key: cord-0692630-znnluq31
authors: Zhang, Jingjing; Zhang, Han; Sun, Litao
title: Therapeutic antibodies for COVID-19: is a new age of IgM, IgA and bispecific antibodies coming?
date: 2022-02-27
journal: MAbs
DOI: 10.1080/19420862.2022.2031483
sha: c913c8e86d07a9671b4c44abcb6ce3c4e7660c8b
doc_id: 692630
cord_uid: znnluq31

Early humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are dominated by IgM and IgA antibodies, which greatly contribute to virus neutralization at mucosal sites. Given the essential roles of IgM and IgA in the control and elimination of SARS-CoV-2 infection, the mucosal immunity could be exploited for therapeutic and prophylactic purposes. However, almost all neutralizing antibodies that are authorized for emergency use and under clinical development are IgG antibodies, and no vaccine has been developed to boost mucosal immunity for SARS-CoV-2 infection. In addition to IgM and IgA, bispecific antibodies (bsAbs) combine specificities of two antibodies in one molecule, representing an important alternative to monoclonal antibody cocktails. Here, we summarize the latest advances in studies on IgM, IgA and bsAbs against SARS-CoV-2. The current challenges and future directions in vaccine design and antibody-based therapeutics are also discussed.

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] [5] [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] [9] [10] [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 COVID-19. 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.

SARS-CoV-2 is an enveloped RNA virus that causes COVID-19, and the spike glycoprotein (S protein) on its surface is a transmembrane homotrimer and the target of neutralizing antibodies (Figure 2a ). The S protein has two functional subunits (S1 and S2), of which the S1 subunit facilitates viral attachment to the surface of host cells. The S1 subunit further includes the N-terminal domain (NTD) and receptor-binding domain (RBD), which represent the key targets for neutralizing mAbs and potential therapies (Figure 2b ). 17 Since the outbreak of the pandemic, neutralizing IgG mAbs against RBD or NTD have been the focus of investigation and development efforts. Of interest, all mAbs authorized or in clinical trials target the RBD, which interacts with the angiotensin-converting enzyme 2 (ACE2) receptor ( Figure 2a ). 18 While most mAbs recognize different epitopes fully or partially overlapping with the ACE2binding sites, some mAbs target sites close or distal to the ACE2binding sites. Although none of the NTD-directed mAbs are under clinical testing, the NTD is an essential and promising target for neutralizing mAbs. 8, [19] [20] [21] [22] However, the neutralization mechanism of NTD-binding mAbs remains unclear. One possible mechanism is that the NTD-specific mAbs may neutralize SARS-CoV-2 by retraining the conformational changes of the S protein. 19 Another study suggested that the anti-NTD mAbs may inhibit SARS-CoV-2 infection at a post-attachment phase and block subsequent virus entry or fusion steps. 21 Therapeutic IgG mAbs against SARS-CoV-2 and the existing antibodies against non-SARS-CoV-2 antigens in COVID-19 have been extensively discussed in several detailed reviews. [23] [24] [25] [26] [27] We thus do not focus on them here, but summarize all the therapeutic IgG antibodies for COVID-19 that we identified in Table 1 , including their origin, development platform, target, features, and the current status of clinical trials. The targets are varied, and include SARS-CoV-2, cytokine and chemokine, and complement. Given the emergence of SARS-CoV-2 variants, we also summarize the neutralization of SARS-CoV-2 VOCs by the existing IgG antibodies with EUAs or in clinical development ( existing mAbs are resistant to the emerging SARS-CoV-2 VOCs, a global consortium study recently provided a detailed epitope landscape on the SARS-CoV-2 S protein and offered a framework for selecting antibody treatment. 115 The result of this effort not only helps us understand how viral variants might affect antibody-based therapeutics but also guides both treatment and prevention.

