WO2021198220A1

WO2021198220A1 - Treatment and prevention of secondary inflammation in patients suffering from a viral infection

Info

Publication number: WO2021198220A1
Application number: PCT/EP2021/058234
Authority: WO
Inventors: Emil Richard George POT; Cornelis Johannes Leenhouts; Poul SÖRENSEN
Original assignee: Allero Therapeutics B.V.
Priority date: 2020-03-30
Filing date: 2021-03-30
Publication date: 2021-10-07

Abstract

The present invention relates to the treatment or prevention of non-IgE mediated secondary inflammation in patients suffering from a viral infection by oromucosal administration of a mucoadhesive carrier being a patch, film or hydrogel comprising immunoglobulins.

Description

TREATMENT AND PREVENTION OF SECONDARY INFLAMMATION IN PATIENTS SUFFERING FROM A VIRAL INFECTION

Field of the Invention The present invention relates to the fields of medicine and inflammation. The present invention relates to the treatment and/or prevention of non-lgE mediated secondary inflammation in patients that are undergoing a viral infection, such as Influenza, RSV or Corona viruses, through blocking inflammatory responses via the Fc receptor (FcR) using oromucosal administration of FcR specific antibodies, small molecules, or immunoglobulin (IG).

State of the Art

The newly emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causes the respiratory disease COVID-19. The clinical spectrum of COVID-19 disease is quite wide and includes severe type with respiratory distress and critically ill patients that need intubation or intensive care in approximately 5% of proven SARS-CoV-2 infections. The virus can result in a dysregulated immune response exemplified by a cytokine storm that seems to be associated with disease severity, as it can lead to capillary leak syndrome, progressive lung injury, respiratory failure, acute lung inflammation and acute respiratory distress syndrome (ARDS)[1j. In addition to ARDS, further complications in the critically ill patients include shock, acute cardiac injury and acute kidney injury. This is in line with what is known from other viral infections like influenza, RSV and previous coronavirus infections (SARS, Middle East Respiratory Syndrome- virus (MERS), as well as with the general fact that infectious and non-infectious triggers can result in a cytokine storm, progressing to vasoplegic shock and finally multi-organ dysfunction syndrome. Fundamental to ARDS is the acute onset of lung inflammation, which is intimately tied to monocyte/macrophage polarization and function. Although neutralizing Abs are the long-term solution to prevent disease, there is concerning evidence that anti-SARS-CoV-2 antibodies may contribute to lethal immunopathology and this involves Fc receptor-mediated antibody-dependent enhancement (ADE) of viral infection and inflammatory responses or vaccine-associated enhanced respiratory disease (VAERD)[2-4j.

VAERD occurs when immunizing with especially conformationally incorrect antigens and can also result in enhanced respiratory disease driven by inflammation and responses that accentuate production of the cytokines interleukin-4 (IL-4), IL-5, and IL-13 resulting in increased mucus production, eosinophil recruitment, airway hyperresponsiveness, and attenuated cytolytic T cell activity, collectively known as Th2 immune responses. ADE occurs when antiviral neutralizing antibodies cannot completely neutralize the virus. Instead, the virus-neutralising Ab (virus-NAb) complex attaches to FcR, leading to viral endocytosis and infection of the target cells. The outcome is an increase in the overall replication of the virus and greater disease severity. Virus-NAb complex binding to FcR can also activate proinflammatory signalling, skewing macrophage responses to the accumulation of proinflammatory (M1 or classically activated) macrophages in lungs. The M1 macrophages secrete inflammatory cytokines such as MCP-1 and IL-8, leading to lung injury. Based on this hypothesis potential therapeutics have been proposed to block SARS-CoV-2-induced inflammatory responses via FcR using FcR targeted specific antibodies, small molecules, or intravenous immunoglobulin (IVIG)[1 ].

IVIG is a blood product containing polyclonal immunoglobulin G isolated and pooled from healthy donors and has been used for over 30 years. As a complex preparation, it contains a large number of bioactive moieties, and the entirety of effects is not yet fully understood. IVIG of higher dose has been a choice of immunomodulatory therapy for autoimmune or inflammatory disease, and for prophylaxis and treatment of severe infections especially in immunocompromised patients [5] Several theories have been proposed to explain its potential immunomodulatory mechanisms, including modulation of expression and function of Fc receptors, interference with complement activation and the cytokine profiles, modulation of idiotype network and cell proliferation. While some of these effects may explain the rapid and passive neutralization of pathogenic autoantibodies, clinically the observed beneficial effects of IVIG are well beyond the half-life of infused IgG, suggesting that the effect may not be due merely to a passive clearance or competition with pathogenic autoantibodies. Moreover, also at replacement dosages and beside their mere substitutive role, immunoglobulin has an active role and modulates the function of several cell types of the immune system, including dendritic cells, B lymphocytes, macrophages and T lymphocytes [6] Interestingly the inhibitory FcR, FcyRIIB (CD32b), may also be targeted to inhibit FcR activation and the FcRn can also be blocked by specific antibodies or inhibited competitively through immunoglobulin binding[7].

