Non-Native Fab Configurations for Multi-Epitope Antigen 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, necessitating an improved platform for enhanced affinity and avidity.
Innovation Solution
Development of antigen binding molecules (ABMs) with at least two Fab domains in non-native configurations, allowing for enhanced binding capabilities through alternative geometries, including Fc domain association and optional spacer domains to increase flexibility and affinity.
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 portion, and multiple Fab domains are connected through Fc domains to form a multi-epitope recognition structure. This segmentation allows each Fab domain to target different epitopes while maintaining overall structural organization.
Solution Approach 2:
The patent employs a nested structure where Fab domains are positioned within a framework of Fc domains. The Fc domains serve as structural scaffolds that hold the Fab domains in specific spatial arrangements, enabling simultaneous access to multiple epitopes on the target molecule while maintaining a compact overall structure.
2Reliability
If conventional antibody formats are used, then the geometry is fixed and simple, but the affinity and avidity for small target molecules or closely spaced epitopes is insufficient
Solution Approach 1:
The patent introduces flexible linkers between the Fc and Fab domains, allowing the Fab domains to dynamically adjust their positions and orientations. This dynamic flexibility enables the antibody to adapt its binding geometry to accommodate small target molecules or epitopes in close proximity, thereby enhancing affinity and avidity through optimal spatial arrangement.
Solution Approach 2:
The patent modifies structural parameters such as linker lengths, Fc domain configurations, and Fab domain orientations to optimize binding geometry. By varying these parameters, the antibody can achieve different spatial arrangements that maximize complementarity to the target antigen, thereby improving binding affinity and avidity for challenging targets.
3Reliability
If alternative antibody-antigen binding geometries are implemented, then affinity and avidity are improved, but the structural complexity increases
Solution Approach 1:
The patent employs universal Fc domains that can serve multiple functions: providing structural support, enabling dimerization, and positioning Fab domains in various configurations. This multi-functionality allows the same Fc domain architecture to support different Fab domain arrangements, thereby achieving enhanced binding affinity through alternative geometries without proportionally increasing overall structural complexity.
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.