GITR Co-stimulatory Domain CAR T Cell Specificity

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current CAR-T cell therapies for cancer treatment often face challenges in specificity and safety due to the lack of effective co-stimulatory domains, leading to off-target cytotoxicity and cytokine release syndrome, particularly when targeting tumor antigens like EGFR, mesothelin, and CD19.

Innovation Solution

Incorporating the GITR intracellular domain as a co-stimulatory domain in chimeric antigen receptors (CARs) to enhance T cell effector function and suppress regulatory T cells, thereby improving the specificity and safety of CAR-T cells by reducing cytokine release and increasing cytotoxic activity against tumor cells overexpressing specific antigens.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Power

If traditional co-stimulatory domains (CD28, CD137) are used in CARs, then T cell activation and cytolytic activity are enhanced, but off-target cytotoxicity and cytokine release syndrome occur

Engineering Contradiction:

Improvecytolytic activityVSAvoidoff-target cytotoxicity and cytokine release syndrome

Core Design Contradiction:

PowerVSObject-affected harmful factors

Solution Approach 1:

The patent changes the co-stimulatory domain parameter from traditional CD28 or CD137 to GITR intracellular domain, which modifies the signaling characteristics and reduces harmful effects while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces GITR intracellular domain as an intermediary signaling component that mediates T cell activation with more controlled cytokine release, reducing the harmful effects associated with traditional co-stimulatory domains

Inventive Principle:

Principle #24Intermediary (Mediator)

2Power

If CAR-T cells are designed to target tumor antigens, then antitumor activity is improved, but specificity against normal cells expressing the same antigen is reduced

Engineering Contradiction:

Improveantitumor activityVSAvoidspecificity

Core Design Contradiction:

PowerVSReliability

Solution Approach 1:

The patent modifies the co-stimulatory signaling parameter to GITR domain, which changes the activation threshold and signaling dynamics to improve specificity while maintaining antitumor potency

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11332513B2Chimeric antigen receptors having GITR intracellular domain as co-stimulatory domain

Publication Date: 2022.05.17 PROMAB BIOTECH

AI summary

The present invention is directed to a chimeric antigen receptor (CAR) fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) comprising VH and VL, wherein scFv binds to a tumor antigen, (ii) a transmembrane domain, (iii) a co-stimulatory domain of GITR intracellular domain, and (iv) an activating domain. In one embodiment, the tumor antigen is human epidermal growth factor receptor (EGFR), human mesothelin, or human CD19. CARs having GITR intracellular domain as a co-stimulatory domain have certain advantages over other traditional CAR co-stimulatory domains.