So far, specific IgM antibodies have been largely developed for SARS-CoV-2 serological testing. Thus, the investigation of therapeutic IgM antibodies against SARS-CoV-2 is very limited. In previous studies, reduced IgM levels have been observed in patients with severe pandemic influenza. 116 As a result, the treatment with IgM-enriched preparations has emerged. Indeed, the clinical trials that evaluate the passive immunotherapy with COVID-19 convalescent plasma (CCP) have rapidly grown owing to the absence of specific antiviral therapy. In CCP, specific antibodies (IgG/IgM/IgA) against SARS-CoV-2 are regarded as active components, since all isotypes display neutralizing activities. 117 However, numerous non-antibody proteins and chemical factors in CCP may drive detrimental outcomes in patients. 118 CCP therapy also raises a flurry of ethical questions. 119 As such, the quality, efficacy and safety of CCP against COVID-19 need to be further investigated and determined.

Instead of CCP, the preparation of polyvalent antibody for COVID-19 is another therapeutic choice. Trimodulin, a polyvalent antibody preparation derived from human plasma, contains IgM (~23%), IgA (~21%) and IgG (~56%). 120 In COVID-19 cell models, addition of trimodulin reduced inflammation and induced stronger immunomodulation compared to intravenous Ig preparation (IVIG). 121 Hence, trimodulin is currently being tested in a Phase 2 clinical trial for COVID-19 (NCT04576728) ( Table 3) . Nonetheless, the IgM component of trimodulin is of minor importance for Fc receptor (FcR)-mediated effector functions, so the beneficial immunomodulatory effects of trimodulin might be attributed to the IgA component, a neglected but critical part of SARS-CoV-2 infection 121 discussed in the following section.

In addition to the polyvalent antibody preparation, recombinant mAbs of IgG, IgM and IgA isotypes sharing the same antigen-binding fragment (Fab) against S protein were developed. 126 Remarkably, the neutralizing ability of IgM and IgA mAbs was dramatically higher than IgG mAbs, suggesting a strategy for developing effective therapies of IgM and IgA instead of IgG for COVID-19. 126 One explanation for the efficient neutralization conferred by IgM and IgA might be their capacity to bind multiple virions. Recently, an elegant work reported six engineered IgM antibodies that exhibit higher binding and neutralizing activities than their parental IgG1 antibodies. Among them, one IgM antibody (IgM-14), engineered from a previously isolated mAb (CoV2-14) by The spike glycoprotein (S protein) expressed on its surface mediates viral attachment to the host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Other major structural proteins of the SARS-CoV-2 particle include envelope (E) protein, membrane (M) protein, and nucleocapsid (N) protein. (b) SARS-CoV-2 S protein is divided into S1 and S2 subunits, of which, the S1 subunit includes the N-terminal domain (NTD, in tv-blue) and receptor-binding domain (RBD, in forest); the S2 subunit includes fusion peptide (FP), heptad region 1 and 2 (HR1, HR2), transmembrane domain (TM) and intracellular tail (IC) which are shown in hot pink. The structure of trimeric SARS-CoV-2 S protein (PDB code 6XR8) 131 is shown (lower), with two molecules on the surface illustrated with white and gray color, respectively, and the third molecule in cartoon indicated with different colors (NTD in tv-blue; RBD in forest, and the S2 in hot pink). phage display, 70 showed over 230-fold potency in neutralizing SARS-CoV-2 compared to its corresponding IgG version (IgG-14) (Table 3) . Strikingly, IgM-14 was more potent than IgG-14 in neutralizing SARS-CoV-2 VOCs, including Alpha, Beta and Gamma variants, as well as 21 other RBD mutants, indicating that IgM-14 is superior to IgG-14 in covering viral escape mutations. In mice, IgM-14 not only conferred potent therapeutic protection against different variants but also displayed desirable pharmacokinetics and safety profiles when administered intranasally. 122 Therefore, two Phase 1 clinical trials of IgM-14 (also known as IGM-6268) were started very recently in healthy volunteers and patients with mild-to-moderate COVID-19.

