Coronavirus disease-2019 (COVID-19) is a global threat induced by a newly emerged virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid spread of COVID-19 not only prompts the development of effective vaccines at an unprecedented pace but also expedites the development of novel therapies, including therapeutic SARS-CoV -2-neutralizing antibodies and the reuse of existing antibodies approved for other indications.

Antibodies are a versatile and important component of the human immune system, of which the monoclonal antibody (mAb) represents a new frontier for the treatment of infectious diseases due to its specificity and potency. As predicted by William Haseltine, a biologist in Harvard, mAbs would be the first therapy specifically developed to target SARS-CoV -2.1 To date, more than 10 mAbs have been granted Emergency Use Authorization (EUA) by the United States or approved by other countries to treat COVID-19, and over 70 mAbs are being evaluated in clinical trials in different therapeutic settings. These trials will be essential for the development of novel COVID-19 treatments in the very near future.

In patients with COVID-19, the severity of the disease correlates to high viral load in the respiratory tract, the primary site of SARS-CoV-2 infection and shedding.2 Analysis of antibody responses has shown that SARS-CoV-2 induces specific antibodies mediated by three major immunoglobulin (Ig) isotypes, IgM, IgA, and IgG.3,4 Among them, specific IgM and IgA are the early antibody responses that start and peak within 7 days, whereas specific IgG antibodies develop more than a week (10–18 days) after infection and persist for months (Figure 1a).4–6 However, almost all neutralizing mAbs in clinical use are the IgG isotype. No IgM or IgA mAbs are currently marketed. Moreover, these IgG mAbs are mostly administered via intravenous (i.v.) infusion. The concentration of IgG antibodies is 200–500 times lower in the lungs than in serum, highlighting that i.v. administration could not induce effective mucosal immune responses.7 What is worse, many potent IgG mAbs, including those with EUAs and some in clinical trials, do not neutralize the emerging SARS-CoV-2 variants of concern (VOCs).8–11 Thus, there is an urgent need for the development of more potent antibody-based therapies against the virus.  

Upon SARS-CoV-2 infection, viruses first affect the upper respiratory tract. Therefore, the mucous membrane is the first line of immune system defense. IgM and IgA are mucosal antibodies in the early stages of immune response against mucosal pathogens. IgM typically assembles into pentamers that contain 10 antigen-binding sites and the joining chain (J-chain) (Figure 1b). The J-chain of pentameric IgM enables its binding to the polymeric Ig receptor (pIgR) on cells, allowing the transcytosis of IgM from the circulation to the mucosal surfaces.16 In contrast, IgA exists in monomeric form (mIgA) in serum but is present as dimers (dIgA) at mucosal surface, termed secretory IgA (sIgA), which contains two IgA molecules with a J-chain and a secretory component (SC) (Figure 1b). In respiratory and gastrointestinal tracts, IgM and sIgA serve as the main mediator of mucosal immunity. These features make the intranasal delivery of IgM or IgA neutralizing antibodies feasible for the treatment of COVID19. Meanwhile, these characteristics also raise questions as to whether SARS-CoV-2-induced IgM or IgA neutralizing antibodies exert more potent effects than IgG, and whether IgM or IgA neutralizing antibodies are superior to IgG in covering escape variants of SARS-CoV-2. If so, more data are needed to show how we can improve the current vaccines or develop novel immunization methods to boost early and mucosal immune response in COVID-19.

Given these considerations, we provide here an overview of IgM and IgA therapeutic antibodies for COVID-19, focusing on those that target SARS-CoV-2. In addition, we also summarize the anti-SARS-CoV-2 bispecific antibodies (bsAbs), which are an important alternative to monoclonal antibody cocktails.


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