BCMA CAR Polynucleotide Optimization for Stable Expression

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Solution Overview

Problem

Existing BCMA-binding chimeric antigen receptors (CARs) and engineered cells for adoptive cell therapy face challenges such as inconsistent RNA expression, antigen-independent signaling, and inhibition by soluble BCMA, limiting their therapeutic efficacy in targeting BCMA-expressing diseases like cancer.

Innovation Solution

Optimized polynucleotides encoding BCMA-binding CARs with modified splice sites and codon usage, incorporating a spacer polypeptide from IgG4 and IgG2, and intracellular signaling domains like CD3ζ, result in consistent surface expression and reduced tonic signaling, enhancing therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional BCMA-binding CARs are used, then antigen binding capability is achieved, but inconsistent RNA expression and antigen-independent signaling occur

Engineering Contradiction:

ImproveRNA expression consistencyVSAvoidantigen-independent signaling

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent modifies nucleotide sequences at splice sites and optimizes codon usage in the CAR encoding polynucleotide. These parameter changes in the genetic sequence ensure consistent RNA expression levels and prevent aberrant splicing that could lead to antigen-independent signaling, while maintaining the amino acid sequence and functional properties of the CAR.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If existing BCMA-CARs are used, then initial therapeutic activity is achieved, but inhibition by soluble BCMA limits efficacy

Engineering Contradiction:

Improvecytolytic activityVSAvoidsoluble BCMA inhibition

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent performs preliminary optimization of the CAR construct by modifying splice sites and codons before the CAR is expressed and deployed therapeutically. This preliminary action ensures that the CAR is pre-configured for consistent expression and resistance to soluble BCMA inhibition, enhancing its productivity and therapeutic efficacy before encountering the harmful factor in vivo.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If CARs with modified splice sites are used, then RNA expression consistency is improved, but increased design complexity occurs

Engineering Contradiction:

Improvesurface expression consistencyVSAvoidpolynucleotide design complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes to the nucleotide sequence by modifying splice site consensus sequences and optimizing codon usage. These modifications are made at the genetic level without altering the amino acid sequence of the CAR, thereby improving surface expression consistency while managing design complexity through targeted sequence optimization rather than structural redesign.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260109774A1Chimeric antigen receptors specific for b-cell maturation antigen and encoding polynucleotides

Publication Date: 2026.04.23 JUNO THERAPEUTICS INC

AI summary

Provided herein are chimeric receptors, such as chimeric antigen receptors (CARs), comprising BCMA-binding molecules, such as anti-BCMA antibodies and antigen-binding fragments thereof, such as 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, such as a non-human reference antibody. Also provided are genetically engineered cells expressing the CARs and uses thereof such as in adoptive cell therapy.