BCMA-Binding Chimeric Antigen Receptors for Consistent RNA Expression

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Solution Overview

Problem

There is a need for improved BCMA-binding chimeric antigen receptors (CARs) and engineered BCMA-CAR expressing targeting cells for use in adoptive cell therapy, as existing CARs may not provide sufficient specificity and stability for effective treatment of diseases such as cancer, autoimmune disorders, and infectious diseases.

Innovation Solution

Development of polynucleotides encoding chimeric antigen receptors with a specific extracellular antigen-binding domain, a spacer of defined length, a transmembrane domain, and an intracellular signaling region, featuring enhanced RNA homogeneity and modified splice donor and acceptor sites, to improve the stability and specificity of BCMA-binding CARs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing CAR designs are used, then the basic function of BCMA binding is achieved, but the specificity and stability are insufficient for effective treatment

Engineering Contradiction:

Improvespecificity and stability of BCMA bindingVSAvoidcomplexity of CAR structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent modifies the spacer length parameter to at least 125 amino acids and optimizes RNA homogeneity to at least 70%, which improves the stability and specificity of BCMA binding without fundamentally changing the overall CAR structure

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The CAR is divided into distinct functional domains: extracellular antigen-binding domain, spacer, transmembrane domain, and intracellular signaling region, allowing each segment to be optimized independently for its specific function

Inventive Principle:

Principle #1Segmentation

2Stability of the object's composition

If the spacer length is increased to improve stability, then the structural integrity is enhanced, but the overall CAR size increases

Engineering Contradiction:

Improvestructural integrity of CARVSAvoidlength of CAR

Core Design Contradiction:

Stability of the object's compositionVSLength of stationary object

Solution Approach 1:

The spacer length is optimized to at least 125 amino acids, which provides sufficient structural integrity while avoiding excessive length that would compromise cell permeability and receptor function

Inventive Principle:

Principle #35Parameter changes

3Manufacturing precision

If RNA homogeneity is increased to improve expression consistency, then the treatment efficacy is enhanced, but the manufacturing complexity increases

Engineering Contradiction:

Improveconsistency of CAR expressionVSAvoidease of polynucleotide production

Core Design Contradiction:

Manufacturing precisionVSEase of manufacture

Solution Approach 1:

The polynucleotide is designed with modified splice donor and acceptor sites that promote RNA homogeneity of at least 70%, ensuring consistent CAR expression while using standard molecular biology techniques for production

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12428486B2Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides

Publication Date: 2025.09.30 JUNO THERAPEUTICS INC

AI summary

Provided herein are chimeric receptors, including chimeric antigen receptors (CARs), comprising BCMA-binding molecules, including anti-BCMA antibodies and antigen-binding fragments thereof, including heavy chain variable (VH) regions and single-chain antibody fragments, and encoding polynucleotides. In some embodiments, the anti-BCMA chimeric receptors specifically bind to BCMA. Among the anti-BCMA-binding molecules are human antibodies, including those that compete for binding to BCMA with reference antibodies, including a non-human reference antibody. Also provided are genetically engineered cells expressing the CARs and uses thereof including in adoptive cell therapy.