CD20 Single-Domain CAR Binding for Stable, Lower-Toxicity Therapy
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Solution Overview
Problem
Current CD20-targeting therapies, such as conventional monoclonal antibodies and CAR-T cell therapy, face challenges like refractory diseases, cytokine release syndrome, and on-target off-tumor toxicity, necessitating the development of stable and small-sized CD20-binding molecules for more effective treatments.
Innovation Solution
Development of anti-CD20 single domain antibodies (sdAbs) with specific CDR sequences and chimeric antigen receptors (CARs) that include these sdAbs, along with engineered immune effector cells, to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional monoclonal antibodies are used to target CD20, then therapeutic effect is achieved, but molecule size is large and stability is reduced
Solution Approach 1:
The patent segments the conventional monoclonal antibody structure into a single domain antibody (sdAb) format, retaining only the essential antigen-binding variable domain while eliminating the constant regions and other non-essential portions. This segmentation reduces molecular weight and improves tissue penetration while maintaining CD20 binding capability and therapeutic effectiveness.
Solution Approach 2:
The patent extracts and isolates the critical antigen-binding fragment (single domain) from the complete monoclonal antibody structure. By taking out only the essential variable domain that binds to CD20, the invention creates a minimized molecule that preserves therapeutic function while eliminating unnecessary molecular mass and improving pharmacokinetic properties.
2Reliability
If CAR-T cell therapy is applied to target CD20, then therapeutic potential is improved, but adverse effects such as cytokine release syndrome and on-target off-tumor toxicity increase
Solution Approach 1:
The patent introduces a single domain antibody as an intermediary binding component in the CAR structure. This sdAb mediator provides more stable and specific antigen recognition compared to conventional scFv, thereby improving CAR-T cell efficacy while potentially reducing off-target effects through enhanced binding precision and stability.
Solution Approach 2:
The patent changes the binding domain parameter in CAR-T cells from conventional scFv to single domain antibody (sdAb). This parameter change improves the stability and specificity of antigen binding, leading to enhanced therapeutic efficacy and reduced adverse effects by preventing unnecessary activation against off-target cells.
3Measurement precision
If single domain antibodies are designed with specific CDR sequences, then binding specificity is improved, but molecular complexity increases
Solution Approach 1:
The patent applies local quality by concentrating all antigen-binding specificity into the three CDR regions of the single domain antibody, while the framework regions use standardized or simplified sequences. This allows high binding specificity to be achieved through localized optimization of CDR sequences without requiring complex changes throughout the entire molecular structure.
Data Source
AI summary
The present disclosure provides single domain antibodies that bind to CD20, and chimeric antigen receptors comprising same. Further provided are engineered immune effector cells (such as T cells) comprising the chimeric antigen receptors. Pharmaceutical compositions, kits and methods of treating a disease or disorder are also provided.