Mucosal immune system is by far the largest component of the entire human immune system. Most viruses invade via mucosal sites (e.g., respiratory tracts) where sIgA plays an important role. For years, sIgA has been described as the predominant antibody and the first barrier against pathogens at mucosal sites. Importantly, IgA has been shown to exert neutralizing activities on multiple viruses, such as human immunodeficiency virus (HIV), 127 and influenza virus. 128 In addition, IgA also contributes to virus neutralization to a greater extent than IgG in COVID-19, and the neutralizing IgA remains detectable in saliva for a longer time, 129 suggesting a critical role of IgA during the early phase of SARS-CoV-2 infection. It should be noted that the circulating IgA, even in polymeric form, cannot have the same protective effect as mucosal sIgA to limit infections. Indeed, dIgA derived from COVID-19 convalescent donors is more potent than mIgA and the corresponding IgG against the same target, 123 suggesting that dIgA is a more potent neutralizer than IgG. The same holds true in another in vitro setting (Table 3) . 124 Nevertheless, more studies are urgently required to assess the safety and therapeutic effects of IgA-enriched products in preventing SARS-CoV-2 infection. In 2020, the first human IgA mAb against SARS-CoV-2, named mAb362, was developed. 125 In particular, mAb362 showed cross-reactivity against the RBD of both SARS-CoV-1 and SARS-CoV-2, and competitively blocked ACE2 receptor binding. Notably, mAb362 as mIgA, dIgA and sIgA showed significantly enhanced potency in neutralizing SARS-CoV-2 pseudovirus compared to the IgG isotype. The most potent mAb362 sIgA also neutralized authentic SARS-CoV-2, whereas the IgG isotype did not, indicating effective mucosal immunity of sIgA antibodies against SARS-CoV-2 (Table 3) . Interestingly, in patients with Selective IgA Deficiency (SID), the lack of neutralizing anti-SARS-CoV-2 IgA and sIgA antibodies represents a possible cause of COVID-19 severity, vaccine failure and prolonged viral shedding, 130 emphasizing the importance of IgA antibodies in mucosal immune responses upon SARS-CoV-2 infection.

Combining multiple IgG mAbs has been known to have a synergistic effect on neutralizing SARS-CoV-2 by targeting different epitopes of the RBD. For example, the combination of casirivimab and imdevimab has been granted EUA to treat mild-to-moderate symptoms of COVID-19 in high-risk patients. However, effects similar to those of mAb combinations can be achieved by a single bsAb, which have two distinct specificities and may have reduced timeconsuming and expensive development (Figure 3a) , as well as increased potency due to enhanced functional affinity. Use of bsAb may also decrease the likelihood of viral escape. 135, 136 The first bsAb against SARS-CoV-2 was constructed by linking non-neutralizing binders to neutralizing binders in a bispecific scaffold. 132 Specifically, the authors first identified Fabs that bind to the RBD but do not block ACE2 binding by phage display, and then they assembled them into a knob-inhole (KIH) bispecific IgG scaffold with human-derived variable heavy (VH) binders that block ACE2, resulting in a VH/Fab bsAb (Figure 3b) . Remarkably, these bsAbs showed 20-to 25fold more potency in neutralizing pseudotyped and authentic SARS-CoV-2 than the mono-specific bivalent VH-Fc or IgG alone or even as a cocktail. The study was an attempt to target multiple epitopes, both neutralizing and non-neutralizing, within a single therapeutic molecule, providing a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies.

Soon afterward, another study reported a human bispecific IgG1-like molecule CoV-X2 in a CrossMAb format (Figure 3c ) on the basis of two neutralizing mAbs (C121 and C135) derived from convalescent COVID-19 patients. 38 CoV-X2 could simultaneously bind two non-overlapping RBD epitopes, and showed a broader coverage of SARS-CoV-2 variants, including the escape mutants generated by the parental mAbs; in a mouse model, CoV-X2 also protected mice from disease and suppressed viral escape. 135 Very recently, Cho et al. reported five ultrapotent DVD-Ig bsAbs (Figure 3d ) by combining non-overlapping specificities. 136 Of all the bsAbs that could neutralize authentic SARS-CoV-2, one bsAb, CV1206_521_GS, neutralized SARS-CoV-2 with more than 100-fold higher potency than a cocktail of its constituent antibodies. Further analysis revealed that CV1206_521_GS crosslinked NTD and RBD in adjacent S proteins, a mode of action that is unavailable to conventional mAbs even when used in combination. In addition, two other bsAbs showed the ability to neutralize SARS-CoV-2 VOCs, including Alpha, Beta, Gamma and Delta variants, at near wild-type potency. More importantly, one potent bsAb was effective against SARS-CoV-2 carrying a key variant mutation of E484K in the hamster model. 136 This finding provided a novel design of bsAb by targeting different epitopes to improve the potency in neutralizing SARS-CoV-2 variants.

