Patent Publication Number: US-2023133409-A1

Title: Pharmaceutical compositions and use thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/993,011, titled: “PHARMACEUTICAL COMPOSITIONS AND USE THEREOF”, filed Mar. 22, 2020, the contents of which are incorporated herein by reference in their entirety. 
    
    
     FIELD OF THE INVENTION 
     The present invention is directed to pharmaceutical compositions and methods of using same, such as for treating autoimmune disease, inflammation, viral infection, and cancer. 
     BACKGROUND 
     Interferon γ (IFN-γ) is a pleiotropic cytokine produced mainly by natural killer (NK) cells and specific T-cell subsets and monocytes that plays a central role in promoting innate and adaptive mechanisms of host defense by immune regulation. The biological actions of IFN-γ are particularly broad because almost all normal cells express functionally active IFN-γ receptors on their surface. IFN-γ activates natural and specific immunity against virus infected cells and cancer cells. 
     IFNγ is a key cytokine in the polarization and recruitment of Th1 (CD8+ T cells). IFNγ upregulates the chemokines CXCL9 and CXCL10 that attract cytotoxic cells into tumors and viral infected tissues. In parallel to promoting innate and adaptive mechanisms of host defense, IFNγ negatively regulates the magnitude of immune response by upregulating the immune checkpoint cell surface receptor PD-L1. 
     In humans, blocking PD-L1 or its ligand PD-1 increases anti-tumor effects of T cells and at the other extreme induces autoimmune disease. In humans, tumors that express IFNγ, CXCL10, and PD-L1 have a better chance to response to anti PD-1/PD-L1 therapy and are considered hot tumors. 
     Administration of IFN-γ was shown to stimulate the mobilization of NK cells and their accumulation in the peritoneum, liver, and tumor bearing lung tissue. Furthermore, increased numbers of NK cells in the lung reduced metastasis of Lewis lung carcinoma cells resulting in significantly extended NK-dependent survival. 
     Sequential administration of IFN-γ at an early stage of an infection was demonstrated to protect infected mice from death in a NK cell-dependent manner. Interestingly, there was no significant faster clearance of the virus following IFN-γ treatment. However, IFN-γ treatment significantly reduced recruitment of immune cells to the lung at the inflammatory phase following infection. Thus, reducing inflammation by shaping cellular and cytokine profiles may favorably change the fate of viral pathogenesis. 
     SUMMARY 
     The present invention in some embodiments, is directed to a method for treating an IFN-γ associated disease or disorder in a subject in need thereof, including administering to the subject a pharmaceutical composition including a therapeutically effective amount of a compound capable of manipulating or modulating PD-L1 signaling or pathway. 
     The present invention, in some embodiments, is based, in part, on the finding that an immunosensor can determine the interferon gamma (IFN-γ) dependent status and over-express it in LPA cells that respond to IFN-γ by upregulation of PDL-1 and CXCL10. As disclosed herein below, a sensor containing a reporter gene, e.g., the green fluorescence protein (GFP), that is linked to the mouse PDL-1 promoter can be used in the kits and methods of the invention (see,  FIG.  14   ). 
     According to a first aspect, there is provided a method for treating an IFN-γ associated disease or disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of: (i) a compound selected from the group consisting of the compounds listed in Table 3, wherein the disease is selected from a viral infection, GVHD, inflammation and autoimmunity; (ii) a compound selected from the group consisting of the compounds listed in Table 2, wherein the disease is selected from a viral infection, GVHD, and cancer; (iii) a compound selected from the group consisting of the compounds listed in Table 1, wherein the disease is selected from autoimmunity, inflammation, and viral infection; and (iv) a compound selected from the group consisting of the compounds listed in Table 4, wherein the disease is cancer; thereby treating an IFN-γ associated disease or disorder in the subject. 
     According to another aspect there is provided, a method for identifying the suitability of a compound for treatment of an IFN-γ associated disease or disorder, the method comprising: contacting a cell with the compound and determining the expression levels of PD-L1 and CXCL10, wherein upregulation of PD-L1 and significant downregulation of CXCL10 indicates that the compound is effective in treating a disease or disorder selected from autoimmunity, inflammation, and viral infection; wherein upregulation of PD-L1 and upregulation, having no effect on or mild downregulation of CXCL10 expression indicates that the compound is effective in treating a disease or disorder selected from viral infection, GVHD, and cancer; wherein downregulation of both PD-L1 and CXCL10 indicates that the compound is effective in treating a disease or disorder selected from viral infection, GVHD, inflammation and autoimmunity; and wherein downregulation of PD-L1 and upregulation, having no effect on or mild downregulation of CXCL10 is indicative that the compound is effective in treating cancer. 
     In some embodiments, the compound of Table 1 upregulates PD-L1 and significantly down regulates CXCL10 in the subject. 
     In some embodiments, the compound of Table 2 upregulates PD-L1 and increases, has no effect on, or mildly reduces CXCL10 expression in the subject. 
     In some embodiments, the compound of Table 3 downregulates both PD-L1 and CXCL10 in the subject. 
     In some embodiments, the compound of Table 4 downregulates PD-L1 and upregulates, has no effect on or mildly down regulates CXCL10 in the subject. 
     In some embodiments, the disease is cancer, and the method further comprises administering an anti-PD-L1 therapy to the subject. 
     In some embodiments, the anti-PD-L1 therapy is administered concomitantly to or after the administering a pharmaceutical composition. 
     In some embodiments, determining the expression levels of PD-L1 is performed using an immunosensor comprising a PD-L1 promotor operably linked to a reporter gene. 
     In some embodiments, determining the expression levels of CXCL10 is by an immunoassay. 
     In some embodiments, the immunoassay is enzyme-linked immunosorbent assay (ELISA). 
     Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting. 
     Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. 
     In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the figures and by study of the following detailed description. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIGS.  1 A- 1 B  include vertical bar graphs showing the expression levels of PD-L1 ( 1 A) and CXCL10 ( 1 B) in LivMet cells in the absence (UT) or presence of interferon γ (IFN-γ). 
         FIG.  2    includes a graph showing the upregulating effect of IFN-γ and compound 18 on the expression of GFP in LPA cells. 
         FIGS.  3 A- 3 B  include graphs showing the down-regulating effect of IFN-γ and compound 62 on the expression of GFP in LPA cells. ( 3 A) a graph of a FACS analysis. ( 3 B) a vertical bar graph showing the FITC MFI of the different experimental groups. 
         FIGS.  4 A- 4 B  include graphs showing a validation of the upregulating effect of IFN-γ and compound 18 on the expression of PD-L1 in LivMet cells. ( 4 A) a graph of a FACS analysis. ( 4 B) a vertical bar graph showing the PE MFI of the different experimental groups. 
         FIG.  5    includes a graph showing a validation of the down-regulating effect of IFN-γ and compound 62 on the expression of PD-L1 in LivMet cells. 
         FIG.  6    includes a graph showing the effect of IFN-γ and a series of compounds (1-529) on the expression of GFP in LPA cells. 
         FIG.  7    includes a graph showing the effect of IFN-γ and compound 18 (which stimulates overexpression of PD-L1) on CXCL10 expression in LPA cells (Upregulation, minor down regulation). 
         FIG.  8    includes a graph showing the effect of IFN-γ and compound 62 (which inhibits expression of PD-L1) on CXCL10 expression in LPA cells (Upregulation, minor downregulation). 
         FIG.  9    includes a graph showing the effect of IFN-γ and compound 6 (which stimulates overexpression of PD-L1) on CXCL10 expression in LPA cells (Upregulation, Downregulation). 
         FIG.  10    includes a graph showing the effect of IFN-γ and compound 52 (which inhibits expression of PD-L1) on CXCL10 expression in LPA cells (Downregulation, Downregulation). 
         FIG.  11    includes a schematic non-limiting set up of lentivirus production and infection of target cells. 
         FIG.  12    includes a plot showing the survival % of LivMet cells according to their reaction to different concentrations of puromycin. 
         FIG.  13    includes a graph showing the fluorescent intensity of eGFP in LivMet and LPA cells, untreated and treated with IFNγ. 
         FIG.  14    includes scheme of a non-limiting representation of an immunosensor comprising a promoter of mouse CD274 gene (PDL-1) cloned into lentiviral vector pEZX-LvPF02 vector. 
         FIGS.  15 A- 15 E  include an image, micrographs, and a vertical bar graph showing a challenge experiment in a DTH murine model. ( 15 A) a control Balb/c mice challenged in its right ear which is red and swollen.  FIGS.  15 B- 15 C  include histological micrographs of the mouse DTH model. ( 15 B) a control mouse. ( 15 C) a mouse treated with Deferasirox. ( 15 D) a mouse treated with Penfluridol. ( 15 E) includes a vertical graph showing the effect of selected compounds (Ganetespib, Dinaciclib, Penfluridol, and Deferasirox) on the ear thickness in the mouse DTH model. Dexamethasone, a known anti-inflammatory agent was used a positive control. 
         FIGS.  16 A- 16 C  include vertical bar graphs showing the effect of selected drugs on the expression of PDL-1 in human primary lung immune (CD45+;  16 A) and epithelial (EPCAM+;  16 B) cells, measured via flow cytometry, and the IP-10 levels in their supernatant&#39;s cell culture measured via ELISA ( 16 C). 
     
