Multivalent VHH Polypeptides for Broad Coronavirus Neutralization
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Solution Overview
Problem
Current antibodies targeting the SARS-CoV-2 spike protein show reduced efficacy against emerging variants and lack broad reactivity against multiple coronaviruses, necessitating the development of cross-reactive agents that can neutralize diverse coronaviruses, including SARS-CoV, SARS-CoV-2, and MERS.
Innovation Solution
Engineering single-domain antibodies (VHHs) that target conserved epitopes on the spike protein of various coronaviruses and are formulated into multivalent formats to enhance neutralization potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional immunoglobulins targeting the SARS-CoV-2 spike protein are used, then neutralization potency against wild type strain is achieved, but efficacy against emerging variants and broad reactivity against multiple coronaviruses is reduced
Solution Approach 1:
The patent applies universality by designing VHHs that can bind to multiple coronavirus spike proteins (SARS-CoV, SARS-CoV-2, MERS) through targeting conserved epitopes. The single-domain antibodies are engineered to recognize common structural features across different coronavirus genera, enabling one agent to perform multiple neutralization functions against diverse viral strains and variants
Solution Approach 2:
The patent applies local quality by focusing on specific conserved epitopes within the spike protein structure that are preserved across different coronaviruses. Rather than targeting variable regions, the VHHs are designed to bind to locally conserved regions such as the receptor binding motif (RBM) and other structurally invariant areas, ensuring cross-reactivity while maintaining high neutralization potency
2Reliability
If VHHs targeting distinct conserved epitopes are engineered into multivalent formats, then neutralization potency is significantly enhanced, but molecular complexity increases
Solution Approach 1:
The patent applies merging by combining multiple VHHs targeting different conserved epitopes into single multivalent constructs. These merged molecules simultaneously engage multiple spike protein epitopes, creating a synergistic neutralization effect that significantly enhances potency against diverse coronaviruses while maintaining a manageable molecular architecture through systematic design
Solution Approach 2:
The patent applies segmentation by dividing the neutralization function into multiple independent VHH modules, each targeting a specific conserved epitope. These segmented functional units can be independently designed, optimized, and then recombined into multivalent formats, allowing systematic enhancement of neutralization potency while maintaining modular complexity that facilitates engineering and production
Data Source
AI summary
Disclosed are single-domain antibodies that can bind (e.g., separately) to at least two spike proteins from different coronaviruses. Additionally disclosed are polypeptides that have multiple coronavirus spike-protein binders and can neutralize (e.g., separately) at least two different coronaviruses. These single-domain antibodies and polypeptides can be used for treating coronavirus infections.