Antigen Binding Molecule Formats for Small-Target Multi-Epitope Binding
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Solution Overview
Problem
Conventional antibody formats are limited in their ability to recognize multiple epitopes on a single target molecule, particularly when the target is small or when epitopes are in close proximity, limiting affinity and avidity.
Innovation Solution
Development of antigen binding molecules (ABMs) with at least two Fab domains in a non-native configuration, comprising half antibodies linked through their Fc domains, allowing for enhanced binding to target molecules with greater affinity and/or avidity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional antibody formats are used, then the structure is simple and well-characterized, 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 to bind different epitopes. The patent describes antibody formats where Fab domains are separated and can be arranged in non-native configurations, allowing each domain to independently recognize different epitopes on the target molecule while maintaining overall structural organization through the Fc region.
Solution Approach 2:
The patent introduces non-native configurations of Fab domains that extend beyond the conventional antibody geometry. By arranging Fab domains in spatial configurations not found in natural antibodies (such as side-by-side or extended orientations rather than the typical Y-shape), the molecule gains enhanced ability to access multiple epitopes on small or closely-spaced targets.
2Reliability
If conventional antibody geometry is used, then manufacturing is straightforward, but affinity and avidity for small targets or closely-spaced epitopes are limited
Solution Approach 1:
The patent employs flexible linkers and hinge regions that allow the Fab domains to dynamically adjust their positions and orientations. This dynamic flexibility enables the antibody to adapt its configuration to optimize binding to small targets or to simultaneously engage multiple epitopes that are closely spaced, thereby enhancing both affinity and avidity without requiring a completely rigid complex structure.
3Adaptability or versatility
If Fab domains are arranged in non-native configuration, then multiple epitopes can be recognized, but the structural characterization becomes more difficult
Solution Approach 1:
The patent incorporates stable Fc regions that serve as a rigid structural foundation before the more flexible Fab domains are configured. This pre-established stable core provides a reference framework that simplifies structural characterization, as the Fc region maintains consistent geometry while the Fab domains adopt their non-native configurations for multi-epitope binding.
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.