Non-Native Fab Configurations for Multi-Epitope Binding
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Solution Overview
Problem
Conventional antibody formats limit the ability to recognize multiple epitopes on a single target molecule, particularly when the target is small or epitopes are in close proximity, restricting affinity and avidity.
Innovation Solution
Development of antigen binding molecules (ABMs) with non-native configurations, comprising at least two Fab domains and Fc domains, allowing for enhanced binding capabilities through alternative geometries.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional antibody formats are used, then the structure is simple and well-understood, but the ability to recognize multiple epitopes on a single target molecule is limited
Solution Approach 1:
The antibody is divided into separate Fab domains that can be independently configured. Each Fab domain contains the antigen-binding variable regions, while the Fc domain provides structural support. This segmentation allows the Fab domains to be arranged in non-native configurations to access multiple epitopes on small target molecules.
Solution Approach 2:
The patent introduces non-native spatial arrangements of Fab domains beyond the conventional IgG geometry. By altering the dimensional configuration of the antibody arms and their relative orientations, the molecule can simultaneously reach multiple epitopes on compact target structures that are inaccessible to conventional linear antibody formats.
2Reliability
If conventional antibody geometry is used, then manufacturing is straightforward, but affinity and avidity for small target molecules are restricted
Solution Approach 1:
The patent modifies key geometric parameters of the antibody structure, including the length and orientation of the hinge region, the angle between Fab domains, and the distance from the Fc domain to the antigen-binding sites. These parameter changes optimize the antibody's ability to bind small target molecules with high affinity and avidity while maintaining manufacturability.
3Adaptability or versatility
If non-native Fab domain configurations are implemented, then multiple epitopes can be accessed, but the structural complexity increases
Solution Approach 1:
The Fc domain serves multiple functions: it provides a stable dimerization interface, maintains proper spacing between Fab domains, and enables non-native configurations without requiring separate engineering for each functional aspect. This multi-functionality simplifies manufacturing by using a universal scaffold that accommodates various epitope-recognition geometries.
Data Source
AI summary
Antigen binding molecules (ABMs) comprising Fab domains in non-native configurations, ABM conjugates comprising the ABMs and cytotoxic or cytostatic agents, pharmaceutical compositions containing the ABMs and ABM conjugates, methods of using the ABMs, ABM conjugates and pharmaceutical compositions for treating cancer, nucleic acids encoding the ABMs, cells engineered to express the ABMs, and methods of producing ABMs.