HLA-G Specific CAR for Solid Tumor Targeting
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Solution Overview
Problem
Conventional chimeric antigen receptor immune cell therapies for cancer face limitations in targeting solid tumors due to lack of unique tumor-associated antigens, low efficiency in homing to tumor sites, and inability to overcome immunosuppressive microenvironments, resulting in limited efficacy.
Innovation Solution
Development of a HLA-G specific chimeric antigen receptor that includes an antigen recognition domain, transmembrane domain, IL2 receptor β chain signaling domain, and CD3ζ signaling domain, specifically designed to target human leukocyte antigen G (HLA-G) on tumor cells, combined with a pharmaceutical composition that includes a chemotherapy drug for enhanced tumor cell killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chimeric antigen receptor immune cell therapy is used, then treatment can be provided for leukemia and lymphoma, but efficacy is greatly limited for solid tumors due to lack of unique tumor-associated antigens
Solution Approach 1:
The patent designs a chimeric antigen receptor that targets HLA-G, a molecule expressed across multiple solid tumor types including ovarian, breast, pancreatic, and lung cancers. This universal targeting approach allows a single CAR construct to address multiple solid tumor indications, overcoming the limitation of tumor-specific antigen variability while maintaining reliable therapeutic efficacy through the conserved HLA-G target.
Solution Approach 2:
The patent modifies the conventional CAR structure by incorporating specific signaling domains (CD3ζ for activation, CD28 or 4-1BB for co-stimulation) and optimizing the antigen recognition domain to specifically bind HLA-G. These parameter changes in the CAR molecular structure enable effective recognition and killing of solid tumor cells expressing HLA-G, transitioning the therapy from ineffective to efficacious for solid tumors.
2Productivity
If conventional chimeric antigen receptor immune cell therapy is used, then immune cells can be generated, but homing efficiency to tumor sites is low
Solution Approach 1:
The patent enhances the homing capability of CAR immune cells by incorporating specific signaling domains that upregulate chemokine receptors and adhesion molecules locally at the tumor site. The CD28 or 4-1BB co-stimulatory domains trigger local cellular responses that improve tumor tropism and homing efficiency, allowing immune cells to navigate effectively to solid tumor sites while maintaining high productivity in immune cell generation.
3Reliability
If conventional chimeric antigen receptor immune cell therapy is used, then tumor cells can be targeted, but immunosuppressive microenvironment of solid tumors cannot be overcome
Solution Approach 1:
The patent converts the immunosuppressive microenvironment from a harmful barrier into a beneficial targeting opportunity. By designing the CAR to recognize HLA-G, which is overexpressed on solid tumor cells and tumor-associated cells within the immunosuppressive microenvironment, the therapy transforms the suppressive conditions into enhanced tumor cell recognition and killing, maintaining reliable targeting while overcoming the immunosuppressive barrier.
Solution Approach 2:
The patent creates a composite CAR structure combining multiple functional domains: antigen recognition domain for HLA-G binding, CD3ζ signaling domain for activation, and CD28 or 4-1BB co-stimulatory domains for sustained signaling. This composite molecular structure enables the immune cell to effectively navigate and overcome the immunosuppressive microenvironment while maintaining reliable tumor cell targeting capability.
4Reliability
If HLA-G specific chimeric antigen receptor is combined with chemotherapy drugs, then tumor cell death rates increase significantly, but treatment complexity increases
Solution Approach 1:
The patent merges chemotherapy treatment with CAR immune cell therapy into a unified treatment protocol. The chemotherapy drugs and CAR immune cells work synergistically to achieve significantly increased tumor cell death rates. This combination approach integrates two therapeutic modalities into a coordinated treatment strategy, managing complexity through unified protocol design while maximizing therapeutic efficacy.
Data Source
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AI summary
The present disclosure relates to a HLA-G specific chimeric antigen receptor, a nucleic acid, a HLA-G specific chimeric antigen receptor expression plasmid, a HLA-G specific chimeric antigen receptor expressing cell, a pharmaceutical composition for treating cancer, and use of the HLA-G specific chimeric antigen receptor expressing cell. The chimeric antigen receptor specifically binds to human leukocyte antigen G. The nucleic acid encodes the HLA-G specific chimeric antigen receptor. The HLA-G specific chimeric antigen receptor expression plasmid expresses the HLA-G specific chimeric antigen receptor. The HLA-G specific chimeric antigen receptor expressing cell is obtained by transducing the HLA-G specific chimeric antigen receptor into an immune cell. The pharmaceutical composition for treating cancer includes the HLA-G specific chimeric antigen receptor expressing cell and a pharmaceutically acceptable carrier.