CH3 Modified IgG Bispecific Antibodies Assembly
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Solution Overview
Problem
Current methods for generating fully IgG bispecific antibodies face challenges in achieving efficient assembly and reducing the formation of mis-matched Fab by-products, which affects stability and bioavailability.
Innovation Solution
Introducing specific mutations in the C H 3 domain of IgG1, IgG2, or IgG4 constant regions, combined with known methods for improving HC-LC specific assembly, to facilitate the assembly of fully IgG bispecific antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If co-expression of two distinct HC-LC pairs is used to generate fully IgG bispecific antibodies, then the full IgG architecture is achieved, but mis-matched Fab by-products are formed reducing assembly efficiency
Solution Approach 1:
The patent applies local quality by introducing specific amino acid mutations at defined positions (e.g., L368, L369, L408, L409 in the CH3 domain) to create asymmetric heterodimerization interfaces. These localized modifications enable selective pairing of heavy chains while maintaining the overall IgG structure, thereby reducing mis-matched Fab by-products and improving assembly efficiency.
Solution Approach 2:
The patent employs asymmetry by creating non-identical heavy chain pairs with complementary mutations. The first heavy chain receives specific mutations (e.g., L368R, L369R) while the second heavy chain receives different mutations (e.g., L408R, L409R), establishing directional heterodimerization preferences that prevent random pairing and reduce mis-matched by-products.
2Adaptability or versatility
If scFv fragments are used as building blocks for BsAb generation, then flexibility in antigen binding is achieved, but thermal stability and solubility are reduced due to lack of Fab architecture
Solution Approach 1:
The patent merges the antigen-binding flexibility of scFv fragments with the structural stability of full IgG architecture. By constructing bispecific antibodies that retain complete heavy and light chains with proper Fab regions, the invention combines the advantages of both scFv versatility and IgG stability, eliminating the need to choose between flexibility and structural integrity.
3Ease of operation
If multiple separate antibody agents are administered, then flexibility in dose and timing is maintained, but patient compliance decreases due to multiple injections
Solution Approach 1:
The patent merges the functionality of multiple separate antibody agents into a single bispecific antibody molecule. This consolidation allows both therapeutic activities to be delivered through one injection, improving patient compliance while maintaining the ability to target multiple antigens or pathways simultaneously.
4Ease of operation
If co-formulation of multiple antibody agents is used, then fewer injections are required, but formulation stability and bioavailability become difficult to maintain
Solution Approach 1:
The patent merges multiple antibody functions into a single molecular entity, eliminating the need for co-formulation challenges. The unified bispecific antibody structure ensures consistent stability and bioavailability characteristics while delivering multiple therapeutic activities through a single formulation, avoiding the complexity of maintaining multiple stable antibody components in one formulation.
Data Source
Figure 1A~1F
AI summary
The present invention provides fully IgG bi-specific antibodies comprising designed residues in the interface of the heavy chain-heavy chain (CH3/ CH3) domains, processes for preparing said fully IgG bi-specific antibodies, and nucleic acids, vectors and host cells encoding the same.