In previous studies of SARS and MERS, IVIG therapy has exhibited various clinical benefits with good tolerance[2]. Considering its efficacy in improving passive immunity and modulating immune inflammation, and the overall safety profile, high dose IVIG is pursued as a promising option at the early stage of clinical deterioration of COVID-19 patients as demonstrated in recent case studies [8, 9] Cao et al reported a series of three COVID-19 patients, all of whom were successfully treated by high-dose IVIG (25 grams per day for five days, body weights between 56 and 66 kg) at the early stage of clinical deterioration^].

Based on these observations, a high-dose IVIG administered at the appropriate time point, could successfully block the progression of disease cascade, and finally improve the outcome of COVID- 19. Importantly as noted by Cao et al: “The timing of IVIG administration is very critical in practice. Patients might not receive much benefit when overall systemic damage has already taken place. ”[9]

IVIG, although widely used has however some issues. Especially the high amount that is needed (125 g per patient in the study of Cao et al) renders it a costly treatment. Moreover, and more importantly with expanding use, there are concerns about present and future supplies, especially if the donor pool decreases or is limited by safety issues and increased pathogen screening of donors of the source plasma. Although IVIG generally is considered a safe and efficacious therapeutic modality, in some cases (1 in 1000 to 1 in 100 infusions) it can be associated with adverse effects, such as injection site reaction (e.g. pain, erythema, swelling at injection site), hypotension, diarrhoea, nausea and vomiting, Arthralgia and myalgia, fatigue, fever, rash, headache, tachycardia, chills/rigors, serious toxicities, erythema multiforme, Stevens-Johnson syndrome, haemolysis, thrombosis, hepatic dysfunction, anaphylaxis, aseptic meningitis, acute renal failure and myocardial infarction [10]

In previous studies of RSV infection it was shown that bovine IgG (blgG) and IVIG were effective in blocking infection and development of disease [11] Although in mice it was shown that blgG is able to bind to murine IgG Fc receptors (FcyR) and intranasal administration of blgG prevented RSV disease development in mice, there was no sign of any systemic release or effect of the IgG/IVIG in these mice, rendering no direction for a possible use of such IgG/IVIG treatment in a systemic disease such as ARDS or VAERD after infection by a virus. Also, only direct effect on the lungs via inhaling through the intranasal route and oral cavity was observed.

In previous studies of allergen-driven airway inflammation it was shown that sublingually administered anti-lgE IgG antibodies were effective in blocking allergen-specific lung inflammation probably mediated by the inhibitory CD32b Fc receptor [12] Also in this study it was not shown that the IgGs were taken up systemically and exerting a systemic effect, but rather a local and direct anti-inflammatory effect after the inhalation of IgGs into the lungs via the sublingual administration. On top of that, the study did only reveal that such inhalation could be used for treating lung inflammation, but not ARDS or VAERD.

Other studies have shown that injecting IVIG, so providing it systemically, could be used to prevent infectious animal models to progress into ARDS. However, no prior art was found that shows that immunoglobulins can be formulated into a patch or film and that such would work systemically if administered locally in the oromucoa.

The above discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.

