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Review 1: "Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers"

Published onMar 23, 2022
Review 1: "Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers"
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key-enterThis Pub is a Review of
Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers

AbstractThe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), has caused a global pandemic. Antibodies are powerful biotherapeutics to fight viral infections; however, discovery of the most potent and broadly acting clones can be lengthy. Here, we used 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 were achieved as a result of up to 10,000-fold potency enhancements. 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 Ig-like in vivo bioavailability. This MULTi-specific, multi-Affinity antiBODY (Multabody; or MB) platform contributes a new class of medical countermeasures against COVID-19 and an efficient approach to rapidly deploy potent and broadly-acting therapeutics against infectious diseases of global health importance.One Sentence Summarymultimerization platform transforms antibodies emerging from discovery screens into potent neutralizers that can overcome SARS-CoV-2 sequence diversity.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



The manuscript by Rujas et. al presented a novel approach to the development of more potent neutralizing antibody therapeutics against SARS-CoV-2. This innovative self-assembly strategy resulted in an enhancement of antibody binding affinity and neutralizing potency by 1000-10,000 fold. The use of the apoferritin system as a multivalency generating format is exceptional, as it does not introduce unwanted side effects to the objects. This is in contrast to one of the potential therapeutics to COVID-19 which has an ACE2 unit that may complicate its use due to its native functions in the human body.

The experiments were well-designed and performed properly, the results were clearly presented, and the manuscript is well written. From a scientific point of view, the quality of this work is very high, and I think its publication will greatly benefit not only the coronavirus research community but also the development of effective therapeutics for other pandemic-causing viruses. All these points make this manuscript merits publication in RR-C19.

Specific Comments:

  1. The work can be improved further if the authors can characterize the interaction model between the Spike protein and the MB system directly. This may be challenging for Cryo-EM and crystallography but it could be done with other techniques such as HDX-MS fine-mapping. This will help figure out how many (2 or 3) Spike RBDs are involved in MB binding, which could be the direct cause of the dramatic binding enhancement.

  2. For future work, the authors may try to include bnAbs such as NOVOAB-20 in their MB format. Targeting a highly conservative epitope may make the MB drug effective for not only the current COVID-19 but also future new SARS-Cov-2 variants.

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