Dual CD19/CD22 CAR Constructs for Persistent B Cell Targeting
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Solution Overview
Problem
Existing cancer immunotherapy methods, such as chimeric antigen receptor (CAR) modified autologous T cell therapy, face challenges in effectively targeting B cell malignancies due to variable T cell quality and limited control over CAR-transformed T cell persistence and proliferation, leading to suboptimal treatment outcomes.
Innovation Solution
Development of nucleic acid molecules encoding dual or tandem chimeric antigen receptors (CARs) that combine CD22 and CD19 binding domains, with distinct transmembrane and signaling domains, to enhance T cell persistence and proliferation, thereby improving therapeutic efficacy against B cell malignancies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional CAR-T therapy targeting single antigen (CD19 or CD22) is used, then treatment simplicity is maintained, but therapeutic efficacy is limited due to variable T cell quality and tumor escape mechanisms
Solution Approach 1:
The patent divides the therapeutic function into multiple independent CAR units, each targeting a different antigen (CD19 and/or CD22). These segmented CARs can be expressed individually or in combination, allowing the immune system to attack cancer cells through multiple independent pathways, thereby improving therapeutic reliability while maintaining modular simplicity
Solution Approach 2:
The patent creates universal CAR constructs that can target multiple antigens simultaneously or provide backup targeting options. The dual CAR system serves multiple functions: primary tumor targeting, escape detection, and sustained T cell activation, making the therapy more robust without requiring completely separate treatment protocols
2Duration of action of moving object
If dual CAR system is implemented to improve T cell persistence and proliferation, then therapeutic efficacy is enhanced, but CAR molecule complexity increases
Solution Approach 1:
The dual CAR system is segmented into distinct functional modules with separate transmembrane domains (first and second transmembrane domains) and signaling domains. This segmentation allows each CAR to function independently for T cell persistence and proliferation, reducing interference between the two CAR systems while maintaining enhanced therapeutic efficacy
Solution Approach 2:
The patent employs partial action by implementing dual CAR systems only when clinical need warrants the added complexity. The modular design allows clinicians to select single or dual CAR approaches based on patient-specific factors, providing excessive capability that can be activated only when necessary for improved T cell persistence
3Adaptability or versatility
If dual CAR system with distinct transmembrane and signaling domains is used, then control over T cell proliferation is improved, but manufacturing complexity increases
Solution Approach 1:
The dual CAR construct is segmented into distinct nucleotide sequences encoding separate functional domains. This segmentation enables independent optimization and validation of each CAR component during manufacturing, simplifying quality control and characterization despite the overall complexity of the dual CAR system
Solution Approach 2:
The patent utilizes parameter changes in the nucleotide sequences encoding the dual CAR system to optimize manufacturing. By varying nucleotide sequences while maintaining amino acid sequences (synonymous codon optimization), the patent improves expression levels and manufacturing efficiency without altering the functional properties of the CAR proteins
Data Source
AI summary
The present disclosure provides compositions and methods for treating diseases associated with expression of CD19 and/or CD22, e.g., by administering a recombinant T cell or natural killer (NK) cell comprising a CD22 CAR and a CD19 CAR as described herein. The disclosure also relates to CAR molecules specific to CD22 and/or CD19, methods of making a cell comprising the same and vectors encoding the same.