    
    
     DETAILED DESCRIPTION 
     The present invention, in some embodiments thereof, is directed to a method for manipulating or modulating INF-γ-mediated response, in a subject in need thereof. 
     The invention further provides methods for identifying the suitability of a compound for treatment of an IFN-γ associated disease or disorder, comprising contacting a cell with the compound and determining the expression levels of PD-L1 and CXCL10. 
     The invention further provides methods, composition and kits, for identifying the suitability of a compound for treatment of an IFN-γ associated disease or disorder. 
     The present invention, in some embodiments thereof, is directed to a method for manipulating or modulating INF-γ-mediated PD-L1 response. In some embodiments, INF-γ-mediated response is INF-γ-mediated PD-L1 response. In some embodiments, modulating is increasing or decreasing. In some embodiments, manipulating or modulating the INF-γ-mediated PD-L1 response comprises the manipulation or modulation of PD-L1, CXCL10, or any combination thereof. 
     In some embodiments, the method further comprises manipulating or modulating CXCL9. 
     As used herein, the term “PD-L1 response” comprises numerous cellular components associated with PD-L1 signaling or pathway. In some embodiments, the method comprises manipulating or modulating PD-L1 signaling or pathway. 
     Cellular components involved or related to PD-L1 signaling or pathway, would be apparent to one of ordinary skill in the art of molecular and cellular biology. 
     In some embodiments manipulating or modulating is achieved by contacting a subject in need thereof or a cell thereof with a therapeutically effective amount of a compound capable of upregulating PD-L1, downregulating PD-L1, upregulating, having no effect on or mildly downregulating CXCL10, down regulating, having no effect on or mildly upregulating CXCL10, downregulating CXCL10, or any combination thereof. In some embodiments, upregulating, having no effect on or mildly downregulating is not significantly downregulating. 
     As used herein, the term “significantly”, e.g., significantly upregulate, significantly downregulate, etc., is by at least 50% more, at least 60% more, at least 70% more, at least 80% more, at least 90% more, at least 95% more, or at least 99% more, or any value and range therebetween. Each possibility represents a separate embodiment of the invention. In some embodiments, significantly is by 50-60% more, 50-70% more, 50-80% more, 50-90% more, 50-100% more, 60-70% more, 60-80% more, 50-90% more, 60-100% more, 70-80% more, 70-80% more, 70-90% more, 70-100% more, 80-90% more, 80-100% more, 90-95% more, 90-99% more, or 90-100% more. Each possibility represents a separate embodiment of the invention. 
     As used herein, the term “mildly”, e.g., mildly upregulate, mildly downregulate, etc., is by 10% at most, 20% at most, 30% at most, 40% at most, or 50% at most, or any value and range therebetween. Each possibility represents a separate embodiment of the invention. In some embodiments, mildly is by 20-30%, 20-40%, 20-50%, 30-40%, 30-50%, or 40-50%. Each possibility represents a separate embodiment of the invention. In some embodiments, mildly, e.g., mildly upregulate, mildly downregulate, etc. is by less than 50%. 
     In some embodiments, the present method is directed to treating or preventing an autoimmune disease or condition, inflammation, or viral infection in a subject in need thereof. 
     In some embodiments, the present method is directed to treating or preventing graft versus host disease (GVHD), or cancer progression (e.g., from stage 1 to stage 2, from stage 3 to stage 4, from local tumor to metathesis, etc.). In some embodiments, the method is directed to treating or preventing GVHD, cancer or viral infection. 
     In some embodiments, the present method is direct to treating or preventing viral infection, GVHD, autoimmune disease or condition, or inflammation. 
     In some embodiments, the present method is directed to treating or preventing cancer. 
     As used herein, the term “cancer” encompasses a cell proliferation related disease. 
     According to some embodiments, there is provided a method for treating an IFN-γ associated disease or disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of: (i) a compound selected from the group consisting of the compounds listed in Table 1, wherein the disease is selected from autoimmunity, inflammation, and viral infection; (ii) a compound selected from the group consisting of the compounds listed in Table 2, wherein the disease is selected from a viral infection, GVHD, and cancer; (iii) a compound selected from the group consisting of the compounds listed in Table 3, wherein the disease is selected from a viral infection, GVHD, inflammation and autoimmunity; and (iv) a compound selected from the group consisting of the compounds listed in Table 4, wherein the disease is cancer; thereby treating an IFN-γ associated disease or disorder in the subject. 
     In some embodiments, the pharmaceutical composition comprises a compound selected from the group of compounds listed in Table 1 and wherein the disease is selected from autoimmunity, inflammation, and viral infection. In some embodiments, the pharmaceutical composition comprises a compound selected from the group of compounds listed in Table 2 and wherein the disease is selected from viral infection, GVHD and cancer. In some embodiments, the pharmaceutical composition comprises a compound selected from the group of compounds listed in Table 3 and wherein the disease is selected from autoimmunity, inflammation, GVHD and viral infection. In some embodiments, the pharmaceutical composition comprises a compound selected from the group of compounds listed in Table 4 and wherein the disease is cancer. In some embodiments, there is provided a compound for use in the upregulation of PD-L1 and downregulation of CXCL10. In some embodiments, downregulation is significant downregulation. In some embodiment the compound upregulating PD-L1 and significantly down regulating CXCL10 is selected from Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 A list of compounds that upregulate PD-L1 
               
               
                 and significantly down regulate CXCL10. 
               
