Fully Human Anti-CD22 CARs for High-Affinity T-Cell Killing
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Solution Overview
Problem
Existing CD22-targeted chimeric antigen receptors exhibit insufficient affinity and poor cytotoxicity against CD22-expressing cells, limiting their effectiveness in treating B-cell lymphoma and leukemia.
Innovation Solution
Development of anti-CD22 antibody molecules with specific CDR sequences and CD22-targeted chimeric antigen receptors, including a CD3z intracellular signaling domain and 4-1BB costimulatory signaling domain, to enhance binding affinity and cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CD22-targeted chimeric antigen receptors are used, then the structure is relatively simple, but the binding affinity to CD22 is insufficient and cytotoxicity is poor
Solution Approach 1:
The patent constructs chimeric antigen receptors by combining the anti-CD22 antibody variable region (scFv) with T cell signaling domains (CD3ζ, 4-1BB, CD28), creating a composite molecular structure that integrates antigen recognition with immune activation functions. This composite design achieves high binding affinity (KD ≤2 nM) while maintaining functional effectiveness.
2Reliability
If conventional CD22-targeted chimeric antigen receptors are used, then the design is simpler, but the cytotoxicity against target cells is poor
Solution Approach 1:
The patent merges multiple functional domains into a single chimeric antigen receptor: the antigen-binding scFv domain (from anti-CD22 antibody), the transmembrane domain, and intracellular signaling domains (CD3ζ for activation, 4-1BB or CD28 for costimulation). This integration enables the receptor to simultaneously recognize CD22 and trigger potent T cell-mediated cytotoxicity against B-cell lymphoma and leukemia cells.
Solution Approach 2:
The patent optimizes the cytotoxicity parameter by incorporating dual signaling domains (CD3ζ plus 4-1BB or CD28) which enhance T cell activation thresholds and durability. The engineered CAR-T cells exhibit improved cytotoxicity against CD22-expressing cells compared to conventional single-domain receptors.
3Reliability
If high binding affinity is achieved through optimized CDR sequences, then the KD value improves to ≤2 nM, but the antibody molecule complexity increases
Solution Approach 1:
The patent focuses optimization on the critical antigen-binding interface by designing specific CDR sequences (HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3) with precise amino acid compositions. This local optimization of the variable regions achieves high binding affinity (KD ≤2 nM for IgG, ≤20 nM for Fab) without requiring complex modifications to the overall antibody framework or constant regions.
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-CD22 antibody molecules and chimeric antigen receptors demonstrate improved binding to CD22 with KD values of ≤2 nM and enhanced cytotoxicity against CD22-expressing cells, showing potential for effective treatment of B-cell leukemia and lymphoma.
Implementation Method 1
the heavy chain variable region comprises complementarity-determining regions selected from any of the following groups: HCDR1 having the sequence set forth in SEQ ID NO: 4, HCDR2 having the sequence set forth in SEQ ID NO: 5 and HCDR3 having the sequence set forth in SEQ ID NO: 6
Implementation Method 2
a chimeric antigen receptor combines the antigen-binding specificity of a monoclonal antibody with the effector function of a T cell, thereby promoting the specific killing of cells expressing a particular antigen by such genetically engineered T cells
Implementation Method 3
the chimeric antigen receptor comprises, sequentially from N-terminal to C-terminal, a CD8α signal peptide, the antigen-binding domain, a CD8α hinge region, a transmembrane region, a 4-1BB costimulatory signaling domain, and a CD3z intracellular signaling domain
Implementation Method 4
a chimeric antigen receptor comprises an antigen-binding domain binding to CD22, the antigen-binding domain comprising a light chain variable region and a heavy chain variable region
Data Source
AI summary
The present invention provides an anti-CD22 antibody molecule and a CD22-targeted chimeric antigen receptor (CAR) constructed using the anti-CD22 antibody molecule. The present invention also provides an application of the anti-CD22 antibody molecule and the CAR in the preparation of drugs for treating CD22-related diseases.