Monovalent Antibody Hinge Engineering for Plasma Residence
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Solution Overview
Problem
Current therapeutic antibodies, particularly Fab fragments, exhibit inferior pharmacokinetics due to their small size and inability to interact with FcRn, leading to rapid clearance and instability in vivo, making them unsuitable for long-term therapeutic applications where monovalent binding is required without cross-linking effects.
Innovation Solution
Development of a monovalent antibody comprising a light chain with a variable region and a modified heavy chain from human IgG4, devoid of cysteine residues in the hinge region, which maintains stability and allows for specific antigen binding without forming heterotetramers, thereby preventing cross-linking and enhancing plasma residence time.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If Fab fragments are used for monovalent antigen binding, then cross-linking effects are avoided, but pharmacokinetics deteriorate due to rapid clearance and short plasma residence time
Solution Approach 1:
The patent creates a composite antibody structure by fusing Fc regions from different immunoglobulin classes (e.g., IgG1 Fc with IgG4 hinge region) to generate hybrid Fc domains that combine properties of both parent molecules. This composite structure enables monovalent binding capability while maintaining extended plasma residence time through FcRn interaction.
Solution Approach 2:
The invention modifies specific local regions of the antibody molecule, particularly the hinge region and Fc domain, while preserving the overall antibody structure. By engineering cysteine residues in the hinge region and modifying Fc domain characteristics, the patent achieves monovalent binding with improved pharmacokinetics without altering the antigen-binding variable regions.
2Stability of the object's composition
If full-length antibodies are used for therapeutic applications, then stability and plasma residence time are improved, but cross-linking effects occur leading to unwanted immune complex formation
Solution Approach 1:
The patent extracts and removes the capability for cross-linking by engineering the antibody to exist primarily as monovalent binding units. Through modifications to the hinge region and Fc domain structure, the invention prevents dimerization while retaining the Fc region for stable plasma circulation and FcRn interaction.
Solution Approach 2:
The invention changes key structural parameters of the antibody, specifically modifying the hinge region cysteine residues and Fc domain configuration, to alter the valency from bivalent to monovalent. These parameter changes prevent cross-linking while maintaining stability and plasma residence time through controlled FcRn binding.
3Object-generated harmful factors
If dimeric monovalent antibodies (Fab/c) are used, then monovalent binding is achieved, but structural complexity increases and stability is compromised
Solution Approach 1:
The patent merges the Fc regions of different immunoglobulin classes into hybrid Fc domains that can function as monovalent units. By combining IgG1 Fc with IgG4 hinge region characteristics, the invention creates a simplified single-unit structure that achieves monovalent binding without the complexity of dimeric constructions.
Data Source
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AI summary
The present invention provides monovalent antibodies with a long half-life when administered in vivo, methods of making such monovalent antibodies, pharmaceutical compositions comprising such antibodies, and uses of the monovalent antibodies.