As described above the functions mediated by serum IgA are dependent on the interaction with FcαRI. In case of infection IgA-antibodies recognize and opsonize invading pathogens and their toxins. Binding of multivalent IgA-immune complex to FcαRI induces – depending on the immune effector cell type – several pro-inflammatory effector functions. These include firstly direct clearance mechanism like neutralization, phagocytosis, degranulation, NET formation, release of reactive oxygen species (ROS) or antibody dependent cellular cytotoxicity (ADCC). And secondly the further activation of the immune response, for example due to the release of inflammatory cytokines or chemokines, antigen presentation or the recruitment of neutrophils by the chemoattractant LTB4 [reviewed in (13, 51, 86, 87)].

Independent of FcαRI, IgA has the ability to induce the alternative and lectin pathway of the complement system, thereby promoting complement dependent pathogen clearance (94).

In contrast, and in the absence of any pathogenic antigen, monomeric serum IgA mediates important immunomodulatory functions via FcαRI and ITAMi signaling, thereby restoring a homeostatic state after inflammation. It was shown that IgA downregulates several inflammatory cell responses, e.g. IgG-mediated phagocytosis, chemotaxis, oxidative burst and inflammatory cytokine release [reviewed in (87, 91, 95)]. Furthermore, IgA blocks IgG-mediated complement activation (96) and counteracts IgE-FcϵRI-induced mast cell degranulation (97, 98). ITAMi signaling is therefore described as a critical mechanism to maintain immune homeostasis (92, 98).

Apart from FcαRI and innate immune cells, it was shown that IgA is able to modulate the T-cell response. Saha et al. demonstrated that monomeric serum IgA is able to inhibit Th17-cell mediated inflammation, and concurrently expand FoxP3⁺ Treg-cells via F(ab’)₂ binding to cytokine receptors (99).

The main function of SIgA on the lung mucosa is to provide protection against invading pathogens. This is possible due to its unique properties, which include high valency binding to pathogens (due to its multimeric structure) and the high resistance to bacterial proteases (due to SC) (1, 100).

During infection SIgA induces agglutination of bacteria and virus, thereby preventing pathogen binding to lung epithelium ( Figure 1A ). Agglutinated pathogens are rapidly cleared through the mucus, a process known as immune exclusion. The fact that pIgR can transport IgA alone or in complex with an antigen, allows the efficient intracellular neutralization of virus within infected epithelial cells during transport to the mucosa. In addition, pathogens that invaded into the lamina propria can be opsonized by dimeric IgA and transported back to the mucosa, a process called antigen excretion. In addition to pathogens, SIgA can also efficiently neutralize pathogenic toxins and enzymes ( Figure 1B ) (13, 16, 17, 87). The importance of IgA multimerization for efficient pathogen binding and neutralization was demonstrated several times and has to be highlighted as a central element in therapeutic IgA antibody development (101–104).

Like serum IgA, activation of FcαRI bearing effector leucocytes via SIgA has been reported, although binding of SIgA to FcαRI is partially hampered due to steric hindrance of SC ( Figure 1C ) (51, 87, 89, 105). Based on transgenic mouse and in vitro studies, SIgA binding can promote inflammatory activation of the mucosal immune response e.g. phagocytosis, ADCC, ROS generation, degranulation and inflammatory cytokine secretion (1, 2, 23, 51, 74). Furthermore, the binding of SIgA opsonized pathogens to FcαRI on neutrophils, induces LTB4-release and recruitment of further neutrophils to the lung ( Figure 1C ) (87, 89).

Despite the generally well-known anti-pathogenic functions, SIgA mediates also important immunomodulatory effects on different mucosal immune cell types. Similar to monomeric serum IgA, it is proposed that the low affinity binding of SIgA to FcαRI, in absence of antigen, leads to immunomodulatory effects via inhibitory ITAMi signaling on mucosal effector leukocytes ( Figure 1D ) (2, 74, 89).

The anti-inflammatory effects of SIgA were frequently demonstrated by looking at the cytokine response. Under homeostatic conditions SIgA can reduce the pathogen-mediated inflammatory cytokine response, downregulates the oxidative burst and the release of inflammatory cytokines of neutrophils and epithelial cells in vitro ( Figure 1D ) (59, 60, 97, 106, 107). However, not only SIgA but also the SC alone has immunomodulatory properties. It was shown that the SC can neutralize IL-8, an important chemokine for neutrophil migration ( Figure 1D ) (108).

