Fabs-in-tandem immunoglobulins for dual antigen binding
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Solution Overview
Problem
Current methods for generating bispecific or multispecific antibodies are limited in efficiency and effectiveness for treating inflammatory diseases, cancers, and other disorders, as they often require complex production processes and have challenges in achieving high affinity and stability.
Innovation Solution
Development of multivalent and multispecific binding proteins, specifically Fabs-in-tandem immunoglobulins (FIT-Ig), which can bind two or more antigens with high affinity, constructed using parental monoclonal antibodies and optimized for therapeutic applications, including the use of variant Fc regions for modified effector functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional methods (quadroma technology, chemical conjugation) are used to generate bispecific antibodies, then dual antigen binding capability is achieved, but production complexity and manufacturing difficulty increase significantly
Solution Approach 1:
The antibody is divided into separate Fab and Fc domains that can be independently expressed and then assembled. The Fab fragments containing different antigen specificities are produced separately and then combined with Fc regions to form the complete bispecific antibody, simplifying the production process compared to conventional methods.
Solution Approach 2:
The Fc region serves multiple functions: it provides structural stability, enables dimerization of Fab fragments, and offers a platform for further functional modifications. This universal component allows the same Fc region to be paired with different Fab fragments to create various bispecific antibodies.
2Adaptability or versatility
If conventional bispecific antibody formats are used, then dual specificity is achieved, but binding affinity and stability are compromised
Solution Approach 1:
The high-affinity binding capabilities of complete monoclonal antibodies are merged with the dual-specificity requirement by combining two Fab fragments (each retaining their original high affinity for their respective antigens) with Fc regions. This merging approach preserves the binding affinity of parental antibodies while achieving dual specificity.
Solution Approach 2:
The bispecific antibody is constructed as a composite molecule combining Fab fragments from different parental antibodies with Fc regions. This composite structure leverages the strengths of each component: the Fab fragments provide high-affinity antigen binding while the Fc regions provide structural stability and enable proper folding and assembly.
3Stability of the object's composition
If standard Fc regions are used in bispecific antibodies, then structural stability is maintained, but therapeutic efficacy and effector functions are limited
Solution Approach 1:
The Fc region is modified by changing specific amino acid parameters (such as residue substitutions at defined positions) to alter its properties. These parameter changes enhance effector functions like ADCC and CDC while maintaining the overall structural stability of the antibody molecule.
Solution Approach 2:
Specific local regions of the Fc domain are modified with targeted amino acid changes that enhance effector functions without compromising the global structural integrity. The modifications are localized to specific residues that interact with immune cells or complement proteins, leaving the overall Fc structure stable.
Data Source
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AI summary
The present invention provides multivalent and multispecific binding proteins that are capable of binding two or more antigens, or two or more epitopes. The present invention also provides methods of making and using such multivalent and multispecific binding proteins, including methods of using such binding proteins for prevention or treatment of various diseases, or for detecting specific antigens in vitro or in vivo.