            
           
           
               
               
               
            
               
                   
                   
                 Biosimilar 
               
               
                   
                   
                 compounds (generics, 
               
               
                 Compound 
                 CAS Number 
                 derivatives, etc.) 
               
               
                   
               
               
                 Deferasirox 
                 201530-41-8 
                 Exjade, Desirox, 
               
               
                   
                   
                 Defrijet, Desifer, 
               
               
                   
                   
                 Rasiroxpine and 
               
               
                   
                   
                 Jadenu 
               
               
                 Clofazimine 
                 2030-63-9 
                 Lamprene 
               
               
                 Dronedarone HCl 
                 141625-93-6 
                 Class III 
               
               
                   
                   
                 antiarrhythmic drugs 
               
               
                   
                   
                 amiodarone 
               
               
                 Axitinib (AG 013736) 
                 319460-85-0 
               
               
                 Benzethonium Chloride 
                 121-54-0 
                 Methylbenzethonium 
               
               
                   
                   
                 chloride 
               
               
                 Cetylpyridinium Chloride 
                 123-03-5 
                 Cationic quaternary 
               
               
                   
                   
                 ammonium 
               
               
                 Terfenadine 
                 50679-08-8 
                 Antihistamine 
               
               
                 Cyclosporin A 
                 59865-13-3 
               
               
                 Glycopyrrolate 
                 596-51-0 
                 Muscarinic 
               
               
                   
                   
                 anticholinergic 
               
               
                 Chlorocresol 
                 59-50-7 
               
               
                 Docetaxel Trihydrate 
                 148408-66-6 
               
               
                 Epirubicin HCl 
                 56390-09-1 
               
               
                 Doxorubicin (Adriamycin) HCl 
                 25316-40-9 
               
               
                 S- (+)-Rolipram 
                 85416-73-5 
                 Phosphodiesterase-4 
               
               
                   
                   
                 inhibitors 
               
               
                   
               
            
           
         
       
     
     In some embodiments, any biosimilar compound (e.g., generics, derivatives, etc.) listed in any one of Tables 1-4, can be used according to the herein disclosed method as a substitute for its corresponding compound listed in the tables (in the “Compound column”). 
     In some embodiments, Deferasirox can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Clofazimine can be used for treating or preventing a disease or a condition selected from: autoimmunity, viral infection, or a combination thereof. 
     In some embodiments, Dronedarone HCl can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Axitinib can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Benzethonium Chloride can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, or a combination thereof. 
     In some embodiments, Cetylpyridinium Chloride can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, or a combination thereof. 
     In some embodiments, Terfenadine can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Cyclosporin A can be used for treating or preventing a viral infection, or a combination thereof. 
     In some embodiments, Glycopyrrolate can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Chlorocresol can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Docetaxel trihydrate can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Epirubicin Hydrochloride can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, Doxorubicin Hydrochloride can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, S-(+)-Rolipram (is the (S)-enantiomer of rolipram) can be used for treating or preventing a disease or a condition selected from: autoimmunity, inflammatory, viral infection, or a combination thereof. 
     In some embodiments, there is provided a compound for use in the upregulation of PD-L1 and increase or mild reduction of CXCL10. In some embodiments, there is provided a compound for use in the upregulation of PD-L1 and increase, not effecting or mild reduction of CXCL10. In some embodiments, there is provided a compound for use in the upregulation of PD-L1 and not significant downregulation of CXCL10. In some embodiment the compound upregulating PD-L1 and increasing, not effecting or mildly reducing of CXCL10 is selected from Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 A list of compounds that upregulate PD-L1 and 
               
               
                 increase or mildly reduce CXCL10 expression. 
               
            
           
           
               
               
               
            
               
                   
                   
                 Biosimilar 
               
               
                   
                   
                 compounds (generics, 
               
               
                 Compound 
                 CAS Number 
                 derivatives, etc.) 
               
               
                   
               
               
                 Penfluridol 
                 26864-56-2 
                   
               
               
                 Pizotifen 
                 15574-96-6 
               
               
                 Mechlorethamine HCl 
                 55-86-7 
               
               
                 Trifluridine (Viroptic) 
                 70-00-8 
                 Anti-herpesvirus 
               
               
                   
                   
                 antiviral drug 
               
               
                 Cytarabine hydrochloride 
                 69-74-9 
               
               
                 Sunitinib 
                 557795-19-4 
               
               
                 Plerixafor 8HCl 
                 155148-31-5 
               
               
                 FT-207 (NSC 148958) 
                 17902-23-7 
               
               
                 Raltitrexed 
                 112887-68-0 
               
               
                 Carbimazole 
                 22232-54-8 
               
               
                 Mycophenolic acid 
                 483-60-3 
               
               
                 Cinepazide maleate 
                 26328-04-1 
                 Tradename Vasodistal 
               
               
                   
                   
                 Brindel 
               
               
                 Azathioprine 
                 446-86-6 
                 Imuran 
               
               
                 Esmolol HCl 
                 81161-17-3 
                 Betal receptor blockers 
               
               
                 Cabozantinib malate 
                 1140909-48-3 
                 Cabometyx and Cometriq 
               
               
                 Sucralose 
                 56038-13-2 
               
               
                 Nefiracetam 
                 77191-36-7 
               
               
                 Drospirenone 
                 67392-87-4 
               
               
                 Zaltoprofen 
                 74711-43-6 
                 Selective COX-2 
               
               
                   
                   
                 inhibitors 
               
               
                 Procarbazine HCl 
                 366-70-1 
               
               
                 Otilonium Bromide 
                 0026095-59-0 
               
               
                 Idarubicin HCl 
                 57852-57-0 
               
               
                 Etoposide 
                 33419-42-0 
               
               
                 IPI-145 (INK1197) 
                 1201438-56-3 
                 Duvelisib, sold under 
               
               
                   
                   
                 the brand name Copiktra, 
               
               
                 Mercaptopurine (6-MP) 
                 50-44-2 
               
               
                 Irinotecan 
                 97682-44-5 
               
               
                 Cabozantinib 
                 849217-68-1 
               
               
                 Carmofur 
                 61422-45-5 
               
               
                 Empagliflozin (BI 10773) 
                 864070-44-0 
               
               
                 Clarithromycin 
                 81103-11-9 
                 Macrolide antibiotics 
               
               
                 Rasagiline Mesylate 
                 161735-79-1 
               
               
                 Sunitinib malate 
                 341031-54-7 
               
               
                 Trilostane 
                 13647-35-3 
               
               
                 Amonafide 
                 69408-81-7 
               
               
                   
               
            
           
         
       
     
