Multivalent Antibody Constructs for SARS-CoV-2 Spike Protein Locking
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Solution Overview
Problem
Current treatments for COVID-19 caused by SARS-CoV-2 lack effective methods to block the virus's entry into host cells, particularly in preventing the Spike protein's interaction with the ACE2 receptor.
Innovation Solution
Development of Multivalent Anti-SARS-CoV2 (MASC) fusion proteins that bind to the Spike protein, locking it in a 'down' position and preventing ACE2 receptor binding, using single domain antibodies (sdAbs) assembled into monomeric, dimeric, or trimeric forms with specific CDRs and framework regions to achieve high affinity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single domain antibodies are assembled into multimeric forms (dimeric, trimeric), then binding affinity and stability are improved, but device complexity increases
Solution Approach 1:
The patent combines multiple single domain antibody units into multimeric structures (dimers, trimers) to enhance binding affinity through cooperative effects. The framework regions of individual sdAbs are engineered to interact and stabilize each other, creating a more reliable binder while the modular assembly approach manages the inherent complexity through standardized interaction interfaces.
Solution Approach 2:
The antibody is divided into independent single domain units that can function autonomously but gain enhanced stability when assembled into multimers. Each domain maintains its binding capability while the collective structure provides improved thermal and chemical stability, resolving the contradiction between simplicity and reliability.
2Duration of action of moving object
If trimeric forms are used to prolong dissociation, then duration of action is improved, but manufacturing precision requirements increase
Solution Approach 1:
The framework regions are pre-engineered with specific interaction interfaces that automatically guide correct assembly into trimeric structures. The design incorporates built-in stabilization mechanisms that form during self-assembly, ensuring proper configuration before the protein undergoes purification and formulation, thereby reducing downstream manufacturing precision requirements.
Solution Approach 2:
The patent modifies amino acid sequences in framework regions to optimize inter-domain interactions, tuning the stability and assembly characteristics. By adjusting parameters such as salt bridges, hydrogen bonding networks, and hydrophobic interactions in the framework, the design achieves prolonged dissociation times while maintaining manufacturability through robust self-assembly properties.
3Reliability
If multivalent constructs are designed to block ACE2 binding, then effectiveness against viral entry is improved, but ease of manufacture decreases
Solution Approach 1:
The single domain antibody framework is designed as a universal platform that can be assembled into different valencies (monomer, dimer, trimer) using the same basic building blocks and assembly rules. This modular universality allows the same manufacturing pipeline to produce multiple variants, maintaining ease of manufacture while achieving enhanced viral entry blocking through multivalent binding to the Spike protein.
Data Source
AI summary
Antibodies, including single-domain antibodies, that bind to SARS-CoV2 virus and methods of treatment using single-do-main antibodies that bind to SARS-CoV2 virus are provided.