Invention

Despite the encouraging early clinical data with IVIG treatments in COVID-19 patients, there is a clear need for a safe, faster, more effective and less immunoglobulin resource intensive treatment in urgent medical situations caused by ARDS, ADE and VAERD, and in particular in the prevention thereto. In addressing this need, we surprisingly found that an alternative approach comprising a low dose polyvalent IgG administered through the oral mucosa using a mouth patch, a therapy we term Oromucosal Immunoglobulin (OMIG), is effective in blocking non-lgE mediated inflammatory responses caused by ARDS, ADE and VAERDS in patients that are suffering from a viral infection. The oral mucosa as an alternative delivery route for allergens is well established in the area of allergen immunotherapy where more than a billion doses have been administered over the last two decades with excellent safety and documented efficacy [13] Although this wide use of the oral mucosa as a delivery route, there are no therapies know where polypeptides or immunoglobulins are being administered to patients via an oral patch or film. An advantage of this administration route, as we found hereunder as part of the invention, is that films or patches can be easily administered and precisely located onto the mucosa associated with the different regions of the oral cavity and applies to a broad patient base including unconscious and comatose patients. We found to our surprise that the enhanced and prolonged exposure of IgG’s at the oral mucosa by the OMIG approach enables anti-inflammatory efficacy comparable to IVIG but at a 500-1000 times lower dose in immune mediated disorders caused by ARDS, ADE or VAERD and in a non-invasive fashion. OMIG therefore has several potential advantages as it would require less immunoglobulins, hence more patients can be served and will potentially allow for earlier and non-intensive care intervention in patients including pediatrics before clinical deterioration begins. Furthermore, in case of shortages of human donor immunoglobulins, OMIG allows for the safe non-invasive administration of bovine IgG or recombinant human monoclonal IgG or Fc fragments thereof. Also to our surprise, we have noticed that because of the local administration to oromucosa, there we significantly less adverse events.

A detailed mapping of the oral mucosal immune system has been performed in both mice and humans yielding comparable information. Collectively, these studies establish that immune cells found in oral tissues encompass both antigen-presenting cells, lymphoid cells, and few pro- inflammatory cells. In addition to such resident immune cells dispersed throughout oral tissues, the human oral immune system also comprises organized lymphoid structures [13]. Importantly for our OMIG approach, the therapeutic potential of administration of polyclonal immunoglobulins oromucosally has been evaluated in a murine model of allergen-driven airway inflammation and it was demonstrated that administered low-dose (micrograms) immunoglobulins exhibited an antiinflammatory activity in lungs in the absence of allergen. This anti-inflammatory activity was observed irrespective of the antigen specificity of the antibodies and did not correlate with a downregulation of circulating CD4+ Th2 cells nor with the induction of Treg lymphocytes [12]

The non-invasive OMIG approach is safer compared to IVIG and requires less immunoglobulins, hence more patients can be served. It also is less labour intensive, and will allow for earlier and non-intensive care intervention in COVID-19 patients.

We demonstrate that the embodiments of the invention can treat and/or prevent secondary inflammation in patients suffering from a viral infection, in particular modulating the function FcR of several cell types of the immune system, including dendritic cells, B lymphocytes, macrophages and T lymphocytes, as well as having an inhibitory effect on FcR via FcgRIIB inhibition [7] The FcRn can also be blocked by specific antibodies or small molecules, that can also be included in the invention hereunder.

Detailed Description of the invention

Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference, in particular Masek et al. [14] and published PCT applications WO2012097763 and W02017130141 .

Definitions

As used herein, certain terms may have the following defined meanings. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Similarly, use of "a compound" for treatment or preparation of medicaments as described herein contemplates using one or more compounds of this invention for such treatment or preparation unless the context clearly dictates otherwise.

As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of" shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this invention. Embodiments defined by each of these transition terms are within the scope of this invention.

Mucoadhesive patch

The goal of the invention is achieved by means of the oral delivery of immunoglobulins or Fc fragments thereof [7]using a mouth patch, film or hydrogel. The mucoadhesive mouth patch, film or hydrogel may consist of several layers. In a preferred embodiment the mouth patch consists of two layers. In one layer, called the protective backing layer, no immunoglobulins are present. The protective backing layer covers the mucoadhesive active layer or nanoscaffold reservoir layer that contains the immunoglobulins (Fig. 1A). In the mouth, the active layer is attached to the oral mucosa. Once attached to the oral mucosa, the function of the protective backing layer is to prevent leakage and washing away of the immunoglobulins by mouth fluids from the active layer. In another embodiment the mouth patch may contain an additional third layer. The third layer is attached to the active layer opposite of the protective backing layer, does not contain immunoglobulins but may provide additional mucoadhesion (Fig. 1B).

Mucoadhesive patches as used here are similar as described in Masek et al. [14] and in published PCT applications WO2012/097763 and W02017/130141 . The manufacturing of this type of mucoadhesive patches may involve electrospinning of the nanofibers in the different layers and is described in detail in WO2016/051159 and W02017/130141. The nanoscaffold reservoir layer or active layer preferably contains or has pores having the size of from 10 nm to 1 ,000 pm and/or is a nanofibrous layer of a thickness in the range 0.1 to 1 ,000 pm; or comprises a layer of biocompatible polymers or a mixture thereof.

