Stable Multi-Antigen Antibody via Variable Domain Substitutions
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Solution Overview
Problem
Multi-specific and multivalent antibodies face challenges with stability, production yield, and purity, limiting their effectiveness as therapeutic agents for diseases involving multiple proteins.
Innovation Solution
Development of antibodies with specific amino acid residues at particular positions in variable domains, such as Serine at AHo position 12 and Arginine at AHo position 50, to enhance stability and binding capabilities, forming VH/VL constructs that lack constant domains and utilize peptide linkers for antigen binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If multi-specific and multivalent antibodies are developed to target multiple antigens, then therapeutic effectiveness for diseases involving multiple proteins is improved, but stability and production yield deteriorate
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions at defined positions in the variable domains of antibody fragments. These substitutions (such as Serine at AHo position 12 and Arginine at AHo position 50) modify the physical-chemical parameters of the antibody structure, enhancing stability while preserving multi-antigen binding capability. This resolves the contradiction by changing molecular parameters to simultaneously achieve versatility and reliability.
Solution Approach 2:
The patent creates composite antibody structures by combining variable domains from different antibodies into single-chain variable fragments (scFv) with specific amino acid compositions. These composite structures integrate multiple binding specificities while incorporating stabilizing amino acid residues, thereby achieving both multi-antigen binding capability and enhanced stability in a unified molecular architecture.
2Adaptability or versatility
If multi-specific and multivalent antibodies are developed to target multiple antigens, then therapeutic effectiveness for diseases involving multiple proteins is improved, but production yield and purity deteriorate
Solution Approach 1:
The patent improves production yield and purity by modifying amino acid parameters at critical positions in the variable domains. These substitutions (such as Serine at AHo position 12 and Arginine at AHo position 50) optimize the physical-chemical properties of the antibody fragments, enhancing their expressibility and reducing aggregation during production, thereby resolving the contradiction between multi-antigen binding capability and manufacturing efficiency.
3Adaptability or versatility
If traditional multi-specific and multivalent antibody formats are used, then binding to multiple antigens is achieved, but stability and solubility are poor
Solution Approach 1:
The patent resolves the stability and solubility issues by introducing specific amino acid substitutions at defined positions in the variable domains. These parameter changes (such as Serine at AHo position 12, Threonine at AHo position 103, and Arginine at AHo position 50) modify the molecular properties to enhance stability and solubility while preserving the ability to bind multiple antigens.
Solution Approach 2:
The patent uses peptide linkers as intermediary elements to connect variable domains in a controlled manner. These linkers mediate the interaction between different variable domains while maintaining appropriate spacing and orientation, thereby improving overall molecular stability and solubility without compromising multi-antigen binding capability.
Data Source
AI summary
The invention provides antibodies that bind to multiple antigens, said antibodies having at least two antibody light chain variable domains and two antibody heavy chain variable domains, wherein each light chain variable domain is linked to a heavy chain variable domain to form a VH/VL construct, and wherein at least one of the VH domains comprises a particular amino acid at AHo position 12, 103 and/or 144, and at least one of the VL domains comprises a particular amino acid at AHo position 47 and/or 50. Nucleic acid molecules, vectors and host cells for expression of the recombinant antibodies of the invention, methods for isolating them, and the use of said antibodies in medicine are also disclosed.