Recombinant Virus-Specific T Cell Receptors to Avoid Graft-Versus-Host Disease
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Solution Overview
Problem
Current therapies for immune-compromised patients, such as those post-transplant, are limited by the lack of specific and safe T cell products to target a variety of viruses, with issues including drug toxicity, resistance, and the risk of graft-versus-host disease.
Innovation Solution
Development of recombinant T cell receptors (rTCR-V) specific to viral antigens restricted by a predetermined HLA type, expressed in T cells with a knocked-out endogenous TCR, to target virally infected cells without causing graft-versus-host disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antiviral pharmacotherapies are used, then viral infections can be treated, but drug toxicity and resistance emerge
Solution Approach 1:
The patent replaces chemical pharmacotherapies with a biological immune system-based approach. Instead of using antiviral drugs that cause toxicity and resistance, the invention uses genetically modified T cells with recombinant TCRs that specifically recognize and eliminate virus-infected cells through immunological mechanisms, thereby substituting chemical treatment with a biological system.
Solution Approach 2:
The patent introduces recombinant T cell receptors (rTCRs) as intermediaries between the immune system and viral antigens. These engineered TCRs serve as mediators that enable T cells to specifically recognize viral peptides presented by HLA molecules on infected cells, facilitating targeted immune response without the harmful effects of conventional drugs.
2Reliability
If donor-derived T cells targeting viral peptides are used, then viral infections can be targeted, but the personalized nature and requirement for virus immune matched donors create barriers
Solution Approach 1:
The patent creates universal T cell products by engineering T cells with recombinant TCRs that can recognize viral antigens across different HLA backgrounds. The use of engineered TCRs with broad specificity allows a single T cell product to potentially treat multiple patients regardless of their specific HLA genotype, eliminating the need for personalized donor matching while maintaining high antiviral specificity.
Solution Approach 2:
The patent changes the specificity parameters of T cells through genetic engineering of recombinant TCRs. By modifying the TCR repertoire ex vivo and introducing engineered TCRs with defined viral antigen specificity, the invention transforms T cells from having MHC-restricted, personalized specificity to having engineered, universal specificity that can target viral antigens across diverse patient populations.
3Reliability
If allogeneic T-cells are used, then immune reconstitution can be enhanced, but graft-versus-host disease risk increases
Solution Approach 1:
The patent applies local quality by endowing T cells with specific, localized functionality through recombinant TCR expression. The engineered T cells are given a specific 'identity' through their engineered TCRs that directs them to recognize only viral antigens presented by HLA molecules, while their endogenous TCRs are knocked out to prevent them from recognizing host tissues. This localized specificity enhancement allows allogeneic T cells to provide immune reconstitution without causing GvHD.
Solution Approach 2:
The patent extracts and eliminates the harmful component of allogeneic T cells by knocking out their endogenous TCR genes. By removing the ability of these T cells to recognize self-antigens and host tissues, the invention extracts the GvHD-causing capability while retaining the cells' ability to provide immune reconstitution and antiviral immunity through their engineered recombinant TCRs.
Data Source
AI summary
Provided herein are compositions comprising T cells expressing a recombinant virus-specific T cell receptor (rTCR-V) specific for a viral antigen restricted by a predetermined HLA type, rTCR-Vs, methods for preparing them, their use for treatment, and libraries containing such rTCR-V or T cells comprising them.