Multivalent COMP-Fusion Antibody Binders for Reduced Immunogenicity
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Solution Overview
Problem
Current antibody therapies often result in unwanted side effects due to anti-rodent antibodies when using mouse or rat-derived antibodies in humans, and there is a need for improved antibody formats that offer enhanced binding affinity and specificity.
Innovation Solution
Development of multivalent binder molecules utilizing the coiled coil domain of human cartilage oligomeric matrix protein (COMP) to pentamerize full-length IgG antibodies or Fab fragments, creating multimeric fusion polypeptides with increased avidity through the fusion of COMP-domains with antibody fragments via peptidic linkers, allowing for specific binding to multiple epitopes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse or rat-derived antibodies are used in humans, then antibody binding function is achieved, but unwanted side effects occur due to anti-rodent antibodies
Solution Approach 1:
The patent extracts only the essential antibody binding function (variable regions) while discarding the problematic rodent-derived constant regions. This is achieved by using single-chain Fv fragments that contain only the antigen-binding variable domains, thereby eliminating the source of anti-rodent antibody reactions while preserving therapeutic binding function.
Solution Approach 2:
The patent introduces human cartilage oligomeric matrix protein (COMP) as an intermediary multimerization domain. This human-derived protein serves as a mediator to assemble the antibody fragments into multivalent structures, providing the necessary multivalency for enhanced binding while being human-compatible and avoiding rodent protein-related immunogenicity.
2Reliability
If multivalent binder molecules are created using COMP-domain fusion, then binding affinity and specificity are enhanced, but molecular weight and structural complexity increase
Solution Approach 1:
The patent segments the antibody into individual single-chain Fv fragments, which are then independently fused to COMP domains. This segmentation allows each fragment to function autonomously while the COMP domain provides standardized multimerization, simplifying the overall design compared to modifying entire antibody molecules.
Solution Approach 2:
The COMP domain serves multiple functions: it provides a standardized interface for multimerization, enables self-assembly into pentameric structures, and contributes to the overall stability of the construct. This multi-functionality reduces the need for additional engineering elements, thereby managing complexity while achieving enhanced binding affinity through multivalency.
Data Source
AI summary
Herein is reported a multimeric fusion polypeptide comprising five monomeric fusion polypeptides each comprising at least a Fab fragment and a COMP-domain of SEQ ID NO: 01 or a functional fragment thereof.