Trispecific Antibody Architecture for BCMA Yield and Low Aggregation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing trispecific antibodies targeting BCMA, GPRC5D, and CD3 face issues such as low purification yield, high aggregation, low antigen affinity, poor spatial positioning, and weak BCMA-mediated tumor cell killing, along with potential non-specific T cell activation and toxicity.
Innovation Solution
A trispecific antibody with specific antigen-binding regions, including an Fab region for BCMA at the N-terminus and Fab regions for CD3 and GPRC5D, optimized through charge mutations and disulfide bond modifications to enhance affinity, reduce aggregation, and improve druggability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the BCMA antigen-binding region is designed as scFv at the C-terminus of Fc, then the antibody can bind to BCMA, but the purification yield is low and aggregation is high
Solution Approach 1:
The patent inverts the conventional position of the BCMA antigen-binding region from the C-terminus of Fc to the N-terminus of Fc. This structural inversion resolves the contradiction by improving purification yield and reducing aggregation while maintaining BCMA binding capability, as the N-terminal position provides better stability and lower aggregation propensity for the scFv domain.
Solution Approach 2:
The patent modifies the molecular structure parameters by changing the position of the BCMA antigen-binding region and optimizing the linker length and composition. These parameter changes improve the physical-chemical properties of the antibody, resulting in reduced aggregation and improved purification yield while preserving the biological function of BCMA binding.
2Reliability
If the BCMA antigen-binding region is designed as scFv at the C-terminus of Fc, then the antibody can bind to BCMA, but the affinity for antigen is low and spatial position is poor
Solution Approach 1:
The patent inverts the position of the BCMA antigen-binding region from C-terminus to N-terminus of Fc, which improves the spatial positioning and antigen affinity. The N-terminal position allows for better orientation and access to the BCMA antigen on the tumor cell surface, enhancing the binding affinity and therapeutic effectiveness.
3Reliability
If the BCMA antigen-binding region includes hotspot sites, then the antibody can bind to BCMA, but the druggability is poor
Solution Approach 1:
The patent extracts or avoids the problematic hotspot sites in the BCMA antigen-binding region that are associated with poor druggability. By redesigning the antigen-binding region to exclude these sites while maintaining binding capability through alternative epitope recognition, the patent improves the druggability and developability of the antibody.
4Reliability
If trispecific antibodies are used to recruit immune cells to tumor sites, then the efficacy of treatment is improved, but the complexity of the antibody structure increases
Solution Approach 1:
The patent combines multiple functional domains (anti-BCMA, anti-GPRC5D, and anti-CD3) into a single trispecific antibody molecule. This merging approach enables the antibody to simultaneously target multiple antigens and recruit immune cells to tumor sites, improving treatment efficacy while maintaining a manageable structural complexity through rational molecular design.
Solution Approach 2:
The patent creates a multi-functional antibody that can bind to three different antigens (BCMA, GPRC5D, and CD3) and perform multiple functions including tumor cell targeting, immune cell recruitment, and enhanced therapeutic efficacy. This universality allows a single molecule to achieve complex therapeutic goals that would otherwise require multiple separate agents.
Data Source
Figure 1A
Figure 1B
Figure 1C
AI summary
The present invention relates to a trispecific antigen-binding protein, and particularly to a trispecific antibody specifically binding to two tumor antigens of GPRC5D and BCMA and a T-cell surface antigen CD3, a pharmaceutical composition comprising the same, a preparation method therefor, and use thereof.