Multispecific Antibodies With Common Light Chain Variable Domain
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Solution Overview
Problem
Current methods for producing multispecific antibodies face challenges such as mispairing of light and heavy chains, leading to reduced production yields and the need for complex purification processes, particularly when using recombinant expression techniques or the 'knobs-into-holes' technology, which requires identical light chains and restricts the development of bispecific antibodies targeting different antigens.
Innovation Solution
The development of multispecific antibodies with a common variable light chain domain (VL) and two different variable heavy chain domains (VH1 and VH2), where the heavy chains consist of CH3, CH2, and CH1 domains, and the light chains include either a kappa or lambda constant domain paired with VH1 or VH2, allowing for correct chain association and purification without the need for heterodimerization modifications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If common light chains are used in multispecific antibodies to prevent mispairing, then production yield is improved, but the requirement for identical light chains restricts the development of bispecific antibodies against different antigens
Solution Approach 1:
The patent inverts the conventional approach by making the heavy chains identical instead of the light chains. The two heavy chains share the same constant region (CH3, CH2, CH1 domains) while the light chains differ in their variable domains (VH1/VL1 and VH2/VL2). This inversion allows the constant heavy chain to serve as the common element that prevents mispairing, while the variable regions maintain diversity for different antigen specificities.
Solution Approach 2:
The identical constant heavy chain region serves multiple functions: it provides structural stability, enables correct chain association through complementary pairing interfaces, and allows the antibody to target multiple antigens through its variable regions. The universal constant region acts as a platform that supports different antigen-binding specificities.
2Productivity
If knobs-into-holes technology is used to heterodimerize heavy chains, then production yield is improved, but the technique requires complex purification procedures due to mispaired byproducts
Solution Approach 1:
The patent employs homogeneous identical constant heavy chains that naturally pair with each other through their complementary light chain variable domains. This homogeneity in the constant region eliminates the formation of mispaired byproducts that would otherwise require complex purification, as the identical heavy chains self-assemble correctly without needing knobs-into-holes modifications.
3Reliability
If identical light chains are required for heterodimerized heavy chains, then chain association is stabilized, but the development of recombinant bispecific antibodies from different parent antibodies becomes challenging
Solution Approach 1:
The patent inverts the conventional requirement by making heavy chains identical instead of light chains. This allows the use of different parent antibodies with different light chain variable domains (VH1/VL1 and VH2/VL2) while maintaining stable chain association through the identical constant heavy chain regions. The inversion simplifies the development process as it does not require optimizing for identical light chains.
Data Source
AI summary
Multispecific antibodies based on antibodies that share a common light chain are described herein. The multispecific antibodies include: modified heavy chains having, by domain exchange, a common light chain variable domain VL; and two modified light chains having, by domain exchange, variable heavy chain domains of a first antibody (VH1) and a second antibody (VH2), wherein one light chain is of kappa isotype and one light chain is of lambda isotype. The present invention also relates to methods for the manufacture of such antibodies and their use.