In addition to infection-mediated inflammation, SIgA has important anti-inflammatory functions in context of allergic reactions. Due to immune exclusion SIgA prevents allergen binding and activation of the mucosal immune response (2, 97), as well as IgE-mediated degranulation of mast cells via cross-linking of FcαRI ( Figure 1E ) (97, 98).

Furthermore, cells of the adaptive immune response can be modulated by SIgA. It was shown that SIgA interacts with DC in mice via SIGNR-1 (the human analog to DC-SIGN), thereby inhibiting pro-inflammatory cytokine production and inducing IL-10 production via expansion of regulatory FoxP3⁺ Treg-cells ( Figure 1F ) (34, 91).

IgAbulin was a plasma-derived preparation consisting mainly of IgA (~70% of Ig’s), but also notable amounts of IgG (~30% of Ig’s) and additionally transferrin (~10% of total protein). Approximately 74% of the total immunoglobulin was monomeric, ~17% dimeric, ~1% polymeric and ~3% fragmented (126, 131, 132).

The anti-inflammatory effects of IgAbulin were investigated in vitro. IgAbulin downregulated FcαRI-dependent the release of TNF-α and IL-6, as well as the oxidative burst of neutrophils and monocytes. In contrast the release of the inhibitory IL1-ra was enhanced (107, 148, 149). IgAbulin demonstrated more potent anti-pathogenic properties than IVIg, by neutralizing streptococcal superantigens in vitro (150).

In a double blind, placebo-controlled study, IgAbulin was administered as a nasal spray to children with rhinitis. Children in the IgAbulin group had significant reduced days with rhinitis compared with placebo (n=40, p=0.004) and the ease of use was convincing (133). In another placebo-controlled trial in children with frequent respiratory infections, IgAbulin was effective in the prophylaxis and reduction of upper respiratory tract infections (n=36, p < 0.012). In this study IgAbulin was applied via nose drops in the nasal cavity and showed a good safety profile, as well as a convenient application to the children (134).

In two similar experimental studies, IgAbulin was used as prophylaxis to prevent infections in adult top-athletes. The nasal application lead to an increase in nasal salvia IgA levels, however reduced upper respiratory tract infections only in one of the studies significantly (n=34, p < 0.01) (135, 136).

Besides intranasal administration, the efficacy of IgAbulin was also tested after oral administration. In a prospective study of infants and children with chronic diarrhea IgAbulin lead to a reduced number of stools per day (n=7, p < 0.05) (131) and in a randomized clinical trial prevents necrotizing enterocolitis (NEC) of preterm infants and neonates (n=179, p=0.0143) (132). However, a meta-analysis concluded no significant benefit after oral IgAbulin administration, which does not support the further use of IgAbulin in NEC (137).

The monomeric form of IgA, which was the main ingredient, could be a reason for the limited efficacy of IgAbulin (100). However, and importantly, no concerns with anaphylactic reaction caused by pre-existing anti-IgA antibodies were observed, which was for a long time considered as a possible risk factor in IgA therapy (126, 151).

The usage of IgAbulin was safe and well-tolerated justifying the use of therapeutic IgA preparations. The application of IgAbulin to prevent respiratory tract infections is the only known clinical delivery of a therapeutic IgA antibody to the mucosa and therefore a potential starting point for further approaches. Using multimeric-polyvalent IgA preparations or higher dosage could be more effective and might be an option to be further investigated in the future.

Venimmun N was a plasma preparation, with an IgA-portion of ~12%, but there are no data about the biochemical structure of these IgA molecules available (126). Venimmun N was used in experimental studies as substitution therapy in patients with immune deficiencies and as prophylaxis for septic complications, with no clear effects (138, 152, 153).

In the treatment of autoimmune diseases, Venimmun N showed contradicting results. Although in case studies the treatment of patients with Crohn’s diseases mediated beneficial immunomodulatory effects, there was no benefit compared to a standard IVIg (139, 154). Moreover, in a prospective crossover trial with 177 immune thrombocytopenic purpura (ITP) patients no significant differences in the response rates of Venimmun N treatment could be demonstrated (140). In a comparative in vitro study, Venimmun showed stronger modulation of TNF-α release than standard IVIg in microglia cell culture. An effect partially attributed to the IgA component. However, another IgM/IgA-enriched preparation Pentaglobin showed much more potent effects on TNF-α release and nitric oxide production (155).

In most of the mentioned studies, Venimmun N was considered as a pure IgG preparation; therefore, no evaluation of the therapeutic effect of IgA in this preparation can be performed.

