Abstract
SARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic. Antibodies can be powerful biotherapeutics to fight viral infections. Here, we use the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC50) values as low as 9 × 10−14 M are achieved as a result of up to 10,000-fold potency enhancements compared to corresponding IgGs. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and IgG-like bioavailability. The MULTi-specific, multi-Affinity antiBODY (Multabody or MB) platform thus uniquely leverages binding avidity together with multi-specificity to deliver ultrapotent and broad neutralizers against SARS-CoV-2. The modularity of the platform also makes it relevant for rapid evaluation against other infectious diseases of global health importance. Neutralizing antibodies are a promising therapeutic for SARS-CoV-2.
Highlights
SARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic
To leverage the full power of binding avidity, we have developed an antibodyscaffold technology using the human apoferritin protomer as a modular subunit to multimerize antibody fragments and propel Monoclonal antibodies (mAbs) into ultrapotent neutralizers against SARS-CoV-2
The seven most potent MBs have IC50 values of 0.2 to 2 ng/mL (9 × 10−14 to 9 × 10−13 M) against SARS-CoV-2 PsVs and are, to our knowledge, within the most potent antibody-like molecules reported to date against SARS-CoV-2
Summary
SARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic. Antibodies can be powerful biotherapeutics to fight viral infections. We use the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers Using this platform, half-maximal inhibitory concentration (IC50) values as low as 9 × 10−14 M are achieved as a result of up to 10,000-fold potency enhancements compared to corresponding IgGs. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and IgG-like bioavailability. MAbs can be isolated by B-cell sorting from infected donors, immunized animals, or by identifying binders in preassembled libraries Despite these methodologies being robust and reliable for the discovery of virus-specific mAbs, identification of the best antibody clone is usually associated with a time-cost penalty. Display of VHH72 on the light chain of human apoferritin achieved a ~10,000fold increase in neutralization potency against SARS-CoV-2 pseudovirus (PsV) compared to the conventional Fc fusion (Fig. 1e), demonstrating the power of avidity to transform binding moieties into potent neutralizers
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