Although antibody cocktails that target different regions of the S protein are still the main format for the treatment of SARS-CoV-2, the newly explored bsAbs can exert potent effects via distinct mechanisms of action that cannot be achieved by conventional mAbs. The details of the design and format of the above bsAbs are summarized in Table 4 .

The COVID-19 pandemic has caused unprecedented health and economic crises worldwide. Historically, it has also triggered unprecedented efforts to develop vaccines and efficacious treatments for the disease. Although several COVID-19 vaccines are being used, all of them are administered intramuscularly or subcutaneously, which might not always induce an effective mucosal immune response. [137] [138] [139] So far, no vaccine to boost mucosal immunity has been developed for SARS-CoV-2 infection. Therefore, the current challenge in vaccine design is to induce long-lasting systemic and mucosal protection against all SARS-CoV-2 variants, and the same is true for antibody-based therapies. In this case, intranasal administration of selected high-affinity polyreactive IgM or sIgA might be a promising approach for COVID-19.

Traditionally, IgM antibodies have proven difficult to express and purify due to their large size and complexity. Thanks to advances in manufacturing, engineered IgM antibodies such as IgM-14 33 can be produced with good quality, and it will be administered by intranasal and intraoral spray in clinical trials. In fact, several engineered IgM antibodies are being investigated in oncology clinical trials, and more than half of these IgM target antigens that are poorly immunogenic, which makes it difficult to generate IgG mAbs. 16 However, multivalent antibodies, like IgM, might have an off-target effects, resulting in low affinity, less specificity and unexpected toxicities. Nonetheless, the use of IgM is anticipated as an essential approach to defend against complex pathogen infections, especially viruses that are difficult to target.

In addition to IgM, specific IgA response has been considered for vaccine design since the 1960s. The rotavirus vaccine is recognized as a model system for the therapeutic potential of intestinal IgA in digestive viral infections. 140 Another example is the oral poliovirus vaccine, which induces strong specific IgA responses to neutralize distinct serotypes. 141 Apart from an oral route, nasal administration is another strategy to induce sIgA in respiratory tracts. For example, intranasal administration of influenza vaccines induces strong IgA responses in nasal mucus, which correlate with vaccine efficacy. 142, 143 A very recent study also reported a single intranasal dose of SARS-CoV-2 vaccine candidate that induces potent IgA responses in hamsters. 144 Although vaccine-induced IgA responses have been largely considered, the development of neutralizing IgA antibodies in preventing viral infections is very limited compared to IgG mAbs. It is noteworthy that IgA antibodies have been reported to have anti-inflammatory roles by inhibiting complement activation mediated by IgM or IgG. In this case, intranasal immunization should be an effective means to generate sIgA responses in respiratory tracts where SARS-CoV-2 could be eliminated without inducing dysregulated inflammatory consequences.

Last, but not least, exploration of novel engineered bsAbs may offer great potential as a versatile alternative to conventional mAbs. In addition, single-domain antibodies (sdAbs) derived from variable heavy homodimer (VHH) domains of antibodies in camels or llamas will become a trend for the next-generation of antibody-based therapeutics in the future. sdAbs are typically a peptide consisting of only heavy chains that retain the full antigen-binding capacity as conventional antibodies. 145 The small size (~15 kDa) of sdAbs allows them to reach antigens that conventional mAbs cannot. 146 Other benefits of sdAbs include flexible formatting, rapid and lowcost development, high production efficiency, and easy administration via nebulized inhalation. 146, 147 Although the small size of sdAbs leads to a rapid renal clearance, strategies to extend their half-life, such as conjugation to the Fc domain of a conventional antibody, have been used. 146 Humanized sdAbs targeting the RBD exhibit potent neutralization activity against both pseudotyped and authentic SARS-CoV-2, and fusion of the human IgG1 Fc to sdAbs further improves their neutralization activity by up to 10 times. 148 Reformatting sdAbs into multivalent constructs 149 or a bispecific format 150 makes them more potent to broadly neutralize SARS-CoV-2 variants. In this regard, sdAb represents a promising therapeutic agent for passive immunization against SARS-CoV-2.

