Fully Human CAR T Cells Targeting FRα for Ovarian Cancer
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) technologies for cancer treatment, particularly for ovarian cancer, rely on murine-derived or 'humanized' antibodies that can trigger a host immune response and produce human anti-mouse antibodies (HAMA), posing risks and limitations.
Innovation Solution
Development of a fully human CAR that targets folate receptor-alpha (FRα) by incorporating a human nucleic acid sequence for the FRα binding domain, an intracellular domain of a costimulatory molecule, and a CD3 zeta signaling domain, minimizing the risk of immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine-derived or humanized antibodies are used in CAR construction, then the CAR can recognize tumor associated antigens, but the host immune system triggers a response producing human anti-mouse antibodies (HAMA)
Solution Approach 1:
The patent changes the species origin parameter of the antibody from murine or humanized to fully human. This parameter change eliminates the immunogenicity difference between the CAR antibody and the human host, preventing HAMA production while maintaining the CAR's ability to recognize tumor associated antigens such as FRα
Solution Approach 2:
The patent uses fully human antibodies that are homologous to the human host's own antibody system. This homogeneity ensures that the immune system does not recognize the CAR antibody as foreign, thereby avoiding the harmful HAMA response while preserving antigen recognition function
2Object-generated harmful factors
If fully human antibodies are used in CAR construction, then the risk of HAMA is minimized, but the availability and development complexity increases
Solution Approach 1:
The patent employs phage display technology to pre-select and identify fully human antibodies that specifically bind to target antigens such as FRα. This preliminary action of screening human antibody repertoires in vitro allows for the direct selection of suitable human antibodies for CAR construction, bypassing the need for animal immunization and simplifying the overall development process
Data Source
AI summary
The invention provides compositions and methods for treating ovarian cancer. Specifically, the invention relates to administering a genetically modified T cell having α-folate receptor (FRα) binding domain and CD27 costimulatory domain to treat ovarian cancer. In an embodiment, the FRα binding domain is fully human, thereby preventing a host immune response.