In a preferred embodiment the manufacturing of protective backing layer and the mucoadhesive active layer may involve electrospinning of the nanofibers. In a more preferred embodiment both the protective layer and the mucoadhesive layer containing the immunoglobulins or Fc fragments thereof are made by electrospinning and both are dissolvable and biodegradable, albeit at different rates, the backing layer dissolving at a slower rate than the mucoadhesive active containing layer.

In yet another preferred use of the invention the multi-layers of the mucoadhesive patch are precasted followed by loading of the nanoscaffold reservoir layer with the immunoglobulins. For this purpose, the immunoglobulins are applied as a solution, colloid or suspension onto the nanoscaffold reservoir layer. Uptake by the reservoir layer occurs by diffusion and absorption. Excess liquid can be removed by conventional drying orlyophilisation techniques. Inclusion of cryoprotective agent(s) may be required to adequately protect the immunoglobulins.

The most suitable biologically compatible material for production of the layers of the mucoadhesive patch, film or hydrogel is a biologically compatible polymer, especially polymer from group of polyvinyl alcohols (PVA), polylactides (PLA), polylactide-co-glycolides (PLGA), polycaprolactones (PCL), polyvinylpyrrolidones (PVP), polyurethanes (PUR), polyacrilic acid (PAA), their copolymers, cellulose derivatives such as for example hydroxypropyl cellulose (HPC), hydroxypropyl methycellulose (HPMC), polyethylene-oxide (PEO), polyethylene glycol/ polyvinylcaprolactam/ polyvinyl acetate copolymer, silk fibroin, chitosan -, alginate-, and hyaluronic acid derivatives, their mixtures as well as numerous polymerizable monomers, mixtures of at least two of these. To speed up the release of the antigen containing substance from the layers, it is possible to create the layer from biologically degradable material. The advantage of this variant is also that after and/or during the release of the antigen containing substance, the layer decomposes in the body of the recipient, so it is not necessary to remove it additionally.

In one embodiment, the polymer layers can also comprise plasticizers, such as polyols, phtalhates or citrates to enhance the plasticity of the layers, and/or absorption accelerators, such as acetylcysteine, surface active substances, chelating substances, fatty acids, polyols, dextran sulphates, sulfoxides, Azone®, (lyso)phosphatidylcholine, metoxysalicylate, menthol, aprotonin, dextran sulphate, cyclodextrins, 23-lauryl ether to facilitate the penetration of particles. Mucoadhesive hydrogels or films as used here mean water swellable, cross-linked polymers that can be impregnated or loaded with immunoglobulins of Fc fragments thereof. Immunoglobulins or Fc fragments thereof loaded into the hydrogel is released in a controlled manner as the hydrogel becomes hydrated within the oral cavity. In a preferred embodiment, the hydrogel matrix in the present invention is comprised of polysaccharides such as chitosan, alginate, and hyaluronic acid. In a more preferred embodiment of the invention the hydrogel matrix is composed of chitosan. Chitosan is a bioactive, biocompatible, biodegradable non-toxic compound with favourable properties for a range of industrial and biomedical applications, including drug delivery, wound healing and biomedical implants. Chitosan is a polysaccharide comprising 1-4-linked residues of 2- mino-2-deoxy-beta-D-glucose (glucosamine) and 2-acetamido-2-deoxy-beta-D-glucose (N- acetylglucosamine). Chitosan is prepared by at least partial deacetylation of the naturally occurring polysaccharide chitin (poly-N-acetylglucosamine or (1- 4)-2-deoxy-beta-D-glucan), which is found naturally in the shells of crustaceans, insects and fungi. Thus acetyl groups are removed from at least some of the N-acetylglucosamine residues of chitin to form glucosamine residues.

