Bispecific CARs Targeting BCMA and CD307e

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Solution Overview

Problem

Current cancer therapies using single antigen-binding chimeric antigen receptors (CARs) face challenges in durability of anti-tumor responses due to potential loss of target antigens by cancer cells, leading to therapy evasion.

Innovation Solution

Development of bispecific chimeric antigen receptors (CARs) that specifically bind to both B-cell maturation antigen (BCMA) and CD307e, enhancing targeting specificity and durability by engaging two antigens simultaneously.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Device complexity

If single antigen-binding CARs are used, then the therapy is simpler to implement, but the durability of anti-tumor response deteriorates due to potential antigen loss by cancer cells

Engineering Contradiction:

ImproveCAR structure complexityVSAvoiddurability of anti-tumor response

Core Design Contradiction:

Device complexityVSDuration of action of stationary object

Solution Approach 1:

The patent combines two antigen-binding domains (anti-BCMA and anti-CD307e) into a single bispecific CAR molecule, creating a unified receptor that can simultaneously recognize and bind to both BCMA and CD307e antigens on cancer cells. This merging approach ensures that cancer cells must lose both antigens to escape therapy, significantly improving response durability while maintaining manageable structural complexity through modular design

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The bispecific CAR is designed to perform multiple functions: it can bind to two different antigens (BCMA and CD307e), activate T cells through multiple signaling domains (CD28 co-stimulatory domain and CD3zeta signaling domain), and provide redundant targeting capabilities. This multi-functionality ensures robust and durable anti-tumor responses even if one antigen is lost or downregulated

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Duration of action of stationary object

If bisspecific CARs targeting two antigens are used, then the durability of anti-tumor response is improved, but the CAR structure and manufacturing complexity increases

Engineering Contradiction:

Improvedurability of anti-tumor responseVSAvoidCAR structure complexity

Core Design Contradiction:

Duration of action of stationary objectVSDevice complexity

Solution Approach 1:

The bispecific CAR is segmented into distinct functional modules: an N-terminal anti-BCMA antigen-binding domain, a central anti-CD307e antigen-binding domain, a transmembrane domain for membrane anchoring, a CD28 co-stimulatory domain for T cell activation, and a CD3zeta intracellular signaling domain for signal transduction. This segmentation allows for systematic design, easier manufacturing, and independent optimization of each domain while maintaining overall functionality

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The CAR construct combines multiple protein domains from different sources into a single chimeric molecule, creating a composite structure that integrates antigen-binding specificity (from antibody variable regions), membrane anchoring (from transmembrane domains), co-stimulation (from CD28), and signaling (from CD3zeta). This composite approach enables the receptor to achieve enhanced durability through multi-antigen targeting while managing complexity through proven modular building blocks

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12065498B2Methods of making bispecific anti-CD307E and anti-BCMA chimeric antigen receptors and uses of the same

Publication Date: 2024.08.20 CELL DESIGN LABS INC

AI summary

Provided herein are chimeric antigen receptors that binds specifically to B-cell maturation antigen (BCMA) and CD307e, nucleic acids that encode these chimeric antigen receptors, and methods of making and using these chimeric antigen receptors.