Bispecific Antibody Format With Fc-Fab Pairing Stability
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Solution Overview
Problem
Current bispecific antibody formats face challenges such as limited stability, mispairing of heavy and light chains, and inability to mediate Fc effector functions, making them difficult to manufacture and less effective in cancer treatment.
Innovation Solution
A new bispecific antibody format comprising an immunoglobulin coupled to Fab fragments via the C-terminal end of the light chain, with specific mutations to promote correct chain association, ensuring stability and tetravalent binding, and inclusion of an Fc domain for enhanced functionality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If fragment-based formats are used to create bispecific antibodies, then manufacturing complexity is reduced, but stability and half-life are limited
Solution Approach 1:
The patent merges fragment-based simplicity with Fc domain functionality by combining Fab fragments with an Fc domain. The Fab fragment provides antigen binding while the Fc domain contributes stability, half-life extension, and effector functions. This hybrid structure resolves the contradiction by integrating the advantages of both fragment-based and full-length antibody formats.
2Stability of the object's composition
If IgG-like formats are used for bispecific antibodies, then stability and half-life are improved, but light chain mispairing occurs during manufacturing
Solution Approach 1:
The patent employs asymmetric chain pairing strategies where the Fc domain is fused to only one heavy chain type (e.g., H1), creating an asymmetric structure. This asymmetry prevents mispairing because the Fc-H1 fusion can only correctly pair with its corresponding light chain L1, eliminating the formation of incorrect heterodimers that would occur in symmetric IgG-like formats.
3Adaptability or versatility
If Fc domain is included in bispecific antibody format, then effector functions are enabled, but structural complexity increases
Solution Approach 1:
The patent segments the antibody structure into distinct functional modules: Fab fragments for antigen binding and Fc domain for effector functions. This segmentation allows independent optimization of each module and simplifies the overall architecture compared to attempting to create dual-functionality within a single integrated structure. The modular design enables the Fc domain to be added as a distinct unit that confers effector functions without complicating the antigen-binding region.
4Adaptability or versatility
If multiple heavy chains and light chains are used in bispecific antibodies, then dual targeting capability is achieved, but wrong pairing of chains occurs
Solution Approach 1:
The Fc domain acts as an intermediary that mediates correct chain pairing. By fusing the Fc domain to a specific heavy chain (e.g., H1), it serves as a molecular identifier that ensures H1 pairs only with its corresponding light chain L1. This intermediary Fc domain prevents wrong pairing between H1-L2 or H2-L1 combinations, thereby maintaining dual targeting capability while ensuring manufacturing precision.
Data Source
AI summary
The present invention provides bispecific antibodies of an antibody format, and which comprise one or more Fab fragments and an immunoglobulin molecule. The invention further provides compositions of said bispecific antibodies, as well as methods and uses of the same. The invention further provides a method of generating bispecific antibodies of the format.