Bicistronic CAR Construct for Dual Antigen Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for cancer, particularly hematological malignancies, face challenges due to the loss of CD19 or CD20 expression by cancer cells, limiting the effectiveness of CAR T-cell therapy, as these cells can evade immune recognition by downregulating or losing antigen expression.
Innovation Solution
Development of bicistronic CAR constructs that encode two separate CARs, one targeting CD19 and the other CD20, allowing simultaneous expression in T cells, which can recognize and bind to both antigens, thereby targeting cancer cells that may lose expression of one antigen but retain the other.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single-antigen CAR T-cell therapy is used, then the treatment is simple and targeted, but cancer cells can evade immune recognition by downregulating or losing antigen expression
Solution Approach 1:
The patent combines two separate CAR constructs (anti-CD19 CAR and anti-CD20 CAR) into a single bicistronic nucleic acid molecule. This merging allows T cells to simultaneously express both CARs and target multiple antigens on cancer cells, preventing immune evasion while maintaining therapeutic effectiveness.
Solution Approach 2:
The bicistronic CAR construct serves multiple functions: it encodes both anti-CD19 and anti-CD20 CARs within a single nucleic acid molecule, enabling T cells to recognize and target cancer cells expressing either or both antigens. This multi-functionality addresses the limitation of single-antigen targeting.
2Adaptability or versatility
If bicistronic CAR constructs encoding two separate CARs are used, then the ability to target multiple antigens is improved, but the complexity of the construct increases
Solution Approach 1:
The patent merges two separate CAR-encoding sequences into a single bicistronic nucleic acid construct. This consolidation reduces the number of separate vectors or transduction steps required while still enabling dual CAR expression in T cells, thus managing complexity.
Solution Approach 2:
The bicistronic construct uses internal ribosome entry sites (IRES) or other cis-acting elements as intermediaries to enable independent translation of two CAR coding sequences from a single mRNA transcript. This mediator mechanism allows dual CAR expression without requiring separate genetic elements.
3Adaptability or versatility
If multiple separate gene therapy vectors are used to engineer T cells with multiple CARs, then multiple antigens can be targeted, but the number of vectors and procedures increases
Solution Approach 1:
The patent combines multiple CAR-encoding sequences into a single bicistronic nucleic acid construct that can be delivered in one transduction event. This merging eliminates the need for sequential transduction with multiple vectors, streamlining the T cell engineering process and improving productivity.
Data Source
AI summary
An embodiment of the invention provides nucleic acids comprising a nucleotide sequence encoding chimeric antigen receptor (CAR) amino acid constructs. Polypeptides, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the CAR constructs are disclosed. Methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal are also disclosed.