     In some embodiments, Penfluridol can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Pizotifen can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, mechlorethamine hydrochloride can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. In some embodiments, cancer is cancer progression. 
     In some embodiments, Trifluridine (Viroptic) can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Cytarabine Hydrochloride can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Sunitinib can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Plerixafor can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Tegafur (e.g., FT-207 (NSC 148958) can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Raltitrexed can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Carbimazole can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Mycophenolic acid can be used for treating or preventing a disease or a condition selected from: viral infection, cancer, or a combination thereof. 
     In some embodiments, Cinepazide maleate can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Azathioprine can be used for treating or preventing a disease or a condition selected from: viral infection, cancer, or a combination thereof. 
     In some embodiments, Esmolol Hydrochloride can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Cabozantinib malate can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Sucralose can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Nefiracetam can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Drospirenone can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Zaltoprofen can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Procarbazine Hydrochloride can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Otilinium Bromide can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Idarubicin Hydrochloride can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Etoposide can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Duvelisib (e.g., IPI-145 (INK1197) can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Mercaptopurine can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Irinotecan can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Cabozantinib can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Carmofur can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Empagliflozin can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Clarithromycin can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Rasagiline mesylate can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Sunitinib malate can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, Trilostane can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, cancer, or a combination thereof. 
     In some embodiments, Amonafide can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, or a combination thereof. 
     In some embodiments, the method of treating cancer further comprises a step of administering an anti-PD-L1 based therapy to the subject. In some embodiments, the method of treating cancer further comprises a step of administering an anti-PD-L1 therapy to the subject. In some embodiments, the pharmaceutical composition further comprises an anti-PD-L1 therapy. In some embodiments, the molecules for treating cancer are for use in combination with an anti-PD-L1 therapy. 
     In some embodiments, the anti-PD-L1 therapy is PD-L1 blockade. In some embodiments, that anti-PD-L1 therapy is an anti-PD-L1 antibody. Anti-PD-L1 antibodies are well known in the art and include but are not limited to cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab and atezolizumab. In some embodiments, the anti-PD-L1 therapy is administered concomitantly with the pharmaceutical composition. In some embodiments, the anti-PD-L1 therapy is administered after the administration of the pharmaceutical composition. In some embodiments, after is after a time sufficient for the upregulation of PD-L1 expression in the subject. 
     In some embodiments, there is provided a compound for use in the downregulation of both PD-L1 and CXCL10. In some embodiment the compound downregulating both PD-L1 and CXCL10 is selected from Table 3. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 A list of drugs that down regulate 
               
               
                 PD-L1 and down regulate CXCL10. 
               
            
           
           
               
               
               
            
               
                   
                   
                 Biosimilar 
               
               
                   
                   
                 compounds (generics, 
               
               
                 Compound 
                 CAS Number 
                 derivatives, etc.) 
               
               
                   
               
               
                 Dinaciclib 
                 779353-01-4 
                   
               
               
                 Ganetespib 
                 888216-25-9 
               
               
                 Ruxolitinib 
                 941678-49-5 
                 Jakafi and Jakavi 
               
               
                 Baricitinib 
                 1187594-09-7 
                 Olumiant 
               
               
                 Mevastatin 
                 73573-88-3 
                 Compactin, ML-236B 
               
               
                 AZD-9291 
                 1421373-65-0 
                 Osimertinib (previously 
               
               
                   
                   
                 known as mereletinib; 
               
               
                   
                   
                 trade name Tagrisso) 
               
               
                 BI6727 
                 755038-65-4 
                 Volasertib 
               
               
                 Simvastatin 
                 79902-63-9 
               
               
                 Heparin sodium 
                 9041-08-1 
               
               
                 Pitavastatin Calcium 
                 147511-69-1 
               
               
                 Pelitinib (EKB-569) 
                 257933-82-7 
               
               
                 Ponatinib (AP24534) 
                 943319-70-8 
               
               
                 Mevastatin 
                 73573-88-3 
                 Compactin, ML-236B 
               
               
                 AZD-9291 
                 1421373-65-0 
                 Osimertinib (previously 
               
               
                   
                   
                 known as mereletinib; 
               
               
                   
                   
                 trade name Tagrisso) 
               
               
                   
               
            
           
         
       
     
     In some embodiments, Dinaciclib can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. Dinaciclib showed a significant anti-inflammatory effect in-vitro and in-vivo and therefor has the higher potential to treat or prevent an autoimmune disease or condition, inflammation, or viral infection. 
     According to some embodiments, there is provided a pharmaceutical composition comprising Dinaciclib, for use in the treatment or prevention of a disease or a disorder selected from: viral infection, GVHD, inflammation, autoimmunity, or any combination thereof. 
     In some embodiments, Ganetespib can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, Ruxolitinib can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, autoimmunity, or a combination thereof. 
     In some embodiments, Mevastatin can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, Baricitinib can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, AZD-9291 can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, BI6727 (e.g., Volasertib) can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, Simvastatin can be used for treating or preventing a disease or a condition selected from: viral infection, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, Heparin Sodium can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, Pitavastatin calcium can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, Pelitinib (e.g., EKB-569) can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, Ponatinib can be used for treating or preventing a disease or a condition selected from: viral infection, GVHD, inflammation, autoimmunity, or a combination thereof. 
     In some embodiments, there is provided a compound for use in the downregulation of PD-L1 and upregulation or mild downregulation of CXCL10. In some embodiments, there is provided a compound for use in the downregulation of PD-L1 and upregulation, not effecting or mild downregulation of CXCL10. In some embodiment the compound downregulating PD-L1 and upregulating, not effecting of mildly downregulating CXCL10 is selected from Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 A list of compounds that downregulate PD-L1 
               
               
                 and upregulate or mildly downregulate CXCL10. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Biosimilar 
               
               
                   
                   
                   
                 compounds (generics, 
               
               
                   
                 Compound 
                 CAS Number 
                 derivatives, etc.) 
               
               
                   
                   
               
               
                   
                 Avanafil 
                 330784-47-9 
                 Stendra 
               
               
                   
                 Chlorhexidine HCl 
                 3697-42-5 
               
               
                   
                 Regorafenib 
                 755037-03-7 
                 Stivarga 
               
               
                   
                   
               
            
           
         
       
