B7-H3 CAR-T Single-Domain Antibody for Recurrent NPC
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Solution Overview
Problem
There is a lack of effective means for treating advanced and recurrent nasopharyngeal carcinoma (NPC), a malignant tumor often associated with Epstein-Barr virus infection, as current therapies like radiotherapy and chemotherapy are insufficient for late-stage patients.
Innovation Solution
A B7-H3 targeted single-domain antibody and chimeric antigen receptor molecule are developed, which specifically bind to tumor cells via the B7-H3 antigen, activating an antigen-dependent antitumor response through a chimeric antigen receptor cell, utilizing a lentiviral vector for expression and transfection into PBMCs to create a targeted therapeutic approach.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If radiotherapy and chemotherapy are used for treatment, then early-stage NPC patients can be treated effectively, but advanced and recurrent patients lack effective treatment means
Solution Approach 1:
The patent changes the treatment approach by targeting B7-H3 antigen specifically, which is highly expressed in NPC cells but lowly expressed in normal tissues. This parameter change in target selection enables effective treatment of advanced and recurrent patients who did not respond to conventional radiotherapy and chemotherapy.
Solution Approach 2:
The patent uses a single-domain antibody (sdAb) as an intermediary that binds to B7-H3 on tumor cells, activating chimeric antigen receptor T cells to kill NPC cells. This intermediary mechanism provides a new effective treatment pathway for advanced and recurrent patients.
2Productivity
If conventional radiotherapy and chemotherapy are applied, then early-stage patients benefit from treatment, but there is no effective means for advanced and recurrent patients
Solution Approach 1:
The patent creates a simplified version of the immune response system by using a single-domain antibody that mimics the binding capability of full antibodies but with higher affinity and smaller size. This copying approach enables more effective targeting of B7-H3 on recurrent and metastatic NPC cells.
Solution Approach 2:
The patent combines multiple functional elements into a composite chimeric antigen receptor molecule that includes the single-domain antibody binding domain, transmembrane domain, and intracellular signal transduction domain. This composite structure enables simultaneous binding to B7-H3 and activation of T cell killing function.
3Reliability
If B7-H3 targeted therapy is developed, then specific antitumor effects can be achieved, but the complexity of developing and implementing the therapy increases
Solution Approach 1:
The patent extracts only the essential variable region of the heavy chain to create a single-domain antibody, removing the light chain and constant regions that are not necessary for binding function. This extraction simplifies the antibody structure while maintaining high affinity for B7-H3, reducing development complexity.
Solution Approach 2:
The patent segments the chimeric antigen receptor into distinct functional domains: the extracellular antigen-binding domain (single-domain antibody), the transmembrane domain, and the intracellular signal transduction domain. This segmentation allows independent optimization of each component and simplifies the overall therapy development process.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The B7-H3 targeted chimeric antigen receptor cell effectively kills nasopharyngeal carcinoma cells, providing a potential treatment for recurrent and metastatic NPC by specifically targeting and destroying tumor cells.
Implementation Method 1
The B7-H3 targeted single-domain antibody... can specifically bind to tumor cells by targeting B7-H3
Implementation Method 2
The intracellular signal transduction domain... After CAR molecules bind to the tumor antigens, CAR molecules activate T cells
Implementation Method 3
utilizing a lentiviral vector for expression and transfection into PBMCs
Data Source
AI summary
The present disclosure provides a targeted B7-H3 single-domain antibody, a chimeric antigen receptor molecule, a chimeric antigen receptor cell, and their application in the preparation of drugs for treating nasopharyngeal carcinoma, which belongs to the field of antibody drug technology; an amino acid sequence of the B7-H3 targeted single-domain antibody provided by the present disclosure is shown in SEQ ID No. 1, and an amino acid sequence of the chimeric antigen receptor molecule is shown in SEQ ID No. 2; the chimeric antigen receptor cell provided by the present disclosure can specifically bind to tumor cells through targeting B7-H3 and exert specific antitumor effects via antigen-dependent mechanism, making it one of the potential effective methods for treating recurrent and metastatic NPC; according to the records of the embodiments, after co-culturing the chimeric antigen receptor cell provided by the present disclosure with the nasopharyngeal carcinoma cell line HK1-EBV, it can significantly kill nasopharyngeal carcinoma cell.