Pentaglobin is a human plasma-derived immunoglobulin preparation containing IgM, IgA and IgG. The immunoglobulin distribution in Pentaglobin (~12% IgM, ~12% IgA and ~76% IgG) is comparable to that in human serum (12, 126). Biochemical characterization of Pentaglobin showed a complex mixture of monomeric IgG, monomeric IgA, dimeric and trimeric IgA, as well as pentameric IgM. The multimeric IgA and IgM species were shown to be associated with notable amounts of J-chain, which could enable the transport to mucosa and support the usage in inflammatory lung diseases (156).

Indeed, in a case report of a common variable immunodeficiency patient it was shown that IgA applied with Pentaglobin can be transported onto the lung and help to reduce exacerbations of bronchiectasis (157, 158). Furthermore, the IgA portion of Pentaglobin was shown to be transported to the lung of rats and mice, with notable amounts of functional active IgA present in the BAL (159, 160). The presence of administered immunoglobulins on the lung helped to defeat bacterial infections and protected lung tissue via immunomodulatory effects in a mouse model of stroke associated pneumonia (160).

In focus of systemic inflammatory diseases, like sepsis and septic shock, the use of plasma-derived immunoglobulin preparations is a promising approach, as these can mediate both – pro- and anti-inflammatory – effector functions (161). These dual functions were demonstrated for Pentaglobin in various in vitro and in vivo studies.

The anti-pathogenic functions of Pentaglobin comprise the opsonization and phagocytosis of pathogens (162–164), as well as the neutralization of bacterial endo- and exotoxins (164–166). Functions, which were mediated more efficiently by Pentaglobin in comparison to standard IVIg (167–169). It was shown that all immunoglobulin species (IgM, IgA and IgG) within Pentaglobin have titers against surface antigens of the most common pathogens involved in sepsis (170).

Pentaglobin showed stronger immunomodulatory properties than IVIg, like the modulation of complement factors (171–173) and cytokines (e.g. IFN-γ, TNF-α, IL-6, IL-8, IL-1β, IL-10) (167–169, 174). Furthermore, Pentaglobin demonstrated immunomodulatory effects on T-cells in vitro and in vivo (168, 175, 176).

In most of the mentioned studies these effects were attributed to the IgM component, thereby not adequately addressing the role of IgA in this polyclonal preparation (126). However, as pure IgM and IgA controls were lacking in these studies, some effects could also be attributed to IgA. Recent data confirm that IgA can have important effector functions in such IgM/A-enriched immunoglobulin preparations (123).

Apart from the preclinical data, there is a lot of clinical experience gathered in the last decades with Pentaglobin. Pentaglobin was approved in 1985 (177) for the use as adjuvant therapy of severe bacterial infections and immunoglobulin substitution in immunocompromised patients.

In septic patients, the levels of the main immunoglobulin isotypes IgM, IgA and IgG are often decreased and were associated with a reduced survival rate (178, 179). Therefore, the supplementation of all three classes seems to be a promising strategy (161). Pentaglobin has been investigated in numerous clinical trials for the adjunctive therapy of sepsis in adult (141–143) and in several trials in paediatric patients and neonates with sepsis (180–183). As mentioned in several reviews the additional IgM- and IgA-components in Pentaglobin mediate beneficial effects in the treatment of inflammatory diseases compared to IVIg (100, 126, 151, 161, 177, 184). This was confirmed in systematic meta-analyses, where a significant reduction of mortality and length of mechanical ventilation was shown after Pentaglobin treatment in patients with severe sepsis and septic shock (141–143). This effect was not that pronounced after IVIg treatment (141, 143).

Furthermore, there were some case reports and small studies regarding the usage of Pentaglobin as adjunctive therapy in COVID-19 (185–188). Although in a large retrospective cohort study, no significant difference in mortality was observed (n=316, p=0.374), a subgroup of severe COVID-19 patients who have not yet received invasive mechanical ventilation may benefit from Pentaglobin therapy (p=0.063). It has been observed that an early and high dose of Pentaglobin seems to help patients with low IgM, IgA and IgG levels (189).

The efficacy and safety of Pentaglobin was shown in various studies and countless regular administrations over decades, therefore Pentaglobin is currently the longest lasting and best characterized therapeutically used preparation containing IgA. Simultaneously there is limited knowledge regarding the functional role of IgA in Pentaglobin. Based on the complexity and heterogeneity of this preparation containing IgM, IgA and IgG, it is challenging to attribute beneficial effects to a distinct component. With emerging data regarding the immunoglobulin biochemistry, it seems to be feasible that these polyclonal immunoglobulin preparations could also mediate protective effects in inflammatory lung diseases, where especially multimeric IgA species could be an object of interest.