In commercial preparations of chitosan, usually from about 50% to about 100% of the N- acetylglucosamine residues of chitin have been deacetylated to glucosamine residues. In the present invention chitosan with a deacetylation percentage of 70% to 95% is preferred. Chitosan dissolves to a significant extent in acidic solution, values below pH 6.5. Thus, soluble chitosan is cationic, allowing it to bind to negatively charged surfaces and biological materials. Chitosan is a prominent example of a polysaccharide that can be crosslinked ionically. Chitosan hydrogels can be physically mixed into stable networks by introducing anionic ions or macromolecules to neutralize the positively charged chitosan and induce electrostatic attraction within the gelatinized network. Ionic crosslinking is a relatively safe technique to use for fabricating biocompatible hydrogels without toxic catalysts. According to the present invention chitosan-based hydrogels formulated with immunoglobulins or Fc fragments thereof can be dried for long-term storage and easy application in the oral cavity. In another preferred embodiment of the invention a thermosensitive chitosan solution is used. To obtain a thermosensitive hydrogel, a chitosan solution is neutralized with a polyol counterionic monohead salt is used to neutralize the chitosan solution. Under these conditions chitosan remains liquid at or below 25oC and can be stored for a long time without losing the thermosensitive properties. The system can then have a pH value within a physiologically acceptable neutral range (pH 6.8-7.2) and it is only the temperature of the milieu that determines the liquid or gel state, gel formation being observed upon an increase in temperature. In a preferred embodiment of the invention the polyol counterionic monohead salt is beta-glycerolphospate and gel formation starts at temperature above 32oC. The production and use of thermosensitive chitosan-based hydrogels is well described in literature, such as “Biological Activities and Application of Marine Polysaccharides” (Argiielles-Monal et al., eds). In a first aspect the invention relates to a mucoadhesive carrier being a patch, film or hydrogel comprising immunoglobulins, wherein the mucoadhesive carrier is mucosally administered to the subject. Mucosal administration of the mucoadhesive carrier is understood to comprise contacting the mucoadhesive carrier to a mucous membrane or mucosa of the subject.

Preferably the invention relates to the use of a mucoadhesive patch, film or hydrogel formulation of immunoglobulins for the preparation of a medicament, medical food or nutraceutical for oromucosal administration to a patient suffering from a viral infection.

Mucosa

Mucosa as used here can be any mucosa such as oral mucosa, rectal mucosa, urethral mucosa, vaginal mucosa, ocular mucosa, pulmonary mucosa and nasal mucosa. Oromucosal administration as used throughout the application encompasses the targeted delivery to the oral mucosa. Oromucosal administration includes buccal, sublingual and gingival routes of delivery. Preferably, said oromucosal delivery is buccal or gingiva administration.

Immunoglobulins In one embodiment of the invention the mouth patch, film or hydrogel is comprised with immunoglobulins derived from human blood plasma, predominantly and preferably IgG, more preferably lgG1. Ig (immunoglobulins) is obtained from a large pool of healthy blood donors to ensure a diverse immunoglobulin repertoire, and the quality of Ig lots are tested based on specifications set around predominant IgG content of more than 95%, more preferably with predominantly lgG1 of more than 55% in the context of the preferred embodiment of the invention. To ensure quality, Ig lots are also routinely checked for viral clearance and endotoxin levels, and additional specifications are set around the levels of other non-lgG proteins, such as pre- kallikrein activator, IgA, and hemagglutinin titers.

Numerous suitable methods of isolating immunoglobulins are known in the art (see e.g. U.S. 7, 138,120). Briefly, the starting material of the present purification process can be blood, serum, or plasma, but is advantageously an immunoglobulin-comprising crude plasma protein fraction. In general immunoglobulins are purified from pooled normal human plasma or may originate from donors with high titers of specific antibodies, i.e. hyperimmune plasma, e.g. convalescent plasma of COVID-19 patients.

Delivery or Administration as used here means any method of delivery or administration via mucoadhesive materials known to the person skilled in the art and includes, but is not limited to patches, biofilms or hydrogels comprising or carrying the immunoglobulins in presence of other compounds that may further enhance the disease status of the patient. The terms “treatment”, “treating”, and the like, as used herein include amelioration or elimination of a developed mental disease or condition once it has been established or alleviation of the characteristic symptoms of such disease or condition. As used herein these terms also encompass, depending on the condition of the patient, preventing the onset of a disease or condition or of symptoms associated with a disease or condition, including reducing the severity of a disease or condition or symptoms associated therewith prior to affliction with said disease or condition. Such prevention or reduction prior to affliction refers to administration of the compound or composition of the invention to a patient that is not at the time of administration afflicted with the disease or condition. “Preventing” also encompasses preventing the recurrence or relapse-prevention of a disease or condition or of symptoms associated therewith, for instance after a period of improvement. It should be clear that mental conditions may be responsible for physical complaints. In this respect, the term “treating” also includes prevention of a physical disease or condition or amelioration or elimination of the developed physical disease or condition once it has been established or alleviation of the characteristic symptoms of such conditions.

As used herein, the term “medicament” also encompasses the terms “drug”, “therapeutic”, or other terms which are used in the field of medicine to indicate a preparation with therapeutic effect.

Preferably the compound or composition is provided in a unit dosage form, for example a mucoadhesive patch, biofilm or hydrogel is administered to the oral cavity of a subject, e.g. a patient.

