Anti-Mesothelin CAR CDR Substitutions for Solid Tumor Binding
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Solution Overview
Problem
Current immunotherapies for solid tumors, such as immune checkpoint inhibitors and CAR-T cell therapies, are hindered by fibrous tissues that interfere with drug delivery, necessitating the development of an antibody with high affinity for mesothelin, a protein overexpressed on the surface of solid cancer cells.
Innovation Solution
Development of an anti-mesothelin antibody with increased affinity, including specific amino acid substitutions in the heavy and light chain complementarity determining regions, and a chimeric antigen receptor (CAR) for targeted cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapies (immune checkpoint inhibitors and CAR-T cell therapies) are used for solid tumors, then general cancer treatment effectiveness is achieved, but fibrous tissues surrounding the tumor interfere with drug delivery and reduce therapy efficiency
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences in the complementarity determining regions (CDRs) of the antibody. Specifically, mutations are introduced in HCDR1 (positions 31, 32, 33), HCDR2 (positions 50, 51, 52), HCDR3 (positions 69, 70, 71), LCDR1 (positions 24, 25, 26), LCDR2 (positions 35, 36, 37), and LCDR3 (positions 56, 57, 58) to enhance binding affinity. This allows the antibody to effectively bind to mesothelin on solid tumor surfaces despite the presence of fibrous tissues, thereby improving therapy efficiency for solid tumors.
2Reliability
If an antibody with high affinity for mesothelin is developed, then binding specificity to mesothelin is improved, but the complexity of antibody development and characterization increases
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions specifically in the complementarity determining regions (CDRs) of the antibody, which are the local regions responsible for antigen binding. Rather than redesigning the entire antibody structure, only specific residues in HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are mutated to enhance mesothelin binding affinity while maintaining the overall antibody framework and reducing development complexity.
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 anti-mesothelin antibody and CAR exhibit enhanced binding affinity to mesothelin-expressing cancer cells, improving therapeutic efficacy against cancers like pancreatic cancer and ovarian cancer.
Implementation Method 1
a chimeric antigen receptor with increased affinity for mesothelin, including an antigen-binding domain, a hinge domain, a transmembrane domain, and an intracellular signaling domain
Data Source
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AI summary
Provided is an anti-mesothelin chimeric antigen receptor that has increased affinity for mesothelin and binds specifically to mesothelin. An anti-mesothelin chimeric antigen receptor according to one aspect has increased affinity for mesothelin and exhibits a specific binding ability to mesothelin, and accordingly, can be useful for the prevention or treatment of cancer in which mesothelin is overexpressed.