     
     In some embodiments, Avanafil can be used for treating or preventing cancer. 
     In some embodiments, Chlorhexidine HCl can be used for treating or preventing cancer. 
     In some embodiments, Regorafenib can be used for treating or preventing cancer. 
     Screening Assays 
     In some embodiments, there is provided a method for identifying the suitability of a compound for treatment of an IFN-γ associated disease or disorder, comprising: contacting a cell with the compound and determining the expression levels of PD-L1 and CXCL10. 
     In some embodiments, upregulation of PD-L1 and significant downregulation of CXCL10 is indicative of the compound being effective in treating a disease or disorder selected from: autoimmunity, inflammation, and viral infection. 
     In some embodiments, upregulation of PD-L1 and upregulation or mild downregulation of CXCL10 expression is indicative of the compound being effective in treating a disease or disorder selected from: viral infection, GVHD, and cancer. 
     In some embodiments, downregulation of both PD-L1 and CXCL10 is indicative of the compound being effective in treating a disease or disorder selected from viral infection, GVHD, inflammation and autoimmunity. 
     In some embodiments, downregulation of PD-L1 and upregulation or mild downregulation of CXCL10 is indicative of the compound being effective in treating cancer. 
     In some embodiments, determining the expression levels of PD-L1 is performed using an immunosensor as disclosed herein. In some embodiments, the immunosensor comprises a PD-L1 promotor. In some embodiments, the promoter is operably linked to a reporter gene. 
     In some embodiments, determining the expression levels of CXCL10 is by an immunoassay. In some embodiments, the immunoassay is ELISA. 
     Methods utilizing antibodies for various detection and quantification (e.g., immunoassays) are common and would be apparent to one of ordinary skill in the art of biochemistry and cell biology. A non-limiting example for such immunoassay includes, but is not limited to ELISA, e.g., direct or indirect ELISA. 
     In some embodiments, the cell is a murine cell. In some embodiments, the cell is a mouse cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is not a cancer cell. In some embodiments, the cell is a primary cell. In some embodiments, the cell is a cell of a cell line. 
     Methods of Determining Suitability of a Subject for Therapy (e.g., Transplantation) 
     In some embodiments, there is provided a method for determining the suitability of a subject for therapy. In some embodiments, the therapy is a transplantation. In some embodiments, transplantation is an organ transplantation. In some embodiments the method comprises obtaining or providing a sample from the subject. In some embodiments, the method comprises the step of contacting the herein disclosed immunosensor with a sample of the subject and determining the expression levels of the reporter gene. In some embodiments, the method comprises a step of determining the level of expression of the reporter gene in the presence of the subject&#39;s sample compared to the level of expression of the reporter gene in the absence of the subject&#39;s sample. In some embodiments, the method further comprises a step of determining the expression level of CXCL10 in the immunosensor in the presence and in the absence of the subject&#39;s sample. In some embodiments, reduction in the expression levels of both the reporter gene and CXCL10 in the presence of the subject&#39;s sample (compared to control, e.g., in the absence of the subject&#39;s sample) is indicative of the subject is not suitable for a therapy, e.g., a transplantation. In some embodiments, upregulation in the expression levels of the reporter gene and upregulation or a mild reduction in the expression level of CXCL10 in the presence of the subject&#39;s sample (compared to control, e.g., in the absence of the subject&#39;s sample) is indicative of the subject is not suitable for a therapy, e.g., a transplantation. 
     In some embodiments, the method further comprises a step of manipulating or modulating the expression levels of PD-L1, CXCL10, or both in a subject determined as being not suitable for therapy, e.g., a transplantation, using a compound as disclosed herein. 
     In some embodiments, the sample is derived or obtained from the subject. In some embodiments, the sample comprises any cell type, tissue, organ, bodily fluid, or any combination thereof of the subject. 
     In some embodiments, the determination step as disclosed herein is performed in vitro. 
     According to some embodiments, there is provided a method for treating or preventing a disease or a disorder selected from the group: viral infection, GVHD, inflammation, autoimmunity, and any combination thereof, in a subject in need thereof, the method comprising administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of Dinaciclib, thereby treating or preventing a disease or a disorder selected from the group: viral infection, GVHD, inflammation, autoimmunity, and any combination thereof, in the subject. 
     In some embodiments, the administering comprises a single administering or multiple administering. 
     In some embodiments, the administering comprises intravenously administering. 
     According to some embodiments, there is provided an expression vector or a plasmid comprising a PD-L1 promoter, and an exogenous reporter gene operably linked thereto. 
     In some embodiments, the expression vector or plasmid comprises any reporter gene configured to be expressed under the regulation of a PD-L1 promoter. 
     In some embodiments, the reporter gene is a bioluminescent reporter gene. In some embodiments, the reporter gene is a chemiluminescent reporter gene. In some embodiments, the reporter gene is a fluorescent reporter gene. 
     Types of reporter genes, including their sequence, and optimal conditions for reaction, are common and would be apparent to one of ordinary skill in the art. In some embodiments, the reporter gene is a green fluorescence protein (GFP). In one embodiment, GFP comprises the enhanced GFP (eGFP). 
     In some embodiments, the expression vector or plasmid further comprises at least one additional regulatory element. In some embodiments, the at least one regulatory element is selected from: SV40, puromycin resistance gene, weak positive element (WPE), a bacterial origin of replication (e.g., pUC ori), ampicillin resistance gene, 5′ LTR (e.g., U5/RSV), reverse response element (RRE), central polypurine tract (cPPT), or any combination thereof. 
     In some embodiments, the expression vector or plasmid disclosed herein, is for use as an immunosensor. In some embodiments, the expression vector or plasmid disclosed herein, is for use in determining the expression levels of PD-L1. 
     In some embodiments, the expression vector or plasmid comprises the nucleic acid sequence: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 1) 
               
               
                   
                 AGCCACCATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGG 
               
               
                   
                   
               
               
                   
                 TGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGG 
               
               
                   
                   
               
               
                   
                 CCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCC 
               
               
                   
                   
               
               
                   
                 ACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCG 
               
               
                   
                   
               
               
                   
                 GCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCT 
               
               
                   
                   
               
               
                   
                 GACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCAC 
               
               
                   
                   
               
               
                   
                 ATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAG 
               
               
                   
                   
               
               
                   
                 GCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGG 
               
               
                   
                   
               
               
                   
                 CAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGAC 
               
               
                   
                   
               
               
                   
                 ACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCA 
               
               
                   
                   
               
               
                   
                 AGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAA 
               
               
                   
                   
               
               
                   
                 CTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAG 
               
               
                   
                   
               
               
                   
                 AAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACA 
               
               
                   
                   
               
               
                   
                 TCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCA 
               
               
                   
                   
               
               
                   
                 GAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGAC 
               
               
                   
                   
               
               
                   
                 AACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACC 
               
               
                   
                   
               
               
                   
                 CCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGT 
               
               
                   
                   
               
               
                   
                 GACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTAC 
               
               
                   
                   
               
               
                   
                 AAGTAGCTCGAGCTGTGGAATGTGTGTCAGTTAGGGTGTG 
               
               
                   
                   
               
               
                   
                 GAAAGTCCCCAGGCTCCCCAGCAGGCAGAAGTATGCAAAG 
               
               
                   
                   
               
               
                   
                 CATGCATCTCAATTAGTCAGCAACCAGGTGTGGAAAGTCC 
               
               
                   
                   
               
               
                   
                 CCAGGCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATC 
               
               
                   
                   
               
               
                   
                 TCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCC 
               
               
                   
                   
               
               
                   
                 CATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCG 
               
               
                   
                   
               
               
                   
                 CCCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCG 
               
               
                   
                   
               
               
                   
                 AGGCCGCCTCTGCCTCTGAGCTATTCCAGAAGTAGTGAGG 
               
               
                   
                   
               
               
                   
                 AGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTCCCG 
               
               
                   
                   
               
               
                   
                 GGAGCTTGTATATCCATTTTCGGATCTGATCGGCGCGGGC 
               
               
                   
                   
               
               
                   
                 CGCGATCCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTAC 
               
               
                   
                   
               
               
                   
                 TGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTC 
               
               
                   
                   
               
               
                   
                 TATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATG 
               
               
                   
                   
               
               
                   
                 TGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCAT 
               
               
                   
                   
               
               
                   
                 TCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGT 
               
               
                   
                   
               
               
                   
                 CTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTT 
               
               
                   
                   
               
               
                   
                 CTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCA 
               
               
                   
