Split Antibody Architecture for Targeted Radioimmunotherapy
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Solution Overview
Problem
Current bispecific antibody formats for pre-targeted radioimmunotherapy face challenges such as off-target association and the need for a clearing agent to manage radiation exposure, which can introduce adverse effects and complicate the timing and dosage of treatment.
Innovation Solution
Development of novel 'split domain' bi-specific antibodies where the VH and VL domains for the effector moiety are split between two antibodies, forming a functional antigen binding site only when associated, reducing off-target association and eliminating the need for a clearing agent.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional bispecific antibody formats are used for pre-targeted radioimmunotherapy, then the antibody can bind to both target cell antigen and effector moiety, but off-target association occurs and clearing agents are required to manage radiation exposure
Solution Approach 1:
The patent divides the antigen binding site into separate VH and VL domains that are distributed across different antibody molecules. The VH domain is incorporated into one antibody while the VL domain is incorporated into another antibody, so that a complete functional binding site is only formed when both antibodies are present at the target cell surface. This segmentation prevents off-target association because incomplete binding sites cannot bind the effector moiety in circulation.
Solution Approach 2:
The patent uses the target cell membrane as an intermediary platform that brings the separated VH-containing antibody and VL-containing antibody into proximity. The cell membrane serves as the organizing structure that enables the separated domains to associate and form functional binding sites only at the intended target location, rather than allowing random association in circulation.
2Object-affected harmful factors
If clearing agents are used to manage radiation exposure in pre-targeted radioimmunotherapy, then radiation exposure to healthy tissues is reduced, but the treatment timing and dosage become more complex and adverse effects may occur
Solution Approach 1:
The patent extracts and removes the need for clearing agents from the treatment protocol by using the split domain architecture. The design inherently prevents off-target binding without requiring additional clearing steps, thereby simplifying the treatment protocol while still protecting healthy tissues from radiation exposure.
Solution Approach 2:
The split antibody system is self-regulating in that it automatically prevents off-target association through its structural design. The separated VH and VL domains cannot form functional binding sites in circulation, so no external clearing agent is needed to prevent off-target effects. The system serves itself by design rather than requiring additional intervention steps.
3Reliability
If the VH and VL domains for the effector moiety are split between two antibodies, then off-target association is reduced and clearing agents are eliminated, but the antibody structure becomes more complex
Solution Approach 1:
The patent applies segmentation by dividing the antigen binding site into separate VH and VL domains that are distributed across different antibody molecules. Each antibody molecule contains only a partial binding site (either VH or VL), which cannot function independently. This segmentation achieves high tumor specificity while the modular nature of the separation makes the complexity manageable through standardized domain structures.
Data Source
AI summary
The present invention relates to antibodies which bind to antigens on target cells and which target effector moieties to said cells, and to methods of using the same.