CLL-1 CAR Receptor Design for Specific Leukemia Cell Targeting
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Solution Overview
Problem
Current engineered immune cells, such as CAR-T cells, lack specificity and potency in targeting the human C-type lectin-like molecule-1 (CLL-1) protein, which is expressed on various hematopoietic cells and leukemia cells, limiting their effectiveness in treating leukemia and autoimmune diseases.
Innovation Solution
Development of antibodies and chimeric antigen receptors (CARs) with specific CDR sequences targeting CLL-1, combined with transmembrane and intracellular domains, to enhance the ability of immune cells to recognize and kill CLL-1-expressing cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current engineered immune cells are used to target CLL-1, then immune cell therapy can be provided, but the specificity and potency in targeting CLL-1 is insufficient
Solution Approach 1:
The CAR is divided into distinct functional domains: an extracellular antigen-binding domain with specific CDR sequences for CLL-1 recognition, a transmembrane domain for membrane anchoring, and intracellular signaling domains for activation. This segmentation allows each component to be optimized independently for its specific function, improving overall targeting specificity and potency while managing structural complexity through modular design
Solution Approach 2:
The patent introduces specific CDR sequences (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, VL CDR3) with defined amino acid compositions that are locally optimized for high-affinity binding to CLL-1. This local quality enhancement at the antigen-binding site improves specificity and potency without requiring changes to the entire CAR structure, thus resolving the contradiction between performance and complexity
2Productivity
If antibodies with specific CDR sequences are developed to target CLL-1, then recognition and killing of CLL-1-expressing cells is enhanced, but the complexity of the therapeutic construct increases
Solution Approach 1:
The patent merges the antibody antigen-binding function with T-cell activation capabilities into a single chimeric antigen receptor construct. The CAR combines the extracellular antigen-binding domain (with specific CDR sequences) from antibodies with intracellular signaling domains from T-cell receptors, creating an integrated therapeutic entity that performs both recognition and activation functions, thereby improving productivity while managing complexity through functional integration
Solution Approach 2:
The CAR construct is designed to be multi-functional: it can recognize CLL-1 through specific CDR binding, transduce activation signals into T-cells, and mediate cytotoxicity against target cells. This universality allows a single therapeutic construct to perform multiple therapeutic actions, improving overall effectiveness without requiring separate components for each function, thus resolving the productivity-complexity contradiction
Data Source
AI summary
Provided herein are antibodies and antigen binding fragments thereof targeting the human C-type lectin-like molecule-1 (CLL-1) protein, as well as chimeric antigen receptors (CAR) derived from such antibodies and fragments, and the uses thereof.