BCMA-Binding Single Variable Domains for Specific APRIL Blocking
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Solution Overview
Problem
Current immunotherapeutic agents targeting BCMA for multiple myeloma are limited, and there is a need for more effective options, particularly those utilizing single variable domain antibodies that can specifically bind to BCMA with high affinity and specificity, while avoiding cross-reactivity with other TNFR family members.
Innovation Solution
Development of BCMA-binding single variable domains, such as VHHs, with specific CDR sequences (SEQ ID NOs: 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20) that exhibit high affinity and specificity for BCMA, blocking APRIL binding and minimizing interaction with BAFFR and TACI, along with methods for constructing antigen-binding molecules and compositions for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional IgG1 antibodies of a four-chain structure are used, then the antibody can bind to BCMA, but the antibody structure is complex and has limited tissue permeability
Solution Approach 1:
The patent segments the conventional four-chain antibody structure into a single variable domain (VHH) that retains BCMA binding capability. This single-domain structure eliminates the complexity of light chains and heavy chains while maintaining the essential antigen-binding function, directly resolving the contradiction between binding reliability and structural complexity
Solution Approach 2:
The patent extracts the critical variable domain (VHH) from the complete four-chain antibody structure. By taking out only the essential antigen-binding portion and removing the cumbersome constant regions and light chains, the invention achieves simplified structure while preserving BCMA binding affinity, thus resolving the structural complexity issue
2Reliability
If conventional antibodies are used, then BCMA targeting is achieved, but specificity is limited due to potential binding to TACI or BAFFR
Solution Approach 1:
The patent applies local quality by designing the VHH domain with specific CDR3 loop characteristics that are locally optimized for BCMA epitope recognition. The unique CDR3 sequence (e.g., SEQ ID NO: 9, 12, or 15) creates a binding interface that is highly specific to BCMA's unique structural features, preventing cross-reactivity with TACI or BAFFR while maintaining strong BCMA binding
3Adaptability or versatility
If existing BCMA-targeting antibodies are developed, then therapeutic options are provided, but the options are still limited in availability and effectiveness
Solution Approach 1:
The patent creates a universal VHH platform that can be adapted for multiple therapeutic applications against BCMA. The single-domain format allows easy construction of bispecific antibodies, antibody-drug conjugates, and other engineered formats, providing versatile therapeutic options while maintaining high BCMA binding affinity and clinical effectiveness
Data Source
AI summary
A BCMA-binding immunoglobulin single variable structural domain and an antigen-binding molecule including an immunoglobulin single variable structural domain and an antigen-binding molecule, a nucleic acid encoding the above, a vector containing the nucleic acid, a cell containing the vector, and a pharmaceutical composition containing the above, as well as a therapeutic use thereof.