Fully Human Anti-CD19 scFv for Low-Immunogenicity CAR-T Cells
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Solution Overview
Problem
Current CD19-targeting CAR-T therapies using heterologous antibodies face issues with immunogenicity, leading to rapid elimination of CAR-T cells and reduced long-term efficacy, necessitating the development of fully human antibodies to enhance compatibility and survival time in the human body.
Innovation Solution
Development of fully human antibodies with specific light and heavy chain variable regions, including combinations of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 sequences, for use in chimeric antigen receptors (CARs) to target CD19, reducing immunogenicity and improving CAR-T cell longevity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If heterologous antibodies are used in CAR-T therapy, then the CAR-T cells can be constructed and initially effective, but the immunogenicity increases leading to rapid elimination of CAR-T cells
Solution Approach 1:
The patent applies parameter changes by transitioning from heterologous antibodies (murine or alpaca-derived) to fully human antibodies in the CAR structure. This fundamental parameter change in antibody origin eliminates the immunogenicity issue while maintaining the therapeutic efficacy, directly resolving the contradiction between initial effectiveness and immune rejection.
Solution Approach 2:
The patent employs homogeneity by using fully human antibodies that are immunologically compatible with the human body. This homogeneity principle ensures that the CAR-T cells recognize CD19 antigen without triggering an immune response against the antibody itself, thereby prolonging survival time while maintaining therapeutic function.
2Ease of manufacture
If heterologous antibodies are used in CAR-T therapy, then the treatment can be administered, but the survival time of CAR-T cells in the human body is reduced
Solution Approach 1:
The patent changes the critical parameter of antibody humanization from partial (humanized) to complete (fully human). This parameter change directly addresses the duration issue by eliminating immunogenicity, thereby extending CAR-T cell survival time from weeks to potentially months or years, while the manufacturing process remains feasible through established phage display and hybridoma technologies.
3Object-affected harmful factors
If fully human antibodies are used, then the immunogenicity is reduced and compatibility is improved, but the development complexity increases
Solution Approach 1:
The patent uses copying principles by utilizing phage display technology to replicate and select fully human antibody sequences from human antibody repertoires. This copying approach allows for the systematic identification and cloning of fully human anti-CD19 antibodies without requiring de novo design, thereby managing development complexity while achieving the goal of reduced immunogenicity.
Data Source
AI summary
Provided are a fully human antibody targeting CD19 or a single chain antibody or fragment thereof. Further provided is a chimeric antigen receptor (CAR) constructed by using a single chain antibody (scFv) derived from the fully human antibody. The fully human antibody and the CAR can be used for the construction of CAR-T cells targeting CD19. Compared with CAR-T cells using murine antibodies, the CAR-T cells have better compatibility with the human body, which is beneficial to their long-term proliferation and survival in the body.