Immunomodulatory composition comprising acetylcysteine and beta-glucan

Abstract

An immunomodulatory composition comprising an active agent, said active agent comprising acetylcysteine and beta-glucan.

Description

[0001] IMMUNOMODULATORY COMPOSITION COMPRISING ACETYLCYSTEINE AND BETA-GLUCAN

[0002] Field of the invention

[0003] This disclosure refers in general to a composition capable of modulating the immune system in a subject; in particular, the composition is an anti -anergic immunomodulatory composition used in the prevention and treatment of cancer and to enhance the immune response to viral infections.

[0004] Background

[0005] The progression of a tumor depends on the cellular microenvironment in which it develops, as well as on its intrinsic characteristics. The cells of the immune system responsible for eliminating the tumor (T lymphocytes, NK cells, monocytes) are recalled to its site and here they carry out their battle against it. The tumor engages various mechanisms to counteract the action of anti-tumor cells, including the increased expression of ligands of immune inhibitors “check-points”, such as the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor and the programmed death-1 (PD-1) receptor. The latter, in cellular homeostasis, serve to slow down the hyperactivation of immune cells, preventing the onset of autoimmune diseases and tissue damage from viral infections. Tumor cells exploit this mechanism to their advantage by increasing the expression of PDL-1 and inhibiting the anti -turn or response of PD-1 positive cells (T lymphocytes, myeloid cells). Blocking the interaction between PDL-1 and PD-1 is currently a widely used anti-tumor therapy (1), but its efficacy decreases over time (2). A class of anti-tumor drugs called “check point inhibitors” are based precisely on the interruption of the bond between PDL-1 and PD-1; this class of anti-tumor drugs, however, has proven effective only in a subgroup of patients and a large percentage of subjects develop acquired resistance after initial responses due to various molecular mechanisms involved.

[0006] Some viruses, especially respiratory viruses such as SARS-Cov-2, influenza, rhinovirus, respiratory syncytial virus (RSV), also exploit the mechanism based on the PDL-l / PD-1 molecular axis to counteract the antiviral response of the immune system (3). SARS-CoV-2 infection, for example, determines the increase in PDL-1 expression by infected lung epithelial cells, an increase in expression that in turn can inhibit the function of T cells through binding to PD-1. Increased PD-1 expression on T cells has been found in patients with COVID-19, associated with their dysfunction and disease severity. Blocking the interaction between PDL-1 and PD-1 in vitro with anti -PD-1 antibodies increased and improved the response of SARS-CoV-2-specific T cells (4). The PD-1 receptor is also involved in regulating the T response to influenza viruses. PD-1 is expressed in a significant proportion (10-40%) of T cells in the airways, and the majority of influenza-specific CD8 T cells express PD-1, particularly the effector memory subset. Blocking the PDL- 1 / PD-l interaction in the airways has been shown to accelerate the clearance of influenza virus (5). Rhinovirus infection leads to the production of immunosuppressive cytokines, such as TGF-[3, which induces an increase in PDL- 1 as a major mechanism to evade the immune response (6). Respiratory syncytial virus (RSV) induces high PDL-1 expression in infected human bronchial epithelial cells. Blocking PDL-1 in vitro resulted in increased production of cytokines (IFN- Y and IL-2) and granzyme B by T cells, demonstrating that the PDL-l / PD-1 interaction can suppress the CD8 T cell response to the virus (7).

[0007] In this context, immunomodulatory strategies targeting the PDL-l / PD-1 molecular axis, in particular capable of effectively inhibiting the interaction between PDL-1 and PD-1 receptor, are of great interest.

[0008] Summary of the invention

[0009] The present disclosure aims to provide new compositions that are particularly effective in modulating the immune system, in particular targeting the PDL-l / PD-1 molecular axis, to be used in the prevention and / or treatment of cancer as well as in enhancing the immune system in order to prevent and treat viral infections.

[0010] According to the present disclosure, the above purpose is achieved thanks to the object specifically referred to in the following claims, which are intended to be an integral part of the present disclosure.