                   
               
               
                   
                 GCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAA 
               
               
                   
                   
               
               
                   
                 AAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAAC 
               
               
                   
                   
               
               
                   
                 CCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGT 
               
               
                   
                   
               
               
                   
                 CAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAG 
               
               
                   
                   
               
               
                   
                 GATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGG 
               
               
                   
                   
               
               
                   
                 GGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTT 
               
               
                   
                   
               
               
                   
                 AAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTT 
               
               
                   
                   
               
               
                   
                 TTCCTTTGAAAAACACGATGATAAGCTTGCCACAACCCAC 
               
               
                   
                   
               
               
                   
                 AAGGAGACGACCTTCCATGACCGAGTACAAGCCCACGGTG 
               
               
                   
                   
               
               
                   
                 CGCCTCGCCACCCGCGACGACGTCCCCCGGGCCGTACGCA 
               
               
                   
                   
               
               
                   
                 CCCTCGCCGCCGCGTTCGCCGACTACCCCGCCACGCGCCA 
               
               
                   
                   
               
               
                   
                 CACCGTCGACCCGGACCGCCACATCGAGCGGGTCACCGAG 
               
               
                   
                   
               
               
                   
                 CTGCAAGAACTCTTCCTCACGCGCGTCGGGCTCGACATCG 
               
               
                   
                   
               
               
                   
                 GCAAGGTGTGGGTCGCGGACGACGGCGCCGCGGTGGCGGT 
               
               
                   
                   
               
               
                   
                 CTGGACCACGCCGGAGAGCGTCGAAGCGGGGGCGGTGTTC 
               
               
                   
                   
               
               
                   
                 GCCGAGATCGGCCCGCGCATGGCCGAGTTGAGCGGTTCCC 
               
               
                   
                   
               
               
                   
                 GGCTGGCCGCGCAGCAACAGATGGAAGGCCTCCTGGCGCC 
               
               
                   
                   
               
               
                   
                 GCACCGGCCCAAGGAGCCCGCGTGGTTCCTGGCCACCGTC 
               
               
                   
                   
               
               
                   
                 GGCGTCTCGCCCGACCACCAGGGCAAGGGTCTGGGCAGCG 
               
               
                   
                   
               
               
                   
                 CCGTCGTGCTCCCCGGAGTGGAGGCGGCCGAGCGCGCCGG 
               
               
                   
                   
               
               
                   
                 GGTGCCCGCCTTCCTGGAGACCTCCGCGCCCCGCAACCTC 
               
               
                   
                   
               
               
                   
                 CCCTTCTACGAGCGGCTCGGCTTCACCGTCACCGCCGACG 
               
               
                   
                   
               
               
                   
                 TCGAGGTGCCCGAAGGACCGCGCACCTGGTGCATGACCCG 
               
               
                   
                   
               
               
                   
                 CAAGCCCGGTGCCTAGACGCGTCTGGAACAATCAACCTCT 
               
               
                   
                   
               
               
                   
                 GGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAAC 
               
               
                   
                   
               
               
                   
                 TATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAA 
               
               
                   
                   
               
               
                   
                 TGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCAT 
               
               
                   
                   
               
               
                   
                 TTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTAT 
               
               
                   
                   
               
               
                   
                 GAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGT 
               
               
                   
                   
               
               
                   
                 GCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCAT 
               
               
                   
                   
               
               
                   
                 TGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTC 
               
               
                   
                   
               
               
                   
                 CCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCC 
               
               
                   
                   
               
               
                   
                 TTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGA 
               
               
                   
                   
               
               
                   
                 CAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCA 
               
               
                   
                   
               
               
                   
                 TGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGA 
               
               
                   
                   
               
               
                   
                 CGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGA 
               
               
                   
                   
               
               
                   
                 CCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTT 
               
               
                   
                   
               
               
                   
                 CCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCC 
               
               
                   
                   
               
               
                   
                 TTTGGGCCGCCTCCCCGCCTGGAATTAATTCTGCAGTCGA 
               
               
                   
                   
               
               
                   
                 GACCTAGAAAAACATGGAGCAATCACAAGTAGCAATACAG 
               
               
                   
                   
               
               
                   
                 CAGCTACCAATGCTGATTGTGCCTGGCTAGAAGCACAAGA 
               
               
                   
                   
               
               
                   
                 GGAGGAGGAGGTGGGTTTTTCCAGTCACACCTCAGGACCT 
               
               
                   
                   
               
               
                   
                 TTAAGACCAATGACTTACAAGGCAGCTGTAGATCTTAGCC 
               
               
                   
                   
               
               
                   
                 ACTTTTTAAAAGAAAAGAGGGGACTGGAAGGGCTAATTCA 
               
               
                   
                   
               
               
                   
                 CTCCCAACGAAGACAAGATCTGCTTTTTGCCTGTACTGGG 
               
               
                   
                   
               
               
                   
                 TCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTG 
               
               
                   
                   
               
               
                   
                 GCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTT 
               
               
                   
                   
               
               
                   
                 GCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGT 
               
               
                   
                   
               
               
                   
                 GACTCTGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAG 
               
               
                   
                   
               
               
                   
                 TGTGGAAAATCTCTAGCAGTAGTAGTTCATGTCATCTTAT 
               
               
                   
                   
               
               
                   
                 TATTCAGTATTTATAACTTGCAAAGAAATGAATATCAGAG 
               
               
                   
                   
               
               
                   
                 AGTGAGAGGCTAGCGTTTTACCGTCGACCTCTAGCTAGAG 
               
               
                   
                   
               
               
                   
                 CTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAAT 
               
               
                   
                   
               
               
                   
                 TGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAA 
               
               
                   
                   
               
               
                   
                 GCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTA 
               
               
                   
                   
               
               
                   
                 ACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAG 
               
               
                   
                   
               
               
                   
                 TCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCC 
               
               
                   
                   
               
               
                   
                 AACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTC 
               
               
                   
                   
               
               
                   
                 CGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGG 
               
               
                   
                   
               
               
                   
                 CTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATAC 
               
               
                   
                   
               
               
                   
                 GGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACAT 
               
               
                   
                   
               
               
                   
                 GTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAG 
               
               
                   
                   
               
               
                   
                 GCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTG 
               
               
                   
                   
               
               
                   
                 ACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCG 
               
               
                   
                   
               
               
                   
                 AAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCT 
               
               
                   
                   
               
               
                   
                 GGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGC 
               
               
                   
                   
               
               
                   
                 TTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGT 
               
               
                   
                   
               
               
                   
                 GGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCG 
               
               
                   
                   
               
               
                   
                 GTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAAC 
               
               
                   
                   
               
               
                   
                 CCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTA 
               
               
                   
                   
               
               
                   
                 TCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCA 
               
               
                   
                   
               
               
                   
                 CTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGT 
               
               
                   
                   
               
               
                   
                 ATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAA 
               
               
                   
                   
               
               
                   
                 CTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCT 
               
               
                   
                   
               
               
                   
                 CTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCT 
               
               
                   
                   
               
               
                   
                 CTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTTTTTT 
               
               
                   
                   
               
               
                   
                 TGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCT 
               
               
                   
                   
               
               
                   
