Trispecific HER2 CD3 CD28 Binding Proteins for T Cell Activation

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Solution Overview

Problem

There is an unmet need for safe and effective therapies for HER2+ cancers, as current HER2-targeting approaches are limited in treating residual disease and lack optimal T cell activation.

Innovation Solution

Trispecific binding proteins that bind to HER2, CD3, and CD28 are administered to provide Signal 1 through anti-CD3 binding and Signal 2 through anti-CD28 binding, recruiting and activating T cells to kill nearby tumor cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current HER2-targeting approaches (trastuzumab, pertuzumab, T-DM1) are used, then HER2+ cancer treatment is provided, but T cell activation is insufficient and residual disease remains

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidinsufficient T cell activation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent combines three binding sites in a single trispecific protein: anti-HER2 binding site, anti-CD3 binding site, and anti-CD28 binding site. This merging allows simultaneous engagement of tumor cells and T cells, providing both Signal 1 (antigen recognition via CD3) and Signal 2 (co-stimulation via CD28) for optimal T cell activation, thereby resolving the insufficiency of current single-target HER2 therapies

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The trisspecific binding protein acts as an intermediary molecule that bridges tumor cells (via HER2 binding) and T cells (via CD3 and CD28 binding). This intermediary function enables direct communication and activation of T cells against HER2+ tumors, overcoming the limitation of current therapies that lack effective T cell engagement mechanisms

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If trispecific binding proteins are administered, then T cell activation and tumor killing are enhanced, but cytokine release syndrome and neurotoxicity may occur

Engineering Contradiction:

Improvetumor cell killing efficiencyVSAvoidcytokine release syndrome and neurotoxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The trisspecific binding protein exhibits local quality by selectively engaging HER2 on tumor cells while providing co-stimulation through CD28 on T cells. This localized interaction at the tumor-T cell interface enhances cytotoxicity specifically at the tumor site while the controlled mechanism reduces systemic cytokine release and neurotoxicity compared to non-specific activation

Inventive Principle:

Principle #3Local quality

3Duration of action of stationary object

If HER2-targeted treatment is administered, then cancer progression is addressed, but data on residual disease HER2 status is limited

Engineering Contradiction:

Improvecancer progression controlVSAvoidresidual disease HER2 status information

Core Design Contradiction:

Duration of action of stationary objectVSLoss of information

Solution Approach 1:

The trisspecific binding protein provides feedback by requiring simultaneous engagement of HER2 on tumor cells and co-stimulatory molecules on T cells for activation. This feedback mechanism ensures that treatment effectiveness is directly linked to HER2 expression status in residual disease, providing natural monitoring of HER2 status through treatment response while controlling progression

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS20250376537A1Methods of treating cancer using trispecific binding proteins targeting her2-expressing tumors

Publication Date: 2025.12.11 SANOFI SA(FR)

AI summary

The present disclosure provides method of treating a subject having a cancer comprising administering to the subject about 0.2 μg to about 4500 μg of a trispecific binding protein, wherein the trispecific binding protein comprises a first antigen binding site that binds a CD28 polypeptide, a second antigen binding site that binds a CD3 polypeptide, and a third antigen binding site that binds a HER2 polypeptide.