IgG4 Bispecific Antibody Disulfide Bond Engineering
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Solution Overview
Problem
IgG4 antibodies face challenges due to their shorter serum half-life and propensity for 'Fab-arm exchange', leading to bispecific antibodies that are functionally monovalent and unstable, which complicates their use as therapeutic agents.
Innovation Solution
A symmetric bispecific antibody with altered disulphide bonds, specifically substituting cysteine residues in the CH1 domain and the hinge region, enhances stability and reduces heavy chain exchange, allowing for the formation of stable bispecific antibodies with improved thermal stability and reduced half-molecule formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If IgG4 antibodies are used as therapeutic agents, then effector function induction is reduced, but serum half-life is shorter and Fab-arm exchange occurs
Solution Approach 1:
The patent applies parameter changes by modifying the disulphide bond configuration in the IgG4 antibody structure. Specifically, it alters the arrangement of disulphide bonds between heavy and light chains to create a stable bispecific format that prevents Fab-arm exchange while maintaining reduced effector function induction. This structural parameter modification resolves the contradiction by enabling longer serum half-life through stable bispecific formation without increasing effector function activation.
2Adaptability or versatility
If Fab-arm exchange occurs in IgG4 antibodies, then bispecific antibodies are formed, but they become functionally monovalent and unstable
Solution Approach 1:
The patent employs asymmetry by creating an asymmetric disulphide bond arrangement in the IgG4 bispecific antibody. The modified configuration features disulphide bonds connecting heavy chains to light chains in a non-symmetric pattern that prevents exchange between arms. This asymmetric structure enables stable bispecific formation while maintaining full bivalent functionality, resolving the contradiction between adaptability and stability.
Solution Approach 2:
The patent applies inversion by reversing the typical IgG4 disulphide bond arrangement. Instead of the conventional configuration that allows Fab-arm exchange, the patent inverts the bond connectivity to create inter-chain disulphide bonds that lock the heavy and light chains together in a stable configuration. This inverted structure prevents exchange while maintaining bispecific capability and full valency.
3Reliability
If disulphide bonds are altered in IgG4 antibodies, then heavy chain exchange is reduced, but production complexity increases
Solution Approach 1:
The patent uses parameter changes by modifying specific disulphide bond parameters in the IgG4 sequence. The alteration involves changing the cysteine residue positions or bonding patterns in a controlled manner that reduces heavy chain exchange. This targeted parameter modification achieves improved reliability while maintaining relatively simple production processes, as the core antibody structure and expression systems remain unchanged.
Data Source
AI summary
The present disclosure relates to a symmetric bispecific antibody of the class IgG4 comprising two heavy chains which each comprise a variable domain, CH1 domain and a hinge region, wherein in each heavy chain:the cysteine in the CH1 domain which forms an inter-chain disulphide bond with a cysteine in a light chain is substituted with another amino acid; andoptionally one or more of the amino acids positioned in the upper hinge region is substituted with cysteine, wherein the constant region sequence of each heavy chain is similar or identical and the variable region in each heavy chain is different, formulations comprising the same, the use of each of the above in treatment and processes for preparing said antibodies and formulations.