Trimodulin is a human plasma-derived native polyvalent antibody preparation for intravenous administration with ~23% IgM, ~21% IgA and ~56% IgG. Based on a new manufacturing process, native immunoglobulins with more active Fc- and Fab-binding sites compared to Pentaglobin were purified.

Trimodulin is in clinical development for the treatment of sCAP and moderate/severe COVID-19, two inflammatory lung diseases. In a post-hoc analysis of a phase II trial (NCT01420744) conducted in sCAP patients, trimodulin showed significant reduction in mortality in a subgroup of invasively ventilated patients with low IgM (≤ 0.8 g/L) and/or high CRP (≥ 70 mg/L) levels (n=92, p=0.006). Furthermore trimodulin prevents secondary infections, based on a reduced number of infection-related adverse events (144). During the recent pandemic, the development of trimodulin was expanded to the additional indication, severe COVID-19. A phase II study in patients with severe COVID-19 [NCT04576728 (145)] showed reduced mortality in a subgroup of hospitalized patients with early systemic inflammation (manuscript under preparation). Based on the promising results from the two phase II trials, development of trimodulin now continues in two phase III trials in sCAP [NCT05722938 (190)] and moderate/severe COVID-19-patients [NCT05531149 (146)].

The comprehensive preclinical characterization identified three relevant modes of action for trimodulin: (i) opsonization and clearance of pathogens, (ii) neutralization of toxins and (iii) modulation of the inflammatory response.

The opsonization and clearance of causal pathogens was shown by a large repertoire of antigen binding activities, as IgM, IgA and IgG antibody titers against relevant bacteria, viruses and fungi were present in trimodulin. It was shown that the antibodies of trimodulin can opsonize and enhance phagocytosis in vitro (123, 191). The trimodulin mediated phagocytosis and inflammatory activation of neutrophils was shown to be dependent on IgA-FcαRI and IgG-FcγR binding, highlighting the anti-pathogenic effects of IgA in this therapeutic antibody preparation (123).

The efficient neutralization of bacterial toxins by IgM, IgA and IgG plasma preparations is known from literature (150, 165–169), but was also demonstrated for trimodulin. Trimodulin can effectively neutralize pneumolysin and protect platelets from pneumolysin-induced damage (192, 193).

The immunomodulatory properties of trimodulin on the release of several cytokines and chemokines (e.g. TNF-α, IL-17a, IFN-γ, MCP-1, IL-8, IL-1ra and IL-10) were assessed in different cell-culture models and shown to be significantly stronger compared to IVIg (123, 124, 194). In a neutrophil-cell model, the endotoxin-induced IL-8 release was reduced via binding of the trimodulin IgA-component to FcαRI and subsequent ITAMi signaling (123). As the FcR-mediated effects of IgM on neutrophils are of minor importance, the beneficial effects over IVIg can be attributed to the IgA component (123, 124). Furthermore, direct binding and neutralization of IL-8 by trimodulin was more potent than by IVIg, an effect that can be related to the multimeric IgM and IgA species (123).

Immunomodulation by trimodulin was also observed on the expression of monocyte and neutrophil cell surface receptors, like FcR, TLR and complement receptors (123, 194). On the neutrophil-like HL-60 cell-line, trimodulin counteracted the endotoxin-mediated upregulation of activating FcR for IgG (FcγRI, FcγRIIA and FcγRIII) as well as IgA (FcαRI). Effects which were not observed due to IVIg treatment (123). These modulatory effects on surface receptor expression seem to counteract inflammatory cell responses, like phagocytosis, ADCC or chemokine release. The altered activation of intracellular signaling cascades via IgA-FcαRI binding could to be key in modulating the neutrophil inflammatory response.

Furthermore, trimodulin has a dual and balancing function on the complement system. By either activating complement and induce opsonophagocytosis, or avoiding excessive activation by interacting with the activated complement factors C3b and C4b (191). This balancing effect on anaphylatoxins were also observed in healthy subjects and sCAP patients treated with trimodulin (144, 191).

