CAR Polypeptide Targeting EBV Glycoprotein for Lytic Phase Cytotoxicity
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Solution Overview
Problem
Current methods for treating human herpesvirus-associated diseases, such as EBV-associated cancers and chronic active infections, are limited by the complexity and time required for generating effective T cells, and existing CAR technologies lack targets that effectively support the lytic phase of viral replication.
Innovation Solution
A chimeric antigen receptor (CAR) polypeptide with an extracellular antigen-binding domain specific to herpes virus antigens like EBV glycoprotein 350/220, which are present on the surface of latently infected cells and support the lytic phase of viral replication, combined with a transmembrane and intracellular signaling domain to redirect immune cell cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard adoptive T cell methods are used to treat herpes virus-associated diseases, then T cell expansion and cytotoxic activity can be achieved, but the process requires long time and complex procedures
Solution Approach 1:
The patent segments the complex T cell manipulation process by using genetically engineered CAR-T cells that can be produced through standardized protocols. The CAR construct is divided into modular components (antigen-binding domain, transmembrane domain, intracellular signaling domain) that can be independently optimized and assembled, streamlining the overall production process while maintaining effective cytotoxic activity against herpes virus-infected cells.
Solution Approach 2:
The invention changes the parameters of T cell generation by using chimeric antigen receptors with specific signaling configurations (e.g., CD28 or 4-1BB co-stimulatory domains combined with CD3ζ signaling domains). These parameter changes in receptor structure and signaling pathways enable more efficient and faster T cell expansion and activation compared to conventional methods, reducing the time required while maintaining reliability.
2Reliability
If CAR technologies target latent viral proteins, then they can recognize EBV-infected cells, but they lack targets that support the lytic phase of viral replication
Solution Approach 1:
The patent applies universality by designing CAR constructs that can target antigens expressed across different phases of viral replication. The CAR system is made multi-functional to recognize both latent and lytic phase antigens, allowing a single therapeutic approach to be effective against infected cells regardless of the viral phase, thereby enhancing adaptability while maintaining reliable recognition.
Solution Approach 2:
The invention introduces dynamics by creating CAR-T cells that can adapt their target recognition based on the viral phase. The system dynamically responds to different antigen expressions during latent and lytic phases, enabling the therapy to remain effective throughout the viral replication cycle. This dynamic adaptability ensures comprehensive coverage of infected cells across all stages of infection.
3Productivity
If high affinity TCRs are required for effective T cell therapy, then memory T cells can be expanded, but T cells from cord blood or seronegative donors lack these receptors and are inefficiently expanded
Solution Approach 1:
The patent uses chimeric antigen receptors as intermediaries that bridge the gap between T cells from diverse donors (including cord blood and seronegative donors) and herpes virus antigens. The CAR construct serves as a mediator that provides the necessary antigen recognition capability regardless of the donor's natural TCR repertoire, enabling efficient expansion and effective therapy from any donor source while maintaining high productivity.
Data Source
AI summary
An isolated chimeric antigen receptor (CAR) polypeptide, wherein the CAR includes an extracellular antigen-binding domain, including an antibody or antibody fragment that binds to a protein encoded by a herpes virus, or to a protein complex including the protein (herpes virus antigen), wherein the herpes virus antigen is present on the surface of a human cell that is latently infected with said herpes virus and supports the lytic phase of viral replication. The invention further relates to a nucleic acid molecule encoding the CAR of the invention, a genetically modified immune cell, preferably a T cell, expressing the CAR of the invention and the use of the cell in the treatment of a medical disorder associated with human herpesvirus, such as herpes virus-associated cancers, chronic active herpes virus infections or primary herpes virus infections. In preferred embodiments the herpes virus is Epstein-Barr virus (EBV) and a preferred herpes virus antigen target of the CAR is the EBV glycoprotein 350/220 (gp350/gp220).