Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants

Zhiqiang Ku, Xuping Xie, Paul R. Hinton, Xinli Liu, Xiaohua Ye, Antonio E. Muruato, Dean C. Ng, Sujit Biswas, Jing Zou, Yang Liu, Deepal Pandya, Vineet D. Menachery, Sachi Rahman, Yu An Cao, Hui Deng, Wei Xiong, Kevin B. Carlin, Junquan Liu, Hang Su, Elizabeth J. HaanesBruce A. Keyt, Ningyan Zhang, Stephen F. Carroll, Pei Yong Shi, Zhiqiang An

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Resistance represents a major challenge for antibody-based therapy for COVID-191–4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern—B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)—and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.

Original languageEnglish (US)
Pages (from-to)718-723
Number of pages6
JournalNature
Volume595
Issue number7869
DOIs
StatePublished - Jul 29 2021

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants'. Together they form a unique fingerprint.

Cite this