The data regarding the immunomodulatory modes of action of trimodulin give a complex picture. The antibody isotypes target several receptors and mechanism simultaneously, leading to more potent immunomodulation compared to a pure IgG preparation. It is difficult to attribute the pharmacological effects to one immunoglobulin component; rather it is feasible that all components together (IgM, IgA and IgG) mediate the observed clinical effects, as mentioned by others (179). Nevertheless, it was clearly shown that the (often neglected) IgA component of trimodulin mediates powerful effects, especially via FcαRI binding on neutrophils (123, 124).

Based on the high IgA content and the potent immunomodulatory activity, trimodulin is a promising preparation for the treatment of inflammatory lung diseases. Further research is necessary to expand the knowledge regarding the role of IgA in this preparation and the intended indications, as this may help to take advantage of the full therapeutic potential of this product.

The direct application of therapeutic IgA antibodies onto the lung offers a great opportunity compared to systemic delivery as it can support the respiratory immune defense before pathogens enter the circulation, which was shown in several animal models (195–202), or protect the lung tissue by anti-inflammatory effects as shown in mice (106, 197, 203, 204). Inhalation ensures a rapid and high amount of drug directly delivered to the site of action in the lung, which is not achieved with other administration forms. Therefore, a lower dose can be used to achieve the same efficacy, which avoids possible side effects (205).

Technically, antibodies can be delivered to the lung via metered dose inhalers, dry powder inhalers or nebulizers (206). These oral inhalation procedures should be distinguished from intranasal administration (e.g. via nasal sprays), as the latter applies the drug to the nasal mucosa, whereas oral inhalation reaches the lung mucosa (7). Inhalation therapy is routinely used in the treatment of chronic lung diseases, e.g. asthma or COPD. Administration by inhalation allows self-administration and is more comfortable to the patient in comparison to invasive administration with a needle (205, 207).

Some monoclonal antibodies applied via inhalation route are currently in preclinical or clinical trials (205, 207). Furthermore, some clinical tests were performed with inhalable IVIg (208, 209). However, development of antibodies for administration by inhalation is challenging and the failure rate high. Firstly, the pre-clinical testing in animal models is difficult as rodents are obligate nose breathers and have several anatomical differences compared to humans, which lead to different distribution and clearance patterns (7, 210). Secondly, the pharmacokinetics of inhaled antibodies are not as favorable, because the half-life is with ~ 1 day (for IgG) much shorter than in human serum (~23 days) (205, 211). Thirdly, stability during the nebulization process can be critical for the development, as immunogenic aggregates can be formed (212).

To circumvent these issues, there are some approaches to enhance stability of proteins during nebulization process and enhance residence time in the lung. These approaches include protein engineering, formulation- and carrier development, or optimization of the nebulization process (212).

Antibody engineering approaches aim to modify the structure of antibodies to enhance lung residence time and stability. These include the generation of smaller antibody fragments, Fc-engineering or PEGylation (213). Conjugation of polyethylene glycol (PEG) chains to proteins increases the molecular size and mucoadhesion, thereby leading to enhanced resistance against proteolytic digestion and alveolar uptake (213–215). The development of formulations and carrier particles specifically for inhalation therapy offers a variety of solutions to prolong residence in the lung. Besides the classical additives (e.g. salts, sugars or surfactants), several carrier-formulations like liposomes, micelles, nano- or micro-particles and microspheres were developed (216). Based on particle size/shape and surface charge/coating the deposition, retention and cellular uptake of carrier particles can be influenced (205, 217, 218). During the nebulization process it is crucial to maintain the molecular integrity and potency of the drug, as well as targeted delivery. These critical parameters are driven by the nebulization device and the particle size (213, 217).

SIgA has an outstanding role in the mucosal immunity and its function is impaired in several inflammatory lung diseases, as mentioned within this review. Therefore, supplementation with inhalable therapeutic IgA antibodies might be a worthwhile strategy (2). Especially with regard to neutrophil-mediated inflammation, modulation by IgA seems to be promising (1, 23, 123, 124).

However, only a limited number of monoclonal IgA antibodies were used for the intranasal delivery to the respiratory system in animals (219, 220) and despite promising results did not reach clinical testing. To avoid further setbacks, e.g. an excess of therapeutic IgA might be applied, as degradation of IgA by neutrophil- and bacterial proteases could have hampered clinical effects in previous approaches. Alternatively, IgA preparations could be improved in a manner that mimics SIgA structural stability, to be efficiently used on the mucosa (27).