The active ingredients may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. These daily doses can be given as a single dose once daily, or can be given as two, four or more smaller doses at the same or different times of the day which in total give the specified daily dose. Preferably, the active ingredient is administered once, twice or four times a day. For instance, a dose could be taken in the morning and others later in the day. More preferably, the administration is four times a day, applying a patch on each buccal side of the cheek.

In all aspects of the invention, the daily maintenance dose can be given for a period clinically desirable in the patient, for example from 1 day up to several years (e.g. for the mammal's entire remaining life); for example from about (2 or 3 or 5 days, 1 or 2 weeks, or 1 month) upwards and/or for example up to about (5 years, 1 year, 6 months, 1 month, 1 week, or 3 or 5 days). Administration of the daily maintenance dose for about 3 to about 5 days or for about 1 week to about 1 year is typical. Other constituents of the final formulations may include preservatives, inorganic salts, acids, bases, buffers, nutrients, vitamins, flavours or other pharmaceuticals.

The immunoglobulins may be delivered in a dose of at least 0.1 mg to 200 mg (dry weight) per day, preferably between 20 and 100 mg per day, most preferably around 60 mg per day. The invention further relates to the following numbered embodiments:

1 . A mucoadhesive carrier comprising immunoglobulins, wherein the mucoadhesive carrier is a patch, film or hydrogel administered to the oral mucosa of a human subject.

2. A mucoadhesive carrier according to embodiment 1 for use as a medicament.

3. A mucoadhesive carrier according to embodiment 1 for the treatment of humans infected with a virus.

4. A mucoadhesive carrier according to embodiment 1 for the prevention of humans infected with a virus progressing into a lung injury, respiratory failure, acute lung inflammation and/or acute respiratory distress syndrome (ARDS).

5. A mucoadhesive carrier for a use according to any one of embodiments 1 - 4, wherein the immunoglobulins are predominantly IgGs, more preferably lgG1.

6. A mucoadhesive carrier for a use according to any one of embodiments 3 - 5, wherein the virus is selected from the group of Influenza or Corona viruses (CoV), preferably MERS-CoV or SARS-CoV, more preferably SARS-CoV-2.

7. A mucoadhesive carrier for a use according to any one of the preceding embodiments, wherein administration of the carrier is combined with treatment of any of the antivirals selected from the group of Chloroquine, Remdesivir, Favilavir, OYA1 , NP-120 (Ifenprodil), APN01 , Brilacidin or SNG001 .

8. A mucoadhesive carrier for a use according to embodiment 7, wherein said carrier is a patch comprising of electrospun fibers.

In this document and in its claims, the verb “to comprise” and its conjugations is used in its nonlimiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article “a” or “an” thus usually means “at least one”.

All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.

The present invention is further described by the following examples which should not be construed as limiting the scope of the invention. EXAMPLES

EXAMPLE A1: Determination of loading and in vitro release of immunoglobulins from a nanoreservoir layer

Introduction

The ability to load immunoglobulins efficiently into precasted nanoscaffold active layer made of different types of polymeric fibers was tested as well as the in vitro release of Immunoglobulins into buffer from these nanoscaffold active layer after drying.

Materials and methods

Materials: Immunoglobulins of blood plasma were bought from Sanquin.

Nanoscaffold active layer: nanoreservoir layers were prepared by electrospinning using polycaprolactone (PCL, Mw 80,000 g/mol, Sigma Aldrich) or a mixture (1 :1) of polycaprolactone and silk fibroin (PSF) polymers. Procedures were as described by Masek et al. (2017, J Control Rel, 249:183-195) and in published PCT applications WO2012097763 and W02017130141. In this way PCL and PSF nanoscaffold active layers were obtained with an average pore size of approximately 5 pm.

Experimental setup: nanoscaffold active layers of 1 cm² were loaded with 10 pL immunoglobulins solution (5 mg/ mL immunoglobulins stock in demineralized water) by putting the droplet onto the surface of the nanoscaffold active layer. The droplet was allowed to be absorbed into the layer and to be dried at the air at room temperature for about 20 min. Dried nanoscaffold active layer with immunoglobulins were either inspected by scanning electron microscopy (SEM; Hitachi8010) or were first submerged into 1 mL PBS for 10 min, followed by drying as described above, prior SEM analysis.

Results

Droplets of immunoglobulin solution put onto the surface of PCL nanoscaffold active layer remained essentially on top of the surface and were not absorbed into the nanoreservoir layer. After 20 min of incubation the droplets were removed and the PCL nanoscaffold active layers were dried. SEM analysis revealed that despite the apparent hydrophobicity of the PCL polymers, Immunoglobulins had been absorbed onto the polymeric fibers and even entered into some pores, albeit to a limited extend. Submerging PCL nanoscaffold active layers with immunoglobulins in PBS, completely released the immunoglobulins from the nanoscaffold active layers indicating that the absorption of immunoglobulins to PCL nanofibers is reversible under these conditions.