                 CAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTC 
               
               
                   
                   
               
               
                   
                 AGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAG 
               
               
                   
                   
               
               
                   
                 ATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAA 
               
               
                   
                   
               
               
                   
                 AAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAA 
               
               
                   
                   
               
               
                   
                 CTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACC 
               
               
                   
                   
               
               
                   
                 TATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCC 
               
               
                   
                   
               
               
                   
                 TGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCT 
               
               
                   
                   
               
               
                   
                 TACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCC 
               
               
                   
                   
               
               
                   
                 ACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCA 
               
               
                   
                   
               
               
                   
                 GCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTAT 
               
               
                   
                   
               
               
                   
                 CCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAG 
               
               
                   
                   
               
               
                   
                 AGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTT 
               
               
                   
                   
               
               
                   
                 GCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTG 
               
               
                   
                   
               
               
                   
                 GTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCG 
               
               
                   
                   
               
               
                   
                 AGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGC 
               
               
                   
                   
               
               
                   
                 TCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCG 
               
               
                   
                   
               
               
                   
                 CAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTC 
               
               
                   
                   
               
               
                   
                 TCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACT 
               
               
                   
                   
               
               
                   
                 GGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGC 
               
               
                   
                   
               
               
                   
                 GGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAA 
               
               
                   
                   
               
               
                   
                 TACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATT 
               
               
                   
                   
               
               
                   
                 GGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTAC 
               
               
                   
                   
               
               
                   
                 CGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACC 
               
               
                   
                   
               
               
                   
                 CAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCT 
               
               
                   
                   
               
               
                   
                 GGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGG 
               
               
                   
                   
               
               
                   
                 GAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTT 
               
               
                   
                   
               
               
                   
                 CCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGT 
               
               
                   
                   
               
               
                   
                 CTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATA 
               
               
                   
                   
               
               
                   
                 AACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCC 
               
               
                   
                   
               
               
                   
                 ACCTGACGTCGACGGATCGGGAGATCAACTTGTTTATTGC 
               
               
                   
                   
               
               
                   
                 AGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAAT 
               
               
                   
                   
               
               
                   
                 TTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTG 
               
               
                   
                   
               
               
                   
                 GTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGGAT 
               
               
                   
                   
               
               
                   
                 CAACTGGATAACTCAAGCTAACCAAAATCATCCCAAACTT 
               
               
                   
                   
               
               
                   
                 CCCACCCCATACCCTATTACCACTGCCAATTACCCTGTGG 
               
               
                   
                   
               
               
                   
                 GCGCAATTAACCCTCACTAAAGGGAACAAAAGCTGGAGCT 
               
               
                   
                   
               
               
                   
                 GCAAGCTTAATGTAGTCTTATGCAATACTCTTGTAGTCTT 
               
               
                   
                   
               
               
                   
                 GCAACATGGTAACGATGAGTTAGCAACATGCCTTACAAGG 
               
               
                   
                   
               
               
                   
                 AGAGAAAAAGCACCGTGCATGCCGATTGGTGGAAGTAAGG 
               
               
                   
                   
               
               
                   
                 TGGTACGATCGTGCCTTATTAGGAAGGCAACAGACGGGTC 
               
               
                   
                   
               
               
                   
                 TGACATGGATTGGACGAACCACTGAATTGCCGCATTGCAG 
               
               
                   
                   
               
               
                   
                 AGATATTGTATTTAAGTGCCTAGCTCGATACATAAACGGG 
               
               
                   
                   
               
               
                   
                 TCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTG 
               
               
                   
                   
               
               
                   
                 GCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTT 
               
               
                   
                   
               
               
                   
                 GCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGT 
               
               
                   
                   
               
               
                   
                 GACTCTGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAG 
               
               
                   
                   
               
               
                   
                 TGTGGAAAATCTCTAGCAGTGGCGCCCGAACAGGGACTTG 
               
               
                   
                   
               
               
                   
                 AAAGCGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGA 
               
               
                   
                   
               
               
                   
                 CTCGGCTTGCTGAAGCGCGCACGGCAAGAGGCGAGGGGCG 
               
               
                   
                   
               
               
                   
                 GCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGAGGC 
               
               
                   
                   
               
               
                   
                 TAGAAGGAGAGAGATGGGTGCGAGAGCGTCAGTATTAAGC 
               
               
                   
                   
               
               
                   
                 GGGGGAGAATTAGATCGCGATGGGAAAAAATTCGGTTAAG 
               
               
                   
                   
               
               
                   
                 GCCAGGGGGAAAGAAAAAATATAAATTAAAACATATAGTA 
               
               
                   
                   
               
               
                   
                 TGGGCAAGCAGGGAGCTAGAACGATTCGCAGTTAATCCTG 
               
               
                   
                   
               
               
                   
                 GCCTGTTAGAAACATCAGAAGGCTGTAGACAAATACTGGG 
               
               
                   
                   
               
               
                   
                 ACAGCTACAACCATCCCTTCAGACAGGATCAGAAGAACTT 
               
               
                   
                   
               
               
                   
                 AGATCATTATATAATACAGTAGCAACCCTCTATTGTGTGC 
               
               
                   
                   
               
               
                   
                 ATCAAAGGATAGAGATAAAAGACACCAAGGAAGCTTTAGA 
               
               
                   
                   
               
               
                   
                 CAAGATAGAGGAAGAGCAAAACAAAAGTAAGACCACCGCA 
               
               
                   
                   
               
               
                   
                 CAGCAAGCGGCCGGCCGCTGATCTTCAGACCTGGAGGAGG 
               
               
                   
                   
               
               
                   
                 AGATATGAGGGACAATTAATTGGAGAAGTGAATTATATAA 
               
               
                   
                   
               
               
                   
                 ATATAAAGTAGTAAAAATTGAACCATTAGGAGTAGCACCC 
               
               
                   
                   
               
               
                   
                 ACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAAAAAAGAG 
               
               
                   
                   
               
               
                   
                 CAGTGGGAATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGC 
               
               
                   
                   
               
               
                   
                 AGCAGGAAGCACTATGGGCGCAGCGTCAATGACGCTGACG 
               
               
                   
                   
               
               
                   
                 GTACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGC 
               
               
                   
                   
               
               
                   
                 AGAACAATTTGCTGAGGGCTATTGAGGCGCAACAGCATCT 
               
               
                   
                   
               
               
                   
                 GTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCA 
               
               
                   
                   
               
               
                   
                 AGAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGC 
               
               
                   
                   
               
               
                   
                 TCCTGGGGATTTGGGGTTGCTCTGGAAAACTCATTTGCAC 
               
               
                   
                   
               
               
                   
                 CACTGCTGTGCCTTGGAATGCTAGTTGGAGTAATAAATCT 
               
               
                   
                   
               
               
                   
                 CTGGAACAGATTTGGAATCACACGACCTGGATGGAGTGGG 
               
               
                   
                   
               
               
                   
                 ACAGAGAAATTAACAATTACACAAGCTTAATACACTCCTT 
               
               
                   
                   
               
               
                   
                 AATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAA 
               
               
                   
                   
               
               
                   
                 GAATTATTGGAATTAGATAAATGGGCAAGTTTGTGGAATT 
               
               
                   
