CLL1-Targeted CAR Structure for Specific AML Cell Killing
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Solution Overview
Problem
There is a lack of effective immunotherapy targeting CLL1 for the treatment of acute myeloid leukemia (AML) due to the unique expression pattern of CLL1 on hematopoietic cells, particularly on AML cells, with limited reports on using CLL1 as a therapeutic target.
Innovation Solution
Development of a chimeric antigen receptor (CAR) targeting CLL1, comprising an antigen binding domain (anti-CLL1 antibody) and additional domains such as a hinge region, transmembrane domain, and signal transduction domain, specifically binding to CLL1-positive tumor cells and enabling immune cells to kill these cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If CLL1 is used as a therapeutic target for AML, then treatment specificity is improved, but therapeutic effectiveness is worsened due to lack of immunotherapy reports
Solution Approach 1:
The patent segments the therapeutic approach by constructing a chimeric antigen receptor (CAR) with distinct functional domains: an antigen binding domain (anti-CLL1 antibody) for target recognition, a hinge region for structural flexibility, a transmembrane domain for membrane integration, and a signal transduction domain for cellular activation. This segmentation enables the system to overcome the lack of prior immunotherapy reports by creating a modular, well-defined therapeutic unit that can be systematically optimized for effectiveness while maintaining specificity for CLL1-positive AML cells.
2Measurement precision
If anti-CLL1 antibody is used as antigen binding domain, then targeting accuracy is improved, but CAR construction complexity is worsened
Solution Approach 1:
The patent applies universality by designing the CAR with standardized, well-characterized domains that can be universally applied to CAR-T cell therapy. The anti-CLL1 antibody fragment (scFv) serves as a modular antigen binding domain that can be combined with standard hinge regions, transmembrane domains, and signal transduction domains (such as CD3ζ, 4-1BB, or OX40). This multi-functional, standardized approach simplifies construction by using proven building blocks while maintaining high targeting accuracy for CLL1-positive tumor cells.
3Productivity
If CAR-T cells are used to kill CLL1-positive tumor cells, then therapeutic efficacy is improved, but off-target effects are worsened
Solution Approach 1:
The patent applies local quality by ensuring that the CAR expression and activity are localized specifically to the desired target cells. The anti-CLL1 antibody domain provides selective binding to CLL1-positive AML cells, while the signal transduction domains (such as CD3ζ, 4-1BB, or OX40) are activated only upon engagement with the target antigen. This localized activation mechanism ensures high therapeutic efficacy against CLL1-positive tumors while minimizing off-target effects on CLL1-negative cells or normal tissues, as the CAR remains inactive in the absence of its specific antigen.
Data Source
AI summary
Provided is a chimeric antigen receptor targeting CLL1 and an application thereof. The chimeric antigen receptor targeting CLL1 comprises an antigen binding domain, a hinge region, a transmembrane domain and a signal transduction domain; the antigen binding domain is an anti-CLL1 antibody. The present application uses an anti-CLL1 antibody as the antigen binding domain to construct a chimeric antigen receptor molecule, the chimeric antigen receptor targeting CLL1 has specific targeting effect on CLL1 positive tumor cells, and immune cells expressing chimeric antigen receptor targeting CLL1 have a significant killing effect in vitro and in vivo, and secrete a large amount of cytokine IFN-γ after co-cultured with CLL1 positive tumor cells, which has a specific clearance effect on CLL1 positive tumor cells.