Droplets of immunoglobulin solution put onto the surface of PSF nanoscaffold active layers were absorbed immediately into the layer. After drying, SEM analysis revealed a dense loading of immunoglobulins onto the PSF fibers with immunoglobulins also having entered into the pores of the nanoscaffold active layer. Submerging PSF nanoscaffold active layer with immunoglobulins in PBS, released >90% of intact and biologically active immunoglobulins from the nanoscaffold active layer, checked by Western Blot and ELISA (for Fc binding), indicating that the absorption of immunoglobulins to PSF nanofibers is reversible under these conditions.

Conclusion

Nanoscaffold active layers of PCL and PSF nanofibers can be used for loading and releasing immunoglobulins, the PSF nanoscaffold active layers being the most efficient.

EXAMPLE A2. Incorporation and in vitro release of human normal immunoglobulins from mucoadhesive patches

Introduction

The ability to incorporate human normal immunoglobulins (Ig) in the electrospinning process to produce mucoadhesive patches was tested as well as the in vitro release of Ig into buffer from these patches.

Materials and methods

Ig: Intratect 10%, BioTest, Germany.

Mucoadhesive patches: patches were produced similar as described in W02017/130141 for the incorporation of Bovine Serum Albumin (BSA). Intratect was added to the polymer solution in various polymer: protein ratios (by weight) prior to electrospinning such to obtain patches with 1.5- 2.5 mg Ig per cm2 patch.

Experimental setup: mucoadhesive patches of 4 cm2 were submerged in 1 mL PBS buffer pH7.4, either for 30 min, 60 min or 90 min at room temperature. After incubation, the PBS buffer solution was collected for analysis to determine and quantify release and Ig integrity by HPLC, SDS-PAGE, ELISA and Western blot. Furthermore, the permeability of released Ig was measured in vitro as follows. Small cut pieces of porcine buccal mucosal membrane (0.4 mm thickness) were mounted into modified Franz diffusion cells. An exposed area of 1 cm2 was provided for permeation. The stirred acceptor phase was PBS pH 7.4. Samples were analysed by HPLC (Agilent Technologies, USA).

Results and Conclusions

We found a suitable polymer: Ig ratio to obtain mucoadhesive patches with a loading of 1 .5-2.5 mg Ig/cm2. The release testing indicated that more than 50% of intact Ig was released after 30 min in vitro incubation in PBS buffer. Moreover, significant amounts of Ig could be detected after 30 min incubation in the modified Franz diffusion cell set up, indicating favourable permeation profiles for Ig. These data increase the likelihood of efficient uptake and transport in vivo across the mucosal membranes of Ig delivered by a mucoadhesive patch. EXAMPLE B:

Introduction

Previous experiences in SARS-Cov2 patients have showed that the main pathogenesis of organ dysfunction lay on the overall cytokine dysregulation and the acute ARDS related onset of lung inflammation, which is intimately tied to monocyte/macrophage polarization and function. We therefore reasoned that the point when status deterioration starts in patients with COVID-19 should be a critical window of opportunity for intervention with OMIG mucoadhesive patches. Materials and methods

Mucoadhesive patches: the mucoadhesive OMIG patches were prepared as described in Example A2. Ig was added to final concentrations such that the resulting patches contained about 2 mg Ig per cm2 and 7.5 mg in total per patch hereinafter referred to as OMIG7.5. Patient inclusion criteria:

5 patients were recruited with laboratory-confirmed SARS-CoV-2 infection and acute respiratory distress syndrome (ARDS) meeting any of the following inclusion criteria: fever > 37.5C, significant lymphocytopenia with a lymphocyte count <1 x10exp9/L(normal: 1.1-3.2), high-sensitive C-reacting protein > 5 mg/L (normally 0-5), shortage of breath, oxygen saturation below 95% at ambient air, CT scan of lungs: infiltrations and opacities, severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; Pao2/Fio2 <300; and mechanical ventilation.

Exposures: Each patient received OMIG7.5 at fixed intervals every 6 hours for 5 days i.e. 60 mg per day and in total an accumulated dose of 300 mg. Each exposure durated for 20 min.