[0011] An embodiment of the present disclosure provides a composition comprising an active agent, said active agent comprising acetylcysteine and betaglucan. In one or more embodiments, the active agent of the composition may further comprise glutamine.

[0012] The composition may be used in the prevention and / or treatment of cancer in a subject. In one or more embodiments, the cancer may be selected from the group consisting of lung, breast, pancreas, bladder, cervix, colon, rectum, liver, kidney, head and neck cancer, in addition to melanoma and non-Hodgkin lymphomas, acute and chronic myeloid leukemias.

[0013] The composition may also be used to enhance the immune system in a subject, in particular in order to prevent or treat seasonal viral infections such as SARS-CoV2 infection, influenza viruses, rhinoviruses and respiratory syncytial virus (RSV).

[0014] Brief description of the figures

[0015] The invention will now be described, purely by way of example, with reference to the attached figures, in which:

[0016] - Figure 1 relates to tests performed to evaluate the cytotoxicity of betaglucan in a human tumor line of thyroid origin (BHT);

[0017] - Figure 2 shows results of a flow cytometric assay performed to evaluate PD-1 expression in the myeloid cell line THP-1 and in the breast cancer cell line MDA-MB-231;

[0018] - Figure 3 shows results of a flow cytometric assay performed to evaluate dectin- 1 expression in the THP-1 cell line;

[0019] - Figure 4 shows results of a flow cytometric assay to evaluate PD-1 expression, expressed as mean fluorescence intensity (MFI), in the THP-1 cell line subjected to the following experimental conditions for 6 h: control (culture medium only), NAC (10 mM), beta-glucan (10 pg / ml), NAC in combination with betaglucan.

[0020] - Figure 5 shows the results of a flow cytometric assay to evaluate the expression of dectin- 1, expressed as mean fluorescence intensity (MFI), in the THP- 1 line subjected to the following experimental conditions for 6 h: control (culture medium only), NAC (10 mM), beta-glucan (10 pg / ml), NAC in combination with beta-glucan.

[0021] - Figure 6 shows the results of a flow cytometric assay to evaluate the expression of PD-1, expressed as mean fluorescence intensity (MFI), in the MDA- MB-231 line subjected to the following experimental conditions for 6 h: control (culture medium only), NAC (1.25 mM), beta-glucan (10 pg / ml), NAC in combination with beta-glucan.

[0022] Detailed description of preferred embodiments

[0023] In the following description, numerous specific details are provided to provide a thorough understanding of embodiments. Embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other cases, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the embodiments.

[0024] Reference throughout this disclosure to “one embodiment” or “an embodiment” indicates that a particular aspect, structure, or feature described in connection with the embodiment is included in at least one embodiment. Therefore, the appearance of the expressions “in one embodiment” or “in an embodiment” in various places in this disclosure do not necessarily all refer to the same embodiment. Furthermore, particular aspects, structures, or features may be combined in any suitable way in one or more embodiments. The headings provided herein are for convenience only and do not construe the scope or meaning of the embodiments.

[0025] An embodiment of the present disclosure provides a composition comprising an active agent, said active agent comprising acetylcysteine, preferably N-acetylcysteine, and beta-glucan. In one or more embodiments, the active agent of the composition may further comprise glutamine.

[0026] In one or more embodiments, the active agent comprises acetylcysteine, preferably N-acetylcysteine, beta-glucan and, optionally, glutamine.

[0027] In one or more embodiments, the composition may comprise acetylcysteine, preferably N-acetylcysteine, beta-glucan and, optionally, glutamine.

[0028] Acetylcysteine, particularly N-acetylcysteine (NAC), is a key precursor for the synthesis of endogenous glutathione (GSH). GSH plays an essential role in the control of cellular redox by neutralizing intracellular reactive oxygen species (ROS) and detoxifying metabolites produced by free radicals. NAC is therefore able to limit the strong redox gradient of the tumor microenvironment. NAC can restore the renewal of exhausted T cells and reverse the dysfunction of effector T cells.

