Humanized BCMA CAR-T Cells With 4-1BB for Lower CRS Toxicity

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current chimeric antigen receptor (CAR) T-cell therapies for multiple myeloma require high doses and often result in severe cytokine release syndrome (CRS) and neurotoxicity, with BCMA-targeting CAR-T cells showing early disappearance due to immunological reactions and sBCMA causing fratricide, limiting their efficacy and persistence.

Innovation Solution

Development of humanized CAR-T cells (ARI2h) with a 4-1BB co-stimulatory domain that retains anti-MM activity, reduces inflammatory cytokine production, and minimizes CRS, while maintaining efficacy against BCMA-expressing cells by addressing the impact of soluble BCMA (sBCMA) through GMP expansion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If high doses of BCMA-targeting CAR-T cells are administered to achieve therapeutic response, then tumor control is improved, but severe cytokine release syndrome and neurotoxicity occur

Engineering Contradiction:

Improvetumor control efficacyVSAvoidcytokine release syndrome and neurotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the CAR structure by replacing the CD28 co-stimulatory domain with 4-1BB, changing the activation parameters of CAR-T cells. This parameter change reduces the intensity of cytokine release while maintaining anti-tumor efficacy, thereby resolving the contradiction between tumor control and toxicity reduction

Inventive Principle:

Principle #35Parameter changes

2Reliability

If murine CART cells are used to treat multiple myeloma, then initial anti-tumor activity is achieved, but cells disappear early due to immunological reactions

Engineering Contradiction:

Improveanti-tumor activityVSAvoidpersistence of CAR-T cells

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent humanizes the murine CART cell construct by replacing the murine single-chain variable fragment (scFv) with a humanized anti-BCMA scFv while retaining the murine 4-1BB and CD3ζ domains. This parameter change in antigen recognition specificity reduces immunological rejection and extends the persistence of CAR-T cells in human patients

Inventive Principle:

Principle #35Parameter changes

3Reliability

If soluble BCMA is present in the tumor microenvironment, then it can bind to CART cells, but this causes fratricide and reduces CAR-T cell efficacy

Engineering Contradiction:

ImproveCAR-T cell efficacyVSAvoidfratricide effect

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent employs a humanized scFv with optimized affinity characteristics that selectively binds to membrane-bound BCMA on multiple myeloma cells while having reduced affinity for soluble BCMA. This local quality differentiation in binding specificity allows CAR-T cells to maintain efficacy against tumor cells without being sequestered by soluble BCMA in the microenvironment

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12509525B2CAR T-cells against BCMA for the treatment of multiple myeloma

Publication Date: 2025.12.30 FUNDACIO DE RECERCA CLINIC BARCELONA INSTITUT D INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER

AI summary

The present invention provides therapeutics for the treatment of Multiple myeloma. In particular, the present invention provides chimeric antigen receptor (CAR) T-cells that can target the B cell maturation antigen.