In summary, a comprehensive understanding of all immune processes involved in SARS-CoV-2 infection will be required to fully control the pandemic. Future vaccine development should aim at inducing rapid and mucosal immune responses via different routes of administration, including but not limited to intranasal delivery, which may achieve desirable results beyond those with conventional vaccine administrations. In terms of antibody-based therapeutics, efforts should be made to develop IgM and IgA antibodies, as well as engineered bsAbs or cross-isotype molecules 151 against SARS-CoV-2.

ACE2, angiotensin-converting enzyme 2; bsAb(s), bispecific antibody(ies); CCP, COVID-19 convalescent plasma; CDR, complementarity-determining region; CH, constant heavy; CL, constant light; COVID-19, coronavirus disease 2019; dIgA, dimeric IgA; EUA, Emergency Use Authorization; Fab(s), antigen-binding fragment(s); FcR, Fc receptor; HIV, human immunodeficiency virusIg, immunoglobulin; i.v., intravenous; IVIG, intravenous Ig preparation; J-chain, joining chain; KIH, knob-in-holem; Ab, monoclonal antibody; mIgA, monomeric IgA; NTD, N-terminal domain; PDB, protein data bank; pIgR, polymeric Ig receptor; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SC, secretory componentsd; Abs, single-domain antibodies; SID, Selective IgA Deficiency; sIgA, secretory IgAS protein, spike glycoprotein; VH, variable heavy; VHH, variable heavy homodimer; VL, variable light; VOCs, variants of concern Acknowledgments This work was supported by the Shenzhen Science and Technology Innovation Commission 

No potential conflict of interest was reported by the authors. 

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

Enhanced SARS-CoV-2 neutralization by dimeric IgA

Increased in vitro neutralizing activity of SARS-CoV-2 IgA1 dimers compared to monomers and IgG

A cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction

Is SARS-CoV-2 neutralized more effectively by IgM and IgA than IgG having the same fab region? Pathogens

HIV-1-specific iga monoclonal antibodies from an HIV-1 vaccinee mediate galactosylceramide blocking and phagocytosis

Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies

IgA dominates the early neutralizing antibody response to SARS-CoV-2

IgA antibodies and Iga deficiency in SARS-CoV-2 infection

Distinct conformational states of SARS-CoV-2 spike protein. Science

Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2

Expanding the boundaries of biotherapeutics with bispecific antibodies

Ligand association rates to the inner-variable-domain of a dual-variable-domain immunoglobulin are significantly impacted by linker design

Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice

Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern

Mucosal IgA responses in influenza virus infections; thoughts for vaccine design

Effect of preexisting serum and mucosal antibody on experimental Respiratory Syncytial Virus (RSV) challenge and infection of adults

The mucosal and serological immune responses to the novel coronavirus (SARS-CoV-2) vaccines. Front Immunol

A systematic review of anti-rotavirus serum IgA antibody titer as a potential correlate of rotavirus vaccine efficacy

Systematic review of mucosal immunity induced by oral and inactivated poliovirus vaccines against virus shedding following oral poliovirus challenge

Intranasal vaccination with an inactivated whole influenza virus vaccine induces strong antibody responses in serum and nasal mucus of healthy adults

Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus

A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters

Naturally occurring antibodies devoid of light chains

Nanobodies as therapeutics: big opportunities for small antibodies

Exploiting nanobodies' singular traits

Humanized single domain antibodies neutralize SARS-CoV-2 by targeting the spike receptor binding domain

Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape

A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

IgGA: a "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions