GRP78-Targeting CAR T Cells for Broad Cancer Therapy
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Solution Overview
Problem
Current CAR T cell therapies for cancer treatment are limited by the need for cancer-specific targets that are expressed in a broad range of malignancies, as conventional approaches often fail to effectively target multiple cancer types due to variability in antigen expression.
Innovation Solution
Development of chimeric antigen receptors (CARs) specifically designed to target glucose-regulated-protein 78 (GRP78), which is overexpressed on the surface of various tumor cells and not in normal tissues, comprising an extracellular target-binding domain, a transmembrane domain, and a cytoplasmic signaling domain, to enable broad cancer targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional CAR T cell therapies use traditional antigen targets, then they can treat specific cancer types, but they fail to effectively target multiple cancer types due to variability in antigen expression
Solution Approach 1:
The CAR T cell is designed with a universal target (GRP78) that is overexpressed across multiple cancer types including solid tumors and hematological malignancies. The extracellular domain of the CAR includes a GRP78-binding peptide that recognizes and binds to GRP78 on the surface of diverse tumor cells, enabling a single CAR T cell product to treat multiple cancer types effectively
Solution Approach 2:
The invention changes the target parameter from traditional antigens with variable expression patterns to GRP78, which exhibits consistent overexpression across different cancer types. This parameter change enables the CAR T cell to maintain reliable treatment effectiveness while achieving broad adaptability across multiple malignancies
2Adaptability or versatility
If CAR T cells target antigens expressed in normal tissues, then they can achieve broad cancer targeting, but they cause toxicity to normal tissues
Solution Approach 1:
The CAR T cell therapy exhibits local quality by selectively targeting cancer cells that overexpress GRP78 while sparing normal tissues with baseline GRP78 expression. The high affinity binding of the GRP78-binding peptide to overexpressed GRP78 on tumor cells enables selective destruction of cancer cells without causing significant toxicity to normal tissues
Solution Approach 2:
The invention exploits the parameter difference in GRP78 expression levels between cancer cells (overexpressed) and normal tissues (baseline expression). By designing the CAR with appropriate binding affinity, the system achieves broad cancer targeting capability while maintaining safety through selective recognition of the overexpressed target on tumor cells
Data Source
AI summary
The present invention provides a chimeric antigen receptor (CAR) comprising an extracellular target-binding domain comprising at least one glucose-regulated-protein 78 (GRP78)-binding moiety. The present invention further provides polynucleotides and recombinant vectors encoding such CARs. The present invention further provides isolated host cells and methods for preparing isolated host cells expressing the CARs. The present invention further provides pharmaceutical compositions comprising the host cells and methods for treating a tumor using the pharmaceutical compositions.