Tetrahedral Antibody Multivalent Binding via Non-Peptidyl Linkages
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Solution Overview
Problem
Conventional antibody engineering struggles to simultaneously engage multiple targets due to the planar configuration of binding domains, which limits the ability of engineered antibodies and antibody-like molecules to interact with multiple antigens effectively.
Innovation Solution
Development of tetrahedral antibodies with a unique domain arrangement, including covalent and non-covalent linkages between Fab and Fc domains, allowing for a tetrahedral structure that enables engagement of multiple targets through specific domain combinations and linkages.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a planar configuration of binding domains is used in engineered antibodies, then the antibody structure maintains simplicity and ease of manufacture, but the ability to simultaneously engage multiple targets is limited
Solution Approach 1:
The patent transitions from a traditional planar (2D) antibody configuration to a tetrahedral (3D) structure. The binding domains are arranged in three-dimensional space with specific spatial coordinates, allowing simultaneous engagement of multiple targets at different spatial locations. The hinge region connects binding domains at angles that enable tetrahedral geometry, fundamentally changing the dimensional arrangement from flat to volumetric.
Solution Approach 2:
The antibody is divided into distinct modular components: separate binding domains (Fab regions) connected through a hinge region to an effector domain (Fc region). Each binding domain can independently engage different targets, and the modular tetrahedral structure allows these segments to be positioned optimally in 3D space for multivalent binding.
2Adaptability or versatility
If a tetrahedral structure with multiple binding domains is implemented, then the ability to bind multiple antigens is enhanced, but the manufacturing and engineering complexity increases
Solution Approach 1:
The tetrahedral antibody structure serves multiple functions simultaneously: it provides multivalent binding to different antigens, maintains structural stability through the hinge region, and enables diverse applications (viral neutralization, bispecific binding, multimeric complex formation). The same structural framework supports various configurations of binding domains to achieve different functional outcomes.
Solution Approach 2:
The patent modifies key structural parameters of the antibody: the hinge region length and flexibility are adjusted to achieve specific inter-domain angles; the spatial coordinates of binding domains are optimized for tetrahedral geometry; the valency (number of binding sites) is increased from typical bivalent to tetravalent or higher configurations.
Data Source
AI summary
This invention provides a tetrahedral antibody comprising a first, second, third, and fourth domain, wherein each of the first and second domains are selected from the group consisting of a Fab domain and an Fc domain, wherein each of the first and second domains comprise a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain, and wherein the first domain and the second domain are joined to each other by a non-peptidyl linkage between the first N-terminus of the first domain and the first N-terminus of the second domain, between first C-terminus of the first domain and the first C-terminus of the second domain, between the first N-terminus of the first domain and the first C-terminus of the second domain, or between the first C-terminus of the first domain and the first N-terminus of the second domain.