DVD-Ig Multispecific Antibody Design for Homogeneous Assembly
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for producing bispecific antibodies face challenges such as molecular heterogeneity, reduced production yields, and increased immunogenicity due to the need for sophisticated purification processes and mutational modifications, which affect their stability and efficacy in binding antigens.
Innovation Solution
Development of dual variable domain immunoglobulins (DVD-Ig) with specific polypeptide chains comprising variable domains and constant domains linked by specific linkers, allowing for high-affinity binding to two or more antigens, and capable of being expressed in both bacterial and mammalian systems.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If cell fusion or chemical conjugation methods are used to produce bispecific antibodies, then multispecific binding capability is achieved, but molecular heterogeneity and reduced production yields occur
Solution Approach 1:
The antibody is divided into separate domain units (VH1, VH2, VL1, VL2) that are independently expressed and then assemble through controlled pairing. This segmentation allows each domain to be optimized separately while ensuring homogeneous final product through designed pairing interfaces.
Solution Approach 2:
Constant domains (CH1, CL) serve as intermediaries that mediate the pairing between variable domains from different parental antibodies. The constant domains provide standardized interaction interfaces that ensure correct assembly and reduce heterogeneity.
2Manufacturing precision
If sophisticated purification procedures are implemented to reduce molecular heterogeneity, then binding specificity is improved, but production complexity and cost increase
Solution Approach 1:
The antibody construct is designed to self-assemble into the correct bispecific configuration through inherent domain pairing preferences. The constant domains and linker structures guide proper assembly automatically, eliminating the need for complex purification procedures to achieve homogeneity.
3Reliability
If mutational modifications are introduced to improve binding affinity, then antigen-binding activity is enhanced, but immunogenicity and stability are adversely affected
Solution Approach 1:
Mutations are introduced locally only in the complementarity determining regions (CDRs) where antigen binding occurs, while the framework regions and constant domains remain unchanged to maintain stability and reduce immunogenicity. This localized modification approach preserves overall protein integrity.
Solution Approach 2:
Instead of modifying the variable domains to improve stability, the invention maintains stable constant domains and uses them to enable flexible optimization of the variable domains for binding affinity. The stable framework supports the potentially immunogenic CDRs.
4Adaptability or versatility
If tandem scFv molecules are constructed to achieve bispecificity, then binding versatility is improved, but solubility and expression efficiency deteriorate
Solution Approach 1:
Constant domains serve as intermediary structures that facilitate proper folding and solubility of the tandem variable domain construct. The CH1 and CL domains provide structured environments that prevent aggregation and enhance expression in bacterial systems.
Solution Approach 2:
The invention creates a composite structure combining variable domains from different antibody types (IgG, IgA, IgM) with their respective constant domains. This composite approach leverages the solubility and expression properties of different antibody frameworks while achieving bispecific binding capability.
Data Source
AI summary
The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention, diagnosis, and/or treatment of disease.