Main outcome and measures:

- Changes of body temperature,

- Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness),

- Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index,

- ARDS

- ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after OMIG mouth patch administration

- Cytokine levels (MCP-1 IL-8, IL17A)

- Percentage of ER admissions, worsening of inflammation

Results:

Following results were observed in patients: supplemental oxygen was discontinued, oxygen saturation level returned to 97-98%, recovered lymphocyte count, decreased ESR, improvement of breathing and hsCRP returned to normal range within 5 days post treatment. Conclusions

We report a case series of COVID-19, all of whom were successfully treated by oromucosal Ig (OMIG7.5) at the early stage of clinical deterioration. Based on these observations, a low dose Ig administered at the appropriate time point, could successfully block the progression of the disease cascade, and finally improve the outcome of COVID-19.

EXAMPLE C: Introduction

Previous experiences with vaccine trials involving conformationally incorrect antigens and nonneutralizing antibodies have shown to be accompanied with the formation of immune complex formation and complement deposition and Th2 biased inflammatory reactions and increased mucus production, eosinophil recruitment, airway hyperresponsiveness, and attenuated cytolytic T cell activity and Th2 immune responses. We therefore reasoned that individuals undergoing vaccine treatment against COVID-19 and other virus mediated diseases should be a candidates for intervention with OMIG mucoadhesive patches in case VAERD symptoms develop or even concomitant treatment with the vaccine treatment in order to dampen potential Th2 immune responses could be considered.

Materials and methods

Mucoadhesive patches: the mucoadhesive OMIG patches were prepared as described in Example A2. Ig was included to final concentrations such that the resulting patches contained 1.5-2 mg Ig per cm2 and 7.5mg in total per patch hereinafter referred to as OMIG7.5.

Patient inclusion criteria:

5 patients undergoing anti SARS-CoV-2 vaccine treatment and hospitalized with VAERD symptoms such as abundant polymorphonuclear leukocyte response in lungs and Th2 biased CD4+ T cell responses including increased eosinophil counts.

Main outcome and measures: - Changes of body temperature,

- Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index,

- ARDS - ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after OMIG mouth patch administration

- Cytokine levels (MCP-1 IL-8, IL17A)

- Percentage of ER admissions, worsening of inflammation

Results:

Following results were observed in patients: supplemental oxygen was discontinued, oxygen saturation level returned to 97-98%, recovered lymphocyte count, decreased ESR, improvement of breathing and hsCRP returned to normal range within 5 days post treatment.

Conclusions

We report a case series of anti COVID-19 vaccine treated patients with VAERD symptoms, all of whom were successfully treated by oromucosal Ig (OMIG7.5) at the early stage of clinical deterioration. Based on these observations, a low dose Ig administered at the appropriate time point, could successfully block the progression of the disease cascade, and finally improve the outcome of COVID-19.

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Claims

1 . A mucoadhesive carrier comprising immunoglobulins or Fc fragments thereof, wherein the mucoadhesive carrier is a patch, film or hydrogel for administration to the oral mucosa of a human subject.

2. A mucoadhesive carrier according to claim 1 , wherein the immunoglobulins are predominantly IgGs, more preferably lgG1.

3. A mucoadhesive carrier according to claim 2, wherein the immunoglobulins are predominantly bovine IgGs, more preferably bovine lgG1.

4. A mucoadhesive carrier according to claim 2, wherein the immunoglobulins are predominantly recombinant human IgGs, more preferably lgG1 or Fc fragments thereof.

5. A mucoadhesive carrier according to any one of claims 1 - 4, wherein said carrier is a patch comprising of electrospun fibers.

6. A mucoadhesive carrier according to any one of claims 1 - 5 for use as a medicament.

7. A mucoadhesive carrier according to any one of claims 1 - 5 for the treatment of humans infected with a virus and/or humans vaccinated against a virus.

8. A mucoadhesive carrier according to any one of claims 1 - 5 for the prevention of humans infected with a virus and/or vaccinated against a virus, progressing into a lung injury, respiratory failure, acute lung inflammation due to antibody dependent enhancement (ADE), vaccine- associated enhanced respiratory disease (VAERD) and/or acute respiratory distress syndrome (ARDS).

9. A mucoadhesive carrier for a use according to claim 7 or 8, wherein the virus is selected from the group of Influenza, RSV or Corona viruses (CoV), preferably MERS-CoV or SARS-CoV, more preferably SARS-CoV-2.

10. A mucoadhesive carrier for a use according to any one of claims 6 - 9, wherein the use of the carrier is combined with a treatment by any of the antivirals selected from the group of Chloroquine, Remdesivir, Favilavir, OYA1 , NP-120 (Ifenprodil), APN01 , Brilacidin or SNGOOI .