                   
               
               
                   
                 GGTTTAACATAACAAATTGGCTGTGGTATATAAAATTATT 
               
               
                   
                   
               
               
                   
                 CATAATGATAGTAGGAGGCTTGGTAGGTTTAAGAATAGTT 
               
               
                   
                   
               
               
                   
                 TTTGCTGTACTTTCTATAGTGAATAGAGTTAGGCAGGGAT 
               
               
                   
                   
               
               
                   
                 ATTCACCATTATCGTTTCAGACCCACCTCCCAACCCCGAG 
               
               
                   
                   
               
               
                   
                 GGGACCCGACAGGCCCGAAGGAATAGAAGAAGAAGGTGGA 
               
               
                   
                   
               
               
                   
                 GAGAGAGACAGAGACAGATCCATTCGATTAGTGAACGGAT 
               
               
                   
                   
               
               
                   
                 CTCGACGGTATCGCCTTTAAAAGAAAAGGGGGGATTGGGG 
               
               
                   
                   
               
               
                   
                 GGTACAGTGCAGGGGAAAGAATAGTAGACATAATAGCAAC 
               
               
                   
                   
               
               
                   
                 AGACATACAAACTAAAGAACTACAAAAACAAATTACAAAA 
               
               
                   
                   
               
               
                   
                 ATTCAAAATTTTCGGGTTTATTACAGGGACAGCAGAGATC 
               
               
                   
                   
               
               
                   
                 CAGTTTATCTAATACGACTCACTATAGGGAGAGAGAGAGA 
               
               
                   
                   
               
               
                   
                 ATTACCCTCACTAAAGGGAGGAGAAGCATGAATTGAAGGA 
               
               
                   
                   
               
               
                   
                 GATAGAACCAGATCTTGGAATTCACTAAGCCAGCGGACAC 
               
               
                   
                   
               
               
                   
                 CCCAGTATTCACCCAGTGCACTACTTTGGAATAGTAGTTT 
               
               
                   
                   
               
               
                   
                 TGTAAGTAAGTGGGGGAAAGCAGAGAATGAAGAAGGCCCT 
               
               
                   
                   
               
               
                   
                 TGAAGTCCAACAGTGAAATGTTTAAAGATGACAGTGCTCT 
               
               
                   
                   
               
               
                   
                 GTGGAGTTCCCAAGGTTTTGTCTTGGAAAAAGTCCACACT 
               
               
                   
                   
               
               
                   
                 TCCAGTTCGCAGAAAGTCTTTCTCAACATCATTTAGAATA 
               
               
                   
                   
               
               
                   
                 GACTTCCCCCACCTGGATCCCGAGACTGGCCGTGATCCAC 
               
               
                   
                   
               
               
                   
                 AGCGTTCACAAAGGGCACGGTTCGAGATGGGAAGTTCTTG 
               
               
                   
                   
               
               
                   
                 AACGGCAAGACAACTGGTTTCATTATGTCGAGGAACTTTG 
               
               
                   
                   
               
               
                   
                 AGGAAGTCACCAAATCCACGATTTAAAAATATATTTCCTA 
               
               
                   
                   
               
               
                   
                 TTATACAGACACACCTACTTTCTAGAATTAAAACTGAGTC 
               
               
                   
                   
               
               
                   
                 ATTTGCTTGATATTAACTCTATAGGTTGTATAACTCTATA 
               
               
                   
                   
               
               
                   
                 TGTAAAGTCATGTCAAGACTGTCACGTATCCACGTATCCA 
               
               
                   
                   
               
               
                   
                 GAAAGGGCTTGAAAGAGATGGGGAATCGGATGGTAATTTG 
               
               
                   
                   
               
               
                   
                 AAGTGTCTGGATTCTGAAGATAAAATTTAAGTCAGAGATC 
               
               
                   
                   
               
               
                   
                 TTATGACTTCAGATATTTTGCTTCTAAAGCGCTCACTGCT 
               
               
                   
                   
               
               
                   
                 CAAGCCTGAAGATTTGAAATTCGGGTCCTCATTACCCATA 
               
               
                   
                   
               
               
                   
                 ATAAATGCAGTGATGGCCCATTTCTGAGACCCTAGCCCTG 
               
               
                   
                   
               
               
                   
                 GCAGCAGGGGCGCGGATGGGGATCCCTGGACCACGCTGGC 
               
               
                   
                   
               
               
                   
                 CGGCTAGTTTGGCCAGCTGCGAGCCCGAGGTTAGGTAAGA 
               
               
                   
                   
               
               
                   
                 GAGACCCTCTTTCAAAAATCAAGGTGGGAGCTGTAGAGGA 
               
               
                   
                   
               
               
                   
                 AGGCAACCTATGTGGATCTCCAAGCACACGCTCCCCCCCA 
               
               
                   
                   
               
               
                   
                 CCCCCACCCCCGACCTCAGGTTCCACTCCCACCCAAAATA 
               
               
                   
                   
               
               
                   
                 GAGCTGAGTTGTTTACTCTGGACTGTTTCTTTGAGGGAAC 
               
               
                   
                   
               
               
                   
                 CTGATTTACAAGAAAGCTAATGCAGGTTTCACTTTCACTT 
               
               
                   
                   
               
               
                   
                 TTAGTTTCGTTTTTAAATAGTGTTTGTTTGTTTTTGTTTT 
               
               
                   
                   
               
               
                   
                 TATCGACAGCCTCTCAGTAGCAGCCCGGTTGTCTTGGAGC 
               
               
                   
                   
               
               
                   
                 TCTCTCTATAGACCAGAGACTCACCTGCCACTGGCTCCTG 
               
               
                   
                   
               
               
                   
                 AGTACTGGAATTAAGGCGTGTGTCACCGCACCGAAGCCTA 
               
               
                   
                   
               
               
                   
                 GTTTCGTTTTTTCTTAAACTGTGAATATCCCAAAGCTGAC 
               
               
                   
                   
               
               
                   
                 TCTAAAGTCATCCGCAGGAAATACTATGAGATAAACTCAT 
               
               
                   
                   
               
               
                   
                 GCTCAAAGGGACTGGGTGGCTTCGGTTTCACAGACAGCGG 
               
               
                   
                   
               
               
                   
                 AGGTTGGACAAGGCTTCCGCGGAGTGGGCGGGGCTCTGAA 
               
               
                   
                   
               
               
                   
                 CTCGAGATAAGACCAGGAAATCGTGGTCCCCAAGCCTCAT 
               
               
                   
                   
               
               
                   
                 GCCAGGCTGCACTTGCACGTCGCGGGCCAGTCTCCTCGCC 
               
               
                   
                   
               
               
                   
                 TGCAGGTAAGGGAGCATCTTCTCGCGGAATCCGCTTGCAG 
               
               
                   
                   
               
               
                   
                 GGCACTTTAAAGAGCCAGAATCCCTAGACCTTTTTAGGAC 
               
               
                   
                   
               
               
                   
                 GGAGAAGGGAACCGGTTTCCTGGGAAAGTTAAGAACTCAG 
               
               
                   
                   
               
               
                   
                 AATCCGCAGTTTTGTGTGTTTATGGATCTTGTGGGTