Bivalent CARs Targeting FLT3 and CD19 Prevent Relapse
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) face challenges, particularly in adults and high-risk pediatric patients, with relapse rates high due to loss of targeted epitopes and resistance to chimeric antigen receptor (CAR) therapies, necessitating new strategies to prevent relapse and improve long-term cures.
Innovation Solution
Development of bivalent and bicistronic chimeric antigen receptors (CARs) that target multiple antigens, such as FLT3, CD19, CD22, CD33, and CD123, with specific antigen binding domains, transmembrane domains, and intracellular signaling domains, expressed in T-cells to enhance potency and reduce antigen escape mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single antigen-targeted CAR therapy is used, then initial remission can be achieved, but relapse occurs due to loss of targeted epitope
Solution Approach 1:
The patent creates bivalent CARs that simultaneously target two different antigens (FLT3 and another antigen such as CD19, CD22, CD33, or CD123) on leukemia cells. This multi-functionality ensures that even if one antigen is lost or downregulated, the CAR-T cells can still recognize and eliminate tumor cells through the other antigen, thereby preventing relapse and extending the duration of remission while maintaining therapeutic efficacy
2Productivity
If intensive chemotherapy is used, then initial response can be achieved, but long-term cure rate remains low due to resistance
Solution Approach 1:
The patent uses CAR-T cells as an intermediary therapeutic agent that bridges the gap between conventional chemotherapy and curative therapy. The CAR-T cells are engineered to specifically recognize FLT3 and other antigens on leukemia cells, providing targeted immunotherapy that overcomes chemotherapy resistance. This intermediary approach allows for sustained anti-tumor activity and improved long-term cure rates without the severe toxicities associated with maximally intensive chemotherapy
3Reliability
If multi-antigen targeting is implemented, then relapse prevention is improved, but CAR construct complexity increases
Solution Approach 1:
The patent merges two separate antigen-binding domains into a single bivalent CAR construct, allowing simultaneous targeting of FLT3 and another antigen (CD19, CD22, CD33, or CD123) within one unified protein structure. This combining approach achieves relapse prevention through multi-antigen targeting while managing construct complexity by integrating multiple functions into a single CAR rather than requiring separate CAR expressions
Data Source
AI summary
The present disclosure provides multispecific chimeric antigen receptors (CARs) having antigenic specificity for FLT3 and CD19, FLT3 and CD22, FLT3 and CD123 or FLT3 and CD33. Nucleic acids, expression constructs, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the multispecific CARs are disclosed. Methods of treating or preventing ALL, AML and/or other forms of cancer in a mammal are also disclosed.