BCMA-Binding CAR Design for Stable Expression

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for B-cell malignancies, particularly multiple myelomas, face challenges in effectively targeting BCMA for therapeutic intervention, necessitating the development of a more potent and stable chimeric antigen receptor (CAR) that can specifically bind to BCMA and promote cytokine release.

Innovation Solution

A chimeric antigen receptor (CAR) is designed with a BCMA-binding domain, a transmembrane domain, a costimulatory domain, and an intracellular signal transduction domain, incorporating specific amino acid sequences for enhanced affinity and stability, and is expressed in CAR-T cells to treat diseases associated with BCMA expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CAR designs are used to target BCMA, then the basic therapeutic function is achieved, but the affinity to BCMA is insufficient and expression stability is poor

Engineering Contradiction:

Improveexpression stabilityVSAvoidCAR structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent optimizes specific parameters of the CAR structure including the transmembrane domain (using CD8α or CD28 sequences) and costimulatory domain (using 4-1BB or CD28 sequences) to improve expression stability and affinity without fundamentally changing the overall CAR architecture. This allows achieving better performance while maintaining reasonable structural complexity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The CAR construct combines multiple functional domains from different sources (antigen-binding domain, transmembrane domain from CD8α/CD28, costimulatory domain from 4-1BB/CD28, and signaling domain) to create a composite receptor that achieves both high affinity for BCMA and stable expression in CAR-T cells.

Inventive Principle:

Principle #40Composite materials

2Ease of manufacture

If the CAR structure is simplified for easier manufacturing, then manufacturing ease is improved, but the affinity and cytokine release capability are reduced

Engineering Contradiction:

ImproveCAR construction easeVSAvoidbinding affinity

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The CAR is divided into distinct functional modules (antigen-binding scFv, transmembrane domain, costimulatory domain, signaling domain) that can be independently optimized and assembled. This segmentation allows for standardized construction methods while maintaining high affinity and functionality through careful selection of each module's sequence.

Inventive Principle:

Principle #1Segmentation

3Reliability

If the CAR is designed for high affinity binding, then binding capability is improved, but the stability of expression in CAR-T cells decreases

Engineering Contradiction:

Improvebinding affinityVSAvoidexpression stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

Different regions of the CAR are optimized for different functions: the antigen-binding domain (scFv with specific CDR sequences) is optimized for high affinity to BCMA, while the transmembrane and costimulatory domains are optimized for stable expression and proper membrane anchoring. This local optimization allows simultaneous achievement of high affinity and stable expression.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP3674328B1Chimeric antigen receptor (CAR) binding to BCMA, and uses thereof

Publication Date: 2023.12.13 NANJING IASO BIOTHERAPEUTICS CO LTD

Figure 1A~1B
Figure 2A~2B
Figure 3~4

AI summary

The invention provides a chimeric antigen receptor (CAR) which can specifically bind to a BCMA protein comprising a BCMA binding structural domain, a transmembrane domain, a costimulatory domain, and an intracellular signaling domain. The invention also provides uses of the CAR in treating diseases or conditions linked to the expression of BCMA.