Kappa/Lambda Fab-Fab Structure for Bispecific Antibody Pairing
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Solution Overview
Problem
Current methods for developing bispecific antibodies face challenges in achieving functional molecules with correct chain combinations, particularly in IgG-like structures, leading to issues such as chain-mismatching, instability, and reduced serum half-life, which complicates production and limits application scenarios.
Innovation Solution
A 'κ/λ' Fab-Fab structure is designed for bispecific antibodies, maintaining the Fab structure without introducing scFv, allowing high spatial freedom for antigen-binding, and enabling efficient purification and scalability, with optional linker peptides and a half-life extension module.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If IgG-like antibody structures containing Fc are used for bispecific antibodies, then the serum half-life is extended through FcRn binding, but chain-mismatching problems occur due to the complexity of combining two different heavy chains and two different light chains
Solution Approach 1:
The patent divides the antibody structure into separate Fab and Fc components. The Fab regions containing the antigen-binding sites are designed as independent modules that can be systematically combined with Fc regions, reducing the complexity of chain pairing and minimizing chain-mismatching issues while preserving Fc-mediated half-life extension.
Solution Approach 2:
The patent introduces a hinge region as an intermediary component that connects the Fab and Fc regions. This hinge region serves as a standardized interface that facilitates proper assembly of the antibody chains and ensures correct pairing between heavy and light chains, thereby improving reliability in chain combination.
2Reliability
If antibody fragment structures without Fc are used for bispecific antibodies, then chain-mismatching is reduced by simplifying the structure, but the serum half-life is reduced due to loss of FcRn binding
Solution Approach 1:
The patent merges the advantages of both antibody fragment and full IgG structures by combining Fab regions (which simplify chain pairing) with Fc regions (which provide half-life extension). This creates a hybrid structure that achieves both reduced chain-mismatching and extended serum half-life simultaneously.
3Adaptability or versatility
If scFv structures are introduced to create bispecific antibodies, then the structural design flexibility is improved, but the antigen-binding specificity and function are compromised due to the engineered nature of scFv
Solution Approach 1:
The patent uses conventional IgG antibodies as ready-made, well-characterized building blocks rather than engineering new scFv structures. This approach leverages the proven antigen-binding specificity of natural antibodies while using modular assembly to achieve the desired bispecific functionality, thereby maintaining high binding reliability.
Data Source
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Figure 4(A)~4(B)
AI summary
Provided are an antigen-binding protein referred to as a "kappa/lambda" Fab-Fab series connection structure, preparation thereof, and use thereof, as well as a universal technical solution for preparing any two conventional IgG antibodies into a bispecific antigen-binding protein molecule having the structure.