Broadly potent anti-SARS-CoV-2 antibody shares 93% of epitope with ACE2 and provides full protection in monkeys.

Due to the rapid evolution of SARS-CoV-2 to variants with reduced sensitivity to vaccine-induced humoral immunity and the near complete loss of protective efficacy of licensed therapeutic monoclonal antibodies, we isolated a potent, broad-spectrum neutralizing antibody that could potentially provide prophylactic protection to immunocompromised patient populations. Spike-specific B-cell clones isolated from a vaccinated post-infected donor were profiled for those producing potent neutralizing antibodies against a panel of SARS-CoV-2 variants. The P4J15 antibody was further characterized to define the structural binding epitope, viral resistance, and in vivo efficacy. The P4J15 mAb shows <20 ng/ml neutralizing activity against all variants including the latest XBB.2.3 and EG.5.1 sub-lineages. Structural studies of P4J15 in complex with Omicron XBB.1 Spike show that the P4J15 epitope shares ∼93% of its buried surface area with the ACE2 contact region, consistent with an ACE2 mimetic antibody. In vitro selection of SARS-CoV-2 mutants escaping P4J15 neutralization showed reduced infectivity, poor ACE2 binding, and mutations are rare in public sequence databases. Using a SARS-CoV-2 XBB.1.5 monkey challenge model, P4J15-LS confers complete prophylactic protection with an exceptionally long in vivo half-life of 43 days. The P4J15 mAb has potential as a broad-spectrum anti-SARS-CoV-2 drug for prophylactic protection of at-risk patient populations.

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Copyright © 2023. Published by Elsevier Ltd.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giuseppe Pantaleo and Didier Trono reports financial support was provided by Aerium Therapeutics. Giuseppe Pantaleo and Roger Le Grand reports financial support was provided by Innovative Health Initiative. Giuseppe Pantaleo and Didier Trono reports financial support was provided by European Union Horizon Europe Program. Giuseppe Pantaleo reports financial support was provided by Swiss Vaccine Research Institute. Giuseppe Pantaleo reports financial support was provided by Swiss National Science Foundation Grants. Henning Stahlberg reports financial support was provided by NCCR TransCure. Didier Trono and Giuseppe Pantaleo reports financial support was provided by CARIGEST S.A. Giuseppe Pantaleo and Didier Trono reports a relationship with Aerium Therapeutics that includes: equity or stocks. Craig Fenwick, Giuseppe Pantaleo, Didier Trono and Priscilla Turelli has patent #EP 22199188.8 pending to Aerium Therapeutics. Declaration of Competing Interest statement included in manuscript. C.F., G.P., P.T., and D.T. are co-inventors on a patent application that encompasses the antibodies and data described in this manuscript (EP 22199188.8). DT and GP are amongst the founders of and own equity in Aerium Therapeutics, which has rights to and is pursuing the development of the antibodies described in the publication and has a Sponsored Research Agreements with the Lausanne University Hospital (CHUV) and the Ecole Polytechnique Fédérale de Lausanne (EPFL). The remaining authors declare no competing interests.