Hence, Longet et al. coupled a recombinant SC to plasma-derived multimeric IgA and IgM, thereby creating secretory like molecules (21, 106). In vitro these SIgA and SIgM molecules were less prone to proteases and protected epithelial cells from bacterial-induced damage (21, 106). In three in vivo mouse models SIgA/IgM, as well as other plasma-preparations (monomeric IgG (IVIg), monomeric IgA and multimeric IgA/M) were applied orally or intranasally. The immunoglobulins reduced mucosal infection and protected the animals from lethal bacterial and viral infection. In contrast to the in vitro data, coupling of the SC to IgA/M was not beneficial and IVIg was more efficient in vivo (195, 197, 202). As part of one study, the immunoglobulins were nebulized and administered via oral inhalation to rats and non-human primates. IgM, IgA and IgG remained structurally and functionally intact during the nebulization and were detectable in the BAL of these animals (202). In addition to the animal models, the nebulized IVIg was tested in a human in vitro air-liquid interface tissue culture model. The IgG formulation reduced viral infections and maintained the integrity of the epithelial tissue (221). Based on this pre-clinical data, a clinical phase I study with the nebulized IVIg (CSL787, not comprising IgA) recently started in healthy subjects and patients with non-cystic fibrosis bronchiectasis [NCT04643587 (222)].

It remains questionable why the multimeric secretory-like IgA preparations were not able to reproduce the in vitro efficacy in these animal models. Perhaps the recombinant SC lost its protective functions in vivo. This could also explain why intravenously applied IgM/A/G, which was transported naturally onto mucosa protected mice from infection (160). Nevertheless, the available data show that application of IgA to the lung via nebulization is feasible and could open the door for future research in this field. Current alternatives to animal testing could be especially useful to answer the open questions (see below).

As outlined above only plasma-derived polyclonal IgA antibodies were used in humans so far; recombinant monoclonal IgA antibodies did not proceed further than experimental or pre-clinical testing. Especially for the production of recombinant IgA antibodies, technical issues were limiting. For example, the purification of IgA requires new capture materials, as the usually for IgG purification used materials do not bind IgA (112, 223). Another issue is the natural ability of IgA to form different multimeric forms, as these require high demands in regard of manufacturability and characterization (e.g. distinction between aggregates) (101). One of the biggest issues are the number of glycosylation sites, because the IgA hinge region is heavily glycosylated, it is problematic to generate consistent glycoforms, as well as to implement proper quality control (101, 112, 120, 224). Furthermore, the complexity of IgA in regard to protein size and glycosylation leads to lower expression yields compared to recombinant IgG (101, 223).

To circumvent the persisting problems with recombinant IgA antibodies, recent antibody engineering strategies successfully improved the manufacturability and the pharmacokinetic properties of IgA. These strategies include modification of the sugar residues (e.g. increased sialylation or removal of N-linked glycosylation sites), addition of an albumin binding domain (which enables recycling by FcRn) or generation of IgG-IgA hybrid antibodies with a similar half-life as IgG1 (27, 112, 120). Furthermore, by using different IgA-engineering approaches and alternative expression systems, the production of IgA multimers was recently successfully established (101, 223).

The idea of therapeutic IgA antibodies gets new attention during COVID-19 pandemic, as a notable high virus neutralization capacity of these multimeric isotypes compared to IgG was shown (225–227). Therefore several studies were published aiming to produce recombinant multimeric IgA antibodies (104, 226, 228, 229). With several advances in manufacturing of recombinant multimeric IgA species, clinical trials seem to be possible (101, 227).

There were promising efforts in inducing a protective SIgA immunity due to intranasal vaccination, which is already successfully used against influenza virus (71). Currently intranasal vaccination is in development against SARS-CoV-2 (76, 77), but these efforts are currently hindered by translation from animals to humans (3). This is a commonly known problem in development of respiratory drugs, especially therapeutic antibodies (205, 207, 230, 231).

Although there were successful efforts with transgenic mouse models, more hope can be gained from new alternative strategies with in silico, human ex vivo tissue-models (e.g. precision-cut lung slices) or 3D-cell culture approaches (4, 7, 230). Due to recent advances in the field of multi-organ chip technologies, which combines the mentioned technologies with microfluidic devices, more systemic and complex responses to the drug can be predicted (230). Although it is clear that animal models will be indispensable in the nearer future and further improvements in the field need to be done (231), these new approaches could improve translational research and could improve our understanding of the behavior of drug candidates, while simultaneously being concordant with the 3R-principles. These approaches may pick up many of the current pitfalls in IgA research and could push the usage of IgA antibodies towards the clinical stage.