CD19-Specific CAR Antibody Variable Region Optimization
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Solution Overview
Problem
Current therapies for B cell malignancies, such as acute lymphocytic leukemia, often fail to respond in some patients, and there is a need for more effective targeting of CD19 antigen to enhance treatment efficacy.
Innovation Solution
Development of a CD19-specific chimeric antigen receptor (CAR) comprising an extracellular domain with an anti-CD19 antibody or antigen-binding fragment, a transmembrane domain, and an intracellular signaling domain, utilizing specific amino acid sequences in the variable regions to enhance binding affinity and cytotoxic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies (chemotherapy, targeted therapy, allogeneic stem cell transplantation) are used for B cell malignancies, then survival rate of child patients can reach over 85%, but some patients remain unresponsive or experience recurrence
Solution Approach 1:
The patent develops a novel anti-CD19 antibody with optimized amino acid sequences in the variable regions (specifically CDRH2 and CDRL1) to enhance binding affinity and cytotoxic activity. This parameter optimization allows the CAR-T therapy to overcome resistance in patients who failed conventional treatments, achieving complete remission in 27 of 30 clinical test cases.
2Reliability
If CAR-T cell therapy targeting CD19 is used to treat refractory acute leukemia patients, then cytotoxicity for target cells increases and complete remission is achieved in 27 of 30 cases, but the therapy requires highly specific antibody sequences to ensure effectiveness
Solution Approach 1:
The patent focuses on optimizing specific local regions of the antibody molecule, particularly the complementarity-determining regions (CDRH2 and CDRL1), to achieve high binding affinity for CD19. This localized optimization ensures that the CAR-T cells maintain high cytotoxicity and reliability in treating refractory leukemia while managing the complexity of antibody sequence design.
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AI summary
The present invention relates to: a novel antibody or an antigen-binding fragment thereof for use in the treatment of cancer by targeting B cell malignancies; a chimeric antigen receptor comprising the same; and uses thereof. The antibody of the present invention is an antibody specifically binding to CD19 highly expressed in cancer cells (particularly, blood cancer) and has very low homology compared to the CDR sequences of conventional CD19 target antibodies, and thus the sequence thereof is unique. In addition, cells expressing a chimeric antigen receptor comprising an anti-CD19 antibody or antigen-binding fragment of the present invention induce immune cell activity in response to a positive cell line expressing CD19, and thus can be usefully used as a therapeutic agent for CAR-immune cells.