TCR Vβ-Targeting Antibodies for Safer T Cell Redirection

Solution Overview

Problem

Current molecules targeting the CD3 epsilon (CD3e) subunit of the T cell receptor for cancer immunotherapy can cause T cell dysfunction, immunosuppressive effects, and cytokine release syndrome (CRS) due to massive T cell activation, posing risks such as neurotoxicity (NT).

Innovation Solution

Development of molecules with antigen binding domains that specifically target the T cell receptor beta variable (TCRβV) region, utilizing specific CDR sequences to bind selectively and minimize non-physiological T cell activation, thereby reducing CRS and NT.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If anti-CD3e monoclonal antibodies are used to redirect T cells for tumor lysis, then T cell activation and tumor cell lysis are promoted, but T cell dysfunction and immunosuppressive effects occur

Engineering Contradiction:

Improvetumor cell lysisVSAvoidT cell function

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies local quality by designing antibodies with specific CDR3 sequences that selectively bind to particular TCR Vβ regions, creating localized specificity rather than universal binding. This allows the antibody to target specific T cell populations with defined functional properties, maintaining T cell functionality while achieving tumor lysis.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying the antibody's binding characteristics through specific CDR3 sequences (such as SYYSYDVLDY, SLNWDYGLDY, QQQQSTQPQ) that alter affinity and specificity parameters. These parameter changes enable selective binding to TCR Vβ regions, promoting tumor lysis while avoiding T cell dysfunction.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If anti-CD3e monoclonal antibodies bind to all T cells, then a large number of T cells are activated, but cytokine release syndrome and neurotoxicity occur

Engineering Contradiction:

ImproveT cell activationVSAvoidcytokine release syndrome

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing antibodies with specific CDR3 sequences that selectively bind to particular TCR Vβ regions, creating localized specificity rather than universal binding. This allows the antibody to target specific T cell populations with defined functional properties, maintaining T cell functionality while achieving tumor lysis.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs partial action by activating only specific subsets of T cells that express particular TCR Vβ regions rather than all T cells. This controlled partial activation achieves sufficient anti-tumor activity while avoiding the excessive activation that leads to cytokine release syndrome and neurotoxicity.

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS12486326B2Anti-TCR antibody molecules and uses thereof

Publication Date: 2025.12.02 MARENGO THERAPEUTICS INC

AI summary

The disclosure provides antibody molecules that bind to TCR Vβ regions and multispecific molecules comprising said antibody molecules. Additionally, disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, pharmaceutical compositions comprising aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.