Modified Bispecific Antibodies With Disulfide-Guided Chain Pairing
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Solution Overview
Problem
The production of bispecific or multi-specific antibodies is challenging due to the inability to control the correct pairing between light and heavy chains, leading to misassembled species and reduced antigen specificity.
Innovation Solution
Modified antibodies with specific amino acid residue substitutions at selected positions in the heavy and light chains to form new disulfide bonds, along with modifications in the Fc region to facilitate heterodimerization, ensuring accurate pairing and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If additional antibody specificities are introduced into a single antibody, then bispecific or multi-specific antibodies can be produced, but misassembled species are generated and antigen specificity is reduced
Solution Approach 1:
The patent applies local quality by introducing cysteine residues at specific localized positions (126, 128, 129, 136, 141, 168, 170, 173, 175, or 187 in heavy chain; 114, 116, 118, 124, 135, 137, 138, 160, 162, or 164 in light chain) to form disulfide bonds that control pairing. This localized modification ensures correct heavy-light chain pairing while maintaining other antibody regions' integrity, thus resolving the contradiction between achieving multiple specificities and maintaining pairing accuracy.
2Ease of manufacture
If conventional antibody production methods are used, then production processes are simple, but assembly accuracy is poor and misassembled species occur
Solution Approach 1:
The patent employs self-service by designing the antibody chains to self-assemble correctly through engineered disulfide bonds. The cysteine residues at specified positions automatically form the correct interchain disulfide bonds during protein folding, eliminating the need for complex external control mechanisms. This maintains production simplicity while dramatically improving assembly accuracy and reducing misassembled species.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enhances assembly accuracy and stability of polypeptide chains, allowing for the production of bispecific or multi-specific antibodies with improved specificity and functionality.
Implementation Method 1
at least one non-cysteine residue on the first heavy chain is substituted with cysteine, wherein the non-cysteine residue is at a position selected from the group consisting of amino acid positions 126, 128, 129, 136, 141, 168, 170, 173, 175 or 187 of the first heavy chain; and at least one non-cysteine residue on the first light chain is substituted with cysteine, wherein the non-cysteine residue is at a position selected from the group consisting of amino acid positions 114, 116, 118, 124, 135, 137, 138, 160, 162 or 164 of the first light chain
Data Source
AI summary
Provided are modified antibodies, the preparing method and the uses thereof. In particular, the modified antibodies are bi-specific antibodies or multi-specific antibodies. The heavy chains and light chains of the modified antibodies are paired with high assembly accuracy and stability.