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. 2023 Jan-Dec;15(1):2212415.
doi: 10.1080/19420862.2023.2212415.

Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2

Meghan M Verstraete  1 , Florian Heinkel  1 , Janessa Li  1 , Siran Cao  1 , Anh Tran  2 , Elizabeth C Halverson  1 , Robert Gene  1 , Elizabeth Stangle  1 , Begonia Silva-Moreno  1 , Sifa Arrafi  1 , Jegarubee Bavananthasivam  2 , Madeline Fung  1 , Mariam Eji-Lasisi  1 , Stephanie Masterman  1 , Steve Xanthoudakis  1 , Surjit Dixit  1 , John Babcook  1 , Brandon Clavette  1 , Mark Fogg  1 , Eric Escobar-Cabrera  1
Affiliations

Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2

Meghan M Verstraete et al. MAbs. 2023 Jan-Dec.

Abstract

As immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and live virus assays, IgM ACE2 decoy had potency comparable or superior to leading SARS-CoV-2 IgG-based mAb therapeutics evaluated in the clinic, which were variant-sensitive in their potency. We found that increased ACE2 valency translated into increased apparent affinity for spike protein and superior potency in biological assays when decavalent IgM ACE2 was compared to tetravalent, bivalent, and monovalent ACE2 decoys. Furthermore, a single intranasal dose of IgM ACE2 decoy at 1 mg/kg conferred therapeutic benefit against SARS-CoV-2 Delta variant infection in a hamster model. Taken together, this engineered IgM ACE2 decoy represents a SARS-CoV-2 variant-agnostic therapeutic that leverages avidity to drive enhanced target binding, viral neutralization, and in vivo respiratory protection against SARS-CoV-2.

Keywords: ACE2; COVID-19; IgM; SARS-CoV-2; antibody engineering; multivalent scaffold; receptor decoys.

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Conflict of interest statement

MMV, FH, JL, SC, LH, RG, LS, BS, SA, MF, MEL, SM, SX, SD, JB, BC, MF, and EEC are current or former employees of Zymeworks Inc., and may hold shares or stock options in Zymeworks Inc. Zymeworks Inc. provided financial support for the study. The work described here is the subject of a patent application assigned to Zymeworks Inc. AT and JB have no conflicts of interest to disclose.

Figures

(A) Schematics of IgG OA, IgG, IgA, and IgM ACE2 decoy designs to illustrate the increasing ACE2 valency from 1 to 10. (B) SPR sensorgrams to depict how the off-rate of ACE2 decoys for binding SARS-CoV-2 Wuhan spike RBD decreases with increasing ACE2 valency, accounting for the increase in measured apparent affinity. (C) Graphs with KD, ka, and kd values plotted for ACE2 decoys measured using SPR sensor chips with different levels of immobilized spike protein show that increased immobilized spike RBD results in decreased off-rate and increased apparent affinity for multivalent ACE2 decoys.
Figure 1.
Avidity-driven binding of ACE2 decoys to SARS-CoV-2 Wuhan (WT) strain spike RBD increases with higher ACE2 valency.
Figure 2.
Figure 2.
Neutralization of SARS-CoV-2 variant spike protein and ACE2 binding by ACE2 decoys and REGEN-COV mAb cocktail by blocking immunoassay, pseudovirus, and live virus neutralization assays.
(A) Graph of hamster weight loss after infection with SARS-CoV-2 Delta (B.1.617.2). IgM ACE2 decoy at the highest doses of 1 mg/kg and 10 mg/kg appear to prevent weight loss of hamsters compared to isotype controls and IgG ACE2 decoys. (B) Graph of viral gRNA copies from nasal swabs after SARS-CoV-2 Delta (B.1.617.2) infection shows a significant decrease on day 2 for hamsters treated with IgM ACE2 decoy.
Figure 3.
In vivo efficacy of intranasal IgM ACE2 decoy and IgG ACE2 decoy for treatment of SARS-CoV-2 Delta (B.1.617.2) infection in a Syrian hamster model.
See this image and copyright information in PMC

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