Fc-Mediated Multimer Assembly for Viral Antigen Binding
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Solution Overview
Problem
Current multimer technologies for expanding antigen specificity and binding are limited in their ability to effectively target evolving viral antigens, such as those from coronaviruses, and lack efficient methods for producing high-purity multivalent binding proteins.
Innovation Solution
Development of protein multimers comprising multiple copies of antigen binding sites, specifically tetramers, octamers, dodecamers, or hexadecamers, using self-associating tetramerization domains to enhance antigen binding avidity and specificity, including the use of engineered polypeptides and nucleic acids for expression in eukaryotic cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multimerisation domains are used to self-assemble protein monomers into multimers, then antigen binding avidity is improved, but manufacturing precision and purity are worsened
Solution Approach 1:
The patent uses Fc regions as intermediary domains that facilitate controlled dimerization through well-defined heterodimeric interfaces. This mediator approach allows precise control over multimer assembly, improving both binding avidity and manufacturing purity by preventing random aggregation while ensuring consistent multimer formation
Solution Approach 2:
The patent employs parameter changes in the form of engineered mutations in Fc regions (such as L234A/L235A mutations) to control self-association properties. By modifying specific parameters of the Fc domain, the patent achieves controlled dimerization that improves antigen binding avidity while maintaining manufacturing precision through predictable assembly behavior
2Reliability
If multiple multimerisation techniques are used (biotin, dHLX, ZIP, BAD, p53), then binding activity is enhanced, but device complexity and production difficulty increase
Solution Approach 1:
The patent employs Fc regions that serve multiple functions simultaneously: they provide the binding interface for antigen recognition, mediate controlled dimerization through heterodimeric assembly, and enable multimer formation without requiring separate multimerisation domains. This multi-functionality reduces production complexity while maintaining enhanced binding activity
Solution Approach 2:
The patent merges the binding function and multimerisation function into a single integrated system using Fc regions. By combining these functions in the Fc domain itself rather than using separate components, the patent simplifies the overall production process while achieving enhanced binding avidity through controlled multimer formation
3Productivity
If Biotin is used for multimerisation, then production efficiency is improved, but harmful factors increase due to immune reactions in humans
Solution Approach 1:
The patent uses Fc regions as temporary, self-limiting multimerisation mediators that perform their function during the intended therapeutic or diagnostic period without requiring permanent modification. The Fc-mediated dimerization is designed to be reversible and controllable, eliminating the need for persistent foreign molecules like biotin that cause immune reactions
Solution Approach 2:
The patent converts the natural self-association tendency of Fc regions, which could potentially lead to unwanted aggregation, into a beneficial controlled dimerisation mechanism. By harnessing this inherent property through engineered mutations, the patent achieves enhanced binding avidity while avoiding the harmful immune reactions associated with foreign multimerisation molecules
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The multimers demonstrate significantly improved antigen binding affinity and specificity, with dodecamer and hexadecamer formats showing synergistic increases in functional affinity, leading to enhanced neutralization potency and purity of multivalent binding proteins.
Implementation Method 1
Multimerisation domains which cause self-assembly of protein monomers into multimers are known in the art
Implementation Method 2
The TRPM tetramerisation domain is held together by extensive core packing and interstrand polar interactions
Data Source
AI summary
The invention relates to multimers such as multimers comprising 4 copies of a binding site or peptide; tetramers of polypeptides; and tetramers, octamers, dodecamers and hexadecamers of epitopes or effector domains, such as antigen binding sites (eg, antibody or TCR binding sites that specifically bind to antigen or pMHC, or variable domains thereof) or peptides such as incretin, insulin or hormone peptides. The invention also relates to methods and uses to expand antigen specificity of binding sites, as well as vaccines, methods of vaccination and assay methods and reagents.