Single-Domain CTLA4 Antibody for Stronger Immune Checkpoint Blockade
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Solution Overview
Problem
Current CTLA4-targeting antibodies, such as Ipilimumab and Tremelimumab, have limited clinical efficacy in treating tumors due to their traditional IgG structure, necessitating the development of novel antibodies with higher affinity and specificity for CTLA4 to enhance anti-tumor immune responses.
Innovation Solution
Development of a single domain antibody with specific CDR regions (SEQ ID NO: 1, 2, and 3) and human immunoglobulin FC regions (SEQ ID NO: 11, 14, 15, 16, 17) that bind to CTLA4 with high affinity, blocking its interaction with CD86 or CD80, enhancing PBMC and T cell activation, and inhibiting tumor growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional IgG antibodies (Ipilimumab and Tremelimumab) are used to target CTLA4, then the antibody structure is stable and complete, but the clinical efficacy is limited and not outstanding
Solution Approach 1:
The patent divides the traditional IgG antibody structure into separate functional domains. Specifically, it isolates the variable domain (VH or VL) that binds to CTLA4 from the constant region, creating a single-domain antibody fragment. This segmentation allows the binding function to be optimized independently, resulting in higher affinity and specificity for CTLA4 while reducing structural complexity compared to full IgG antibodies.
2Device complexity
If single domain antibodies are developed to reduce structural complexity, then the antibody size is reduced and manufacturing is simplified, but the binding affinity and specificity to CTLA4 needs to be enhanced
Solution Approach 1:
The patent applies local quality by optimizing the complementarity-determining regions (CDRs) within the single-domain antibody structure. Specifically, it designs and selects CDR sequences (CDR1, CDR2, CDR3) with specific amino acid compositions and spatial arrangements that maximize binding affinity and specificity for CTLA4. This localized optimization of the binding interface compensates for the reduced overall structure size, ensuring high precision binding despite the simplified antibody architecture.
3Productivity
If traditional CTLA4 antibodies are used, then the immunosuppressive signal is reduced, but the activation of T cells and inhibition of tumor growth is insufficient
Solution Approach 1:
The patent employs parameter changes by modifying the binding parameters of the antibody to CTLA4. The single-domain antibody is engineered with enhanced binding affinity (lower KD value) and optimized epitope recognition compared to traditional IgG antibodies. This parameter optimization allows the antibody to more effectively block the CTLA4-B7 interaction, thereby more potently reversing immunosuppression and activating T cells to inhibit tumor growth.
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 single domain antibodies demonstrate enhanced binding to CTLA4, activating immune cells and inhibiting tumor growth, with improved stability and ADCC activity, offering a more effective treatment approach for cancer and infectious diseases.
Implementation Method 1
an antibody that specifically binds to human CTLA4, comprising three complementarity-determining regions; the three complementarity-determining regions are respectively: CDR1 with an amino acid sequence as shown in SEQ ID NO: 1, CDR2 with an amino acid sequence as shown in SEQ ID NO: 2, and CDR3 with an amino acid sequence as shown in SEQ ID NO: 3
Data Source
AI summary
The present invention discloses an antibody that specifically binds to human CTLA4, comprising three complementarily-determining regions; the three complementarity-determining regions are respectively: CDR1 with an amino acid sequence as shown in SEQ ID NO: 1, CDR2 with an amino acid sequence as shown in SEQ ID NO: 2, and CDR3 with an amino acid sequence as shown in SEQ ID NO: 3. Also disclosed are medicaments and kits comprising the antibodies described above. The antibodies of the present invention exhibit, but are not limited to, the following properties: (1) high affinity and specificity with human CTLA4; (2) able to block the interaction of CTLA4 with CD86 or CD80; (3) able to specifically bind to CTLA4 overexpressing cells; (4) enhancing activation of PBMC and/or T cells; (5) inhibiting tumor growth.