Journal Article

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

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

2021

Overview

Resistance represents a major challenge for antibody-based therapy for COVID-19 1 , 2 , 3 – 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. An engineered IgM antibody administered intranasally in mice shows high prophylactic efficacy and therapeutic efficacy against SARS-CoV-2, and is also effective against multiple variants of concern that are resistant to IgG-based therapeutics.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/1 / 45 / 49/109 / 59/5 / 631/154/51/1568 / 631/250/2152/2153/1291 / 631/250/347 / 631/326/596/4130 / 82 / 82/1 / 82/16 / 82/29 / 82/80 / Administration, Intranasal / Angiotensin-Converting Enzyme 2 - antagonists & inhibitors / Angiotensin-Converting Enzyme 2 - metabolism / Animals / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - genetics / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacokinetics / Antibodies, Neutralizing - administration & dosage / Antibodies, Neutralizing - adverse effects / Antibodies, Neutralizing - genetics / Antibodies, Neutralizing - immunology / Apoptosis Regulatory Proteins - chemistry / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - immunology / Apoptosis Regulatory Proteins - metabolism / Body weight / Clinical trials / COVID-19 / COVID-19 - immunology / COVID-19 - prevention & control / COVID-19 - virology / COVID-19 Drug Treatment / Dosage / Dosage and administration / Dose-Response Relationship, Immunologic / Effectiveness / Engineering / Epitopes / Female / Humanities and Social Sciences / Humans / IgG antibody / Immunoglobulin A - genetics / Immunoglobulin A - immunology / Immunoglobulin G / Immunoglobulin G - immunology / Immunoglobulin M / Immunoglobulin M - administration & dosage / Immunoglobulin M - adverse effects / Immunoglobulin M - immunology / Immunoglobulin M - therapeutic use / Intranasal administration / Intranasal medication / Mice / Mice, Inbred BALB C / Monoclonal antibodies / multidisciplinary / Mutation / Neutralizing / Pharmacokinetics / Protein Engineering / Proteins / Receptors, Virus - antagonists & inhibitors / Receptors, Virus - metabolism / SARS-CoV-2 - classification / SARS-CoV-2 - genetics / SARS-CoV-2 - immunology / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Viruses