[0029] It is also important to note that highly specific acquired immunity mediated by T lymphocytes is not the only one to intervene in anti-tumor surveillance as myeloid cells also participate actively, both in the short term and over a longer period of time after their “training” period. “Trained” monocytes produce cytokines in greater quantities and more quickly than untrained monocytes. They can be trained by various substances including beta-glucans, complex glucose-based polysaccharides constituting the cell wall of yeasts, bacteria, fungi, cereals. Betaglucans bind to various receptors, mainly dectin- 1, inducing the transduction of signals that lead to the activation of phagocytosis, production of reactive oxygen species (ROS) and cytokines.

[0030] Sources of beta-glucans can be different, for example identifiable in cereals (barley, oats, rye), mushrooms, yeasts, bacteria and depending on the sources the structure can also vary significantly. In particular, beta-glucans (P-glucans) share a linear carbon backbone formed by single D-glucose units joined by P-(l / 3) bonds in the case of glucans from yeasts. Oat glucans have a backbone formed by P-(l / 4) bonds or an alternation of |3-(l / 3)-(l / 4) bonds, while some mushroom glucans have P-(l / 6) structures. Furthermore, some yeast and mushroom glucans have ramifications in their backbone that lead to the formation of side chains (“branching”); these influence their respective biological properties and consequently their effects on health.

[0031] The Inventors of the present application have observed that, surprisingly, the specific combination of acetylcysteine, preferably N-acetylcysteine, and betaglucan has proven to be particularly effective in reducing the expression of the PD- 1 receptor in tumor cells, as will be highlighted below. The composition, in particular, exerts a specific inhibitory synergistic effect on PD-1. Such evidence is noteworthy since, as mentioned in the preceding sections, the PDL-l / PD-1 molecular axis is a target of significant interest for the purposes of, for example, the treatment of cancer and viral infections. The composition according to this disclosure is therefore also useful, for example, in enhancing the effect of check point inhibitors both before, during or after therapeutic treatment, helping to limit the depletion of T cells.

[0032] The preferable source of beta-glucan in order to produce the composition according to this disclosure is yeast. In a preferred embodiment, the active agent of the composition comprises beta-glucan derived from yeast, preferably from the yeast Saccharomyces cerevisiae. This source of beta-glucan is capable of inducing a dose-dependent production of superoxide in monocytes, which is crucial for the suppression of pathogens.

[0033] Furthermore, preferably, the beta-glucan usable in the composition described herein is (l,3)-(l,6)-P-D-glucan. This glucan is characterized by the 1,3 backbone and long 1,6 side chains.

[0034] The Inventors of the present application first conducted experimental tests in order to verify a possible cytotoxicity of beta-glucan in human cells. For this purpose, it was used a human tumor line of thyroid origin with high metabolic activity, tested with three different concentrations of beta-glucan and the cytotoxicity was evaluated at 24 h and 72 h of in vitro culture. The Inventors have demonstrated that the administration of beta-glucan does not induce any cytotoxic effect, even at the highest concentration.

[0035] In one or more embodiments, beta-glucan may be present in the composition in object in an amount by weight between 35% and 55%, preferably between 40% and 50% (w / w) relative to the weight of the composition. In one or more embodiments, the composition may comprise acetylcysteine, preferably N-acetylcysteine, in an amount by weight between 35% and 55%, preferably between 40% and 50% (w / w) relative to the weight of the composition.

[0036] The composition may also comprise glutamine, preferably glutamine alpha ketoglutarate (akg), preferably in an amount between 5% and 15%, preferably between 8% and 10% (w / w) of the composition.

[0037] The composition may comprise beta-glucan and acetylcysteine in a weight ratio between 0.5 and 2.5, preferably between 0.9 and 1.5.

[0038] The composition may comprise beta-glucan and glutamine in a weight ratio between 3 and 5, preferably between 3.5 and 4.5.

[0039] The weight ratio between acetylcysteine and glutamine may be between 2.5 and 5, preferably between 3.0 and 4.5.

[0040] In one or more embodiments, the composition may consist of the components of the active agent; in other words, the composition may consist of beta-glucan, acetylcysteine and optionally glutamine.

[0041] In one or more embodiments, the composition may be a pharmaceutical composition further comprising a pharmaceutically acceptable carrier and at least one of the above pharmaceutically acceptable excipients.

[0042] For oral use, the compositions according to the disclosure may be in the form of tablets, capsules, granules, gel, gelling powder, powder.

[0043] The composition may be used in the prevention and / or treatment of cancer in a subject. In one or more embodiments, the cancer may be selected from the group consisting of lung, breast, pancreas, bladder, cervix, colon, rectum, liver, kidney, head and neck cancer, melanoma and non-Hodgkin lymphomas, acute and chronic myeloid leukemias.

[0044] The composition may also be used to enhance the immune system in a subject, in particular for use in the prevention and / or treatment of seasonal viral infections such as SARS-CoV2 infection, influenza viruses, rhinoviruses and respiratory syncytial virus (RSV).

[0045] The disclosure also provides combination preparations comprising the composition described herein and at least one chemotherapeutic agent for simultaneous, separate or sequential use in the prevention and / or treatment of a cancer in a subject.

[0046] The chemotherapeutic agent may be selected, for example, from the group consisting of PDL-l / PD-1 immune check point inhibitors such as anti-PD-1 monoclonal antibodies: nivolumab (Obdivo), pembrolizumab (Keytruda), cemiplimab (Libtayo), and anti-PDL-1 : atezolizumab (Tecentriq), durvalumab (Imfinzi) and avelumab (Bavencio).

[0047] The disclosure also provides a method for preventing and / or treating a cancer in a subject, the method comprising: selecting a composition comprising an active agent, said active agent comprising beta-glucan and acetylcysteine, and optionally glutamine, and administering the composition to the subject. The active agent may further comprise glutamine as described herein. The composition may be administered alone, then the method consists of selecting the composition and administering the composition to the subject. In one or more embodiments, the composition may also be administered - simultaneously, separately or sequentially - with at least one chemotherapeutic agent, preferably selected from the various classes of PD-l / PDL-1 immune checkpoint inhibitors, including anti-PD-1 monoclonal antibodies: nivolumab (Obdivo), pembrolizumab (Keytruda), cemiplimab (Libtayo), and anti-PDL-1, atezolizumab (Tecentriq), durvalumab (Imfinzi) and avelumab (Bavencio).

[0048] The composition may also be used in a method to enhance the immune system in a subject, in particular in a method to prevent and / or treat seasonal viral infections such as SARS-CoV2, influenza viruses, rhinoviruses and respiratory syncytial virus (RSV). The method may comprise: selecting a composition comprising an active agent, said active agent comprising beta-glucan and acetylcysteine, and administering the composition to the subject. The active agent may also comprise glutamine.

[0049] Further specifications, in terms of quantities and ratios between the various components provided by the compositions are contained in the appended claims, which form an integral part of the technical teaching provided herein in relation to the invention.

[0050] EXAMPLES

[0051] Table 1 shows an example of a composition according to embodiments of the present disclosure.

[0052] Table 1 The composition of Table 1 can be obtained by encapsulation in bovine gelatin capsules, starting from the homogeneously mixed functional raw materials. In detail, the appropriately weighed powders are transferred by pneumatic transport into the appropriate containers where they are carefully mixed, for at least 15 minutes until the ingredients are homogenized. If the sample taken for the organoleptic analysis is compliant, the composition can be transferred to the capsule filling machine. The shown dosages have allowed to obtain a functional product. In one or more embodiments of this disclosure, the composition described, and for example reported in Table 1, can be administered twice a day.

[0053] METHODS

[0054] Cells and treatments

[0055] The THP-1 line (Istituto Zooprofilattico Sperimentale della Lombardia e deU’Emilia Romagna “Bruno Ubertini” - ISZLER) grows in suspension in RPMI 1640 culture medium supplemented with glutamine (1%) and fetal bovine serum (10%). The MDA-MB-231 line (ISZLER) grows in adherence in Leibovitz’s L-15 culture medium supplemented with glutamine (1%) and fetal bovine serum (10%).

[0056] The lines are seeded in 24-well culture plates, 500 pl / well, at a concentration of lx106 / ml for THP-1 and 0.25x 106 / ml for MDA-MB-231 with medium alone and with the addition of beta-glucan (Yestimun®, Leiber GmbH, Germany), previously dispersed in DMSO, at a final concentration of 10 pg / ml, NAC (Solime s.r.l. Cavriago, RE) at a final concentration of 10 mM for THP-1 and 1.25 mM for MDA- MB-231, and beta-glucan in combination with NAC at the concentrations described above.

[0057] Characteristic of the beta-glucan used in the exemplary tests is its insolubility in water, but it is dispersible in different liquid matrices. In the examples described here, the Inventors have developed a dispersibility protocol in dimethyl sulfoxide (DMSO). Taking into account the percentage of beta-glucan with respect to the percentage of dry matter of the batch in use for the experiments performed, the following procedure was carried out: beta-glucan content = 83.4% / d.m. (d.m. = dry matter); dry matter = 96.4%; 83.4% of 96.4% = 80.4%; therefore 10 mg of powder contain 8.04 mg of beta-glucan. To obtain 10 mg of beta-glucan, 12.44 mg of powder weighed using an analytical balance are required; this powder is dissolved in 1 ml of dimethyl sulfoxide (DMSO) and in this way a solution with a concentration of 10 mg / ml of beta-glucan is obtained (A). Solution A was diluted 1 : 10 in cell culture medium to obtain the concentration of beta-glucan B (1 mg / ml). Solution B was further diluted 1 : 10 in cell culture medium to obtain the concentration of beta-glucan C (100 pg / ml). Solution C was further diluted and different concentrations were tested on 2 cell lines of different nature: THP-1 of myeloid origin and MDA-MB-231 from breast cancer. The optimal concentration of beta-glucan that gave the most reproducible results was 10 pg / ml. To maintain the dispersibility of beta-glucan during the experiments, an orbital shaker was used on which the cell culture plates were placed, all inserted in the cell culture incubator at constant temperature (37 °C) and CO2 (5%). Different concentrations of NAC were also tested: 100, 50, 10, 5, 1.25, 0.625 mM. The concentrations 100 mM and 50 mM were found to be cytotoxic for both lines. The optimal concentration of NAC for the THP-1 line is 10 mM, while for the MDA-MB-231 line it is 1.25 mM.

[0058] Cytotoxicity assay

[0059] The beta-glucan solution was initially tested on the highly metabolic BHT thyroid carcinoma cell line. Viable cells depend on an intact mitochondrial respiratory chain and an intact mitochondrial membrane. Toxic agents can be identified using mitochondrial dehydrogenases of viable cells. The MTT method uses a tetrazolium salt that is cleaved into formazan by the succinate dehydrogenase system that belongs to the mitochondrial respiratory chain and is active only in viable cells. Mitochondrial succinate dehydrogenase reduces the yellow tetrazolium salt to a purple compound (formazan) that is insoluble in water. After solubilization of the formazan, the amount of dye can be quantified with a microplate reader at 540 nm. In living cells, MTT is cleaved into formazan by the succinate dehydrogenase system, resulting in a purple color and an optical density (OD) value of around 2.

[0060] In experiments with the THP-1 and MDA-MB-231 lines, cytotoxicity was assessed in all experimental conditions using two methods. The first method involves counting cells stained with the vital dye trypan blue under an optical microscope. This dye only enters the membrane of dead cells, and therefore the ratio between blue cells and unstained cells provides the percentage of mortality and its reciprocal that of viability. The second method uses flow cytometry of cells treated in the various experimental conditions and stained with Viakrome, a new fluorescent dye that covalently binds free thiols present on cellular proteins. Living cells will be weakly stained by the covalent bond of proteins expressed on the cell surface, while dead cells, whose membranes have lost structural integrity, will be strongly stained by the covalent bond of intracellular and membrane proteins. To further enhance ease of use, this novel thiol chemistry is available in a range of dyes excited by common flow cytometry lasers. Viakrome 405 was used for the experiments described.

[0061] PD-1 and dectin-1 expression

[0062] THP-1 cells counted and brought to a concentration of | / I O6 / ml were seeded in 24-well cell culture plates, 500pl / well. MDA-MB-231 cells counted and brought to a concentration of 0.25 x106 / ml were seeded in 24-well cell culture plates, 500pl / well. Beta-glucan and NAC reagents were added at the final concentrations reported above. Cells were cultured for 6 hours and then harvested to be stained for flow cytometry. MDA-MB-231 with anti -PD-1 antibody conjugated to the fluorochrome APC, anti -dectin-1 antibody conjugated to the fluorochrome AF488, were washed and fixed with 1% paraformaldehyde before reading on the Cytoflex flow cytometer (Kaluza analysis software). The results are expressed as mean fluorescence intensity (MFI).

[0063] RESULTS

[0064] After verifying that beta-glucan did not have cytotoxic effects on human cells (Figure 1), the expression of PD-1 in the tumor lines used, namely THP-1 and MD-MB-231 (Figure 2) and dectin-1, the main receptor of beta-glucan, in THP-1 cells (Figure 3) was evaluated.

[0065] The effect of the administration of the composition was initially tested on the myeloid line THP-1; the detected result highlighted a synergistic effect on the inhibition of PD-1 which is equal to 35% (MFI) compared to the control. Betaglucan alone induced a PD-1 inhibition of 4% while NAC alone determined an inhibition of 22% (Figure 4). Cell viability in this experiment ranges from 92% to 96% with a vital dye (trypan blue) and from 93% to 97% with another dye (Viakrome) in the various treatments.

[0066] The synergistic inhibitory effect exerted by the combination of beta -glucan and NAC appears specific for PD-1 as it is not found on the expression of dectin-1 (Figure 5). The data obtained is from the same experiment shown for PD-1. Note instead the 22% inhibition of dectin-1 by beta-glucan alone suggesting that it is using its receptor inducing a certain degree of internalization.

[0067] In the breast cancer cell line MDA-MB-23, PD-1 inhibition (MFI) was 55% compared to the control, showing a significant enhancement of the inhibitory effect exerted by beta-glucan alone (45%) and NAC alone (32%) (Figure 6). Also in this experiment, cell viability varied from 88% to 97% with a vital dye (trypan blue) and from 83% to 90% with the second dye (Viakrome) in the various treatments.

[0068] It should be noted that the lower viability, although by far acceptable, found in the MDA-MB-231 line may depend on its adherent nature compared to the nonadherent nature of the THP-1 line, with consequent greater disturbance given by the detachment of the cells from the culture plates before being labeled for flow cytometry analysis (to detach them a reagent containing ethylenediaminetetraacetic acid (EDTA), glycerol and sodium citrate is used).

[0069] The Inventors of the present application also observe that glutamine is an amino acid that is normally added (1% vol / vol) to the culture media of cells in vitro, both tumor cells and primary cells, and consequently is also present in the cell culture media used in the tests described herein. Glutamine can follow different metabolic pathways including glutaminolysis which leads to the production of alpha-keto-glutarate (akg) important for the M2 polarization (anti-inflammatory) of monocytes with their consequent metabolic and epigenetic reprogramming.

[0070] In light of the above, the composition described herein has been shown to exert a significant inhibitory effect on the expression of PD-1 on the cell surface of the tested cells. The composition can be used alone or also in combination preparations with at least one chemotherapeutic agent; this also allows to significantly reduce the dosage of chemotherapeutic drugs ensuring a more effective and safe anti-cancer approach.

[0071] References Adil Parvez, Furqan Choudhary, Priyal Mudgal, Rahila Khan, Kamal A. Qureshi, Humaira Farooqi and Ashok Aspatwar:, PD-1 and PD-L1 : architects of immune symphony and immunotherapy breakthroughs in cancer treatment; Frontiers in Immunology, 2023, doi: 10.3389 / fimmu.2023.1296341. Qingyang Lei, Dan Wang, Kai Sun, Liping Wang and Yi Zhang: Resistance mechanisms of anti-PDl / PDL-1 therapy in solid tumors; Frontiers in Cell and Developmental Biology; 2020, doi: 10.3389 / fcell.2020.00672. Meredith C. Rogers, John V. Williams: Reining in the CD8+ T cell: Respiratory virus infection and PD-1 -mediated T-cell impairment; 2019, PlosPathog 15(1): el007387. Cristian Loretelli, Ahmed Abdelsalam, Francesca D’Addio, et al.: PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response; 2021, JCI Insight, doi: 10.1172 / jci.insight.146701. Beth McNally, Fang Ye, Meredith Willette, Emilio Flano: Local blockade of epithelial PDL-1 in the airways enhances T cell function and viral clearance during Influenza virus infection; 2013, J Virol 87: 12916-12924. Zuqin Yang, Hannah Mitlander, Tytti Vuorinen and Susetta Finotto: Mechanism of Rhinovirus immunity and asthma; Frontiers in Immunology, 2021 doi: 10.3389 / fimmu.2021.731846. Aurica G. Telcian, Vasile Laza-Stanca, Michael R. Edwards, et al.: RSV- induced bronchial epithelial cell PD-L1 expression inhibits CD8+ T cell nonspecific antiviral activity; 2011, JID 203:85-94.

Claims

CLAIMS1. An immunomodulatory composition comprising an active agent, said active agent comprising acetylcysteine and beta-glucan.

2. The immunomodulatory composition according to claim 1, wherein the active agent further comprises glutamine, preferably glutamine alpha ketoglutarate (akg).

3. The immunomodulatory composition according to claim 1 or claim 2, wherein the weight ratio between beta-glucan and acetylcysteine is between 0.5 and 2.50, preferably between 0.9 and 1.5.

4. The immunomodulatory composition according to any one of the preceding claims, wherein the weight ratio between beta-glucan and glutamine is between 3 and 5, preferably between 3.5 and 4.5.

5. The immunomodulatory composition according to any one of the preceding claims, wherein the weight ratio between acetylcysteine and glutamine is between 2.5 and 5, preferably between 3 and 4.5.

6. The immunomodulatory composition according to any one of the preceding claims, wherein beta-glucan is present in an amount by weight between 35% and 55%, preferably between 40% and 50% (w / w) relative to the weight of the composition.

7. The immunomodulatory composition according to any one of the preceding claims, wherein acetylcysteine is present in an amount by weight between 35% and 55%, preferably between 40% and 50% (w / w) relative to the weight of the composition.

8. The immunomodulatory composition according to any one of the preceding claims, for use in medicine.

9. The immunomodulatory composition according to claim 8, for use in enhancing the immune system in a subject, preferably for use in preventing and / or treating viral infections, more preferably SARS-CoV2 infection, influenza virus infection, rhinovirus infection, respiratory syncytial virus infection.

10. The immunomodulatory composition according to claim 8, for use in preventing and / or treating a cancer in a subject.

11. The immunomodulatory composition for use according to claim 10, wherein the cancer is selected from the group consisting of cancer of the lung, breast, pancreas, bladder, cervix, colon, rectum, liver, kidney, head and neck, in addition to melanoma and non-Hodgkin lymphomas, acute and chronic myeloidleukemias.

12. A combination preparation comprising the immunomodulatory composition according to any one of claims 1 to 7 and at least one chemotherapeutic agent for simultaneous, separate or sequential use in the prevention and / or treatment of cancer in a subject.

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