Split Antibodies for Targeted Radionuclide Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current pre-targeted radioimmunotherapy methods require a clearing or blocking agent to manage the timing and dosage of radiolabeled compounds, which can introduce adverse effects and complicate the process, and existing bispecific antibodies face challenges in development and stability.
Innovation Solution
Development of 'split antibodies' comprising a first antibody with a VH domain for a radiolabeled compound and a second antibody with a VL domain, which associate to form a functional antigen binding site only when bound to target cells, eliminating the need for a clearing agent and enhancing stability with an Fc domain for prolonged circulation and increased tumor uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a clearing or blocking agent is used in pre-targeted radioimmunotherapy, then the timing and dosage of radiolabeled compounds can be managed, but adverse effects are introduced and the process is complicated
Solution Approach 1:
The patent divides the bispecific antibody into two separate single-domain antibodies (sdAbs), each binding to a different antigen. This segmentation eliminates the need for clearing agents by allowing the radiolabeled sdAb to bind directly to its target antigen without interference from the other antigen-binding site, thus resolving the technical contradiction by removing the harmful clearing phase while maintaining reliable timing control
Solution Approach 2:
The patent extracts the two antigen-binding sites from a single bispecific antibody and places them in separate single-domain antibodies. This extraction eliminates the steric hindrance and binding interference that would require clearing agents, allowing direct administration of radiolabeled compounds without the complicating clearing phase, thereby reducing adverse effects while maintaining dosage control
2Reliability
If a clearing or blocking agent is used in pre-targeted radioimmunotherapy, then the timing and dosage of radiolabeled compounds can be managed, but the process is complicated
Solution Approach 1:
The patent segments the bispecific antibody into two separate single-domain antibodies, eliminating the need for clearing or blocking agents. This simplifies the treatment protocol from multiple steps (administration, clearing phase, radiolabeling) to a more straightforward process, reducing procedural complexity while maintaining reliable timing and dosage control through the inherent specificity of the separated binding sites
Solution Approach 2:
By extracting the two antigen-binding functions into separate sdAbs, the patent eliminates the need for complex clearing phases and blocking agent administrations. The process complexity is reduced by removing these intermediate steps, while timing and dosage reliability is maintained through the direct binding kinetics of the separated antibody domains
3Reliability
If bispecific antibodies are used to bind to target cells and effector moieties, then targeted therapy is achieved, but development is not trivial and stability challenges arise
Solution Approach 1:
The patent segments the complex bispecific antibody into two simpler single-domain antibodies, each with a single antigen-binding site. This segmentation simplifies the development and manufacturing process while maintaining targeted therapy reliability, as each sdAb can be independently characterized and produced with well-defined binding kinetics to its specific antigen
Solution Approach 2:
The patent extracts the two antigen-binding sites from a single bispecific antibody construct and places them in separate sdAbs. This extraction simplifies development by allowing independent optimization of each binding site, improves manufacturing by eliminating the complexity of producing stable bispecific antibodies, and maintains targeted therapy through the specific binding of each sdAb to its respective antigen
4Duration of action of moving object
If split antibodies with Fc domains are used, then circulation time is prolonged and tumor uptake is increased, but the antibodies must maintain stability
Solution Approach 1:
The patent merges the antigen-binding function of single-domain antibodies with the Fc domain of immunoglobulins. This combination provides the benefits of both: the sdAb portion ensures specific target binding with rapid clearance of unbound antibody, while the Fc domain prolongs circulation half-life through reduced renal clearance and FcRn recycling, thereby achieving both extended duration of action and maintained stability
Solution Approach 2:
The patent creates a composite antibody structure combining single-domain antibody variable regions with Fc constant regions. This composite design integrates the rapid target binding kinetics of sdAbs with the prolonged circulation properties of Fc domains, achieving both extended duration of action and structural stability through the synergistic combination of these two functional elements
Data Source
AI summary
The present invention relates to a set of antibodies which bind to antigens on target cells and which target radionuclides to said cells, and to methods of using the same. The antibodies each comprising a Fab binding to the target antigen fused at the C-terminus of the VH to the N-terminus of the Fc and a VH or VL binding to a radiolabelled compound. The VH or VL are fused at the C-terminus to the N-terminus of the Fc. VH and VL form an antigen binding site when the antibody binds via the scFv to the target antigen.