiction:

Improveeffectiveness of immune response modulationVSAvoidability to target immunological synapse and overcome immune checkpoint inhibition

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by modifying the amino acid sequence of CD80 to create variants with altered binding affinities. Specifically, variants are engineered to have increased affinity for PD-L1 while maintaining or enhancing binding to CTLA-4 and CD28, thereby changing the binding parameters to achieve superior immunomodulatory effects compared to wild-type CD80

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by fusing CD80 variants with Fc regions of antibodies (creating CD80-Fc fusion proteins). This composite structure combines the antigen-binding capability of CD80 with the multimerization and effector functions of the Fc region, enabling simultaneous engagement of multiple targets (PD-L1, CTLA-4, CD28) and enhanced T cell activation

Inventive Principle:

Principle #40Composite materials

2Manufacturing precision

If variant CD80 fusion proteins with altered binding affinity are developed, then binding selectivity and affinity for PD-L1, CD28, and CTLA-4 is improved, but protein engineering complexity increases

Engineering Contradiction:

Improvebinding affinity and selectivity of CD80 variantsVSAvoidprotein engineering complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the CD80 protein into functional domains (IgV domain for antigen binding, IgC domains for structural stability) and engineering specific amino acid modifications in the IgV domain to alter binding affinity while maintaining the overall protein structure through the Fc fusion

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent achieves multi-functionality by designing CD80 variants that can simultaneously bind to multiple targets (PD-L1, CTLA-4, and CD28) with appropriate affinities. The Fc fusion further enhances this by providing multimerization capability and antibody effector functions, allowing a single protein to perform multiple immunomodulatory functions

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20220177587A1Methods and uses of variant CD80 fusion proteins and related constructs

Publication Date: 2022.06.09 ALPINE IMMUNE SCIENCES INC

AI summary

Provided herein are variant CD80 polypeptides, immunomodulatory proteins comprising variant CD80 polypeptides, and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of oncological conditions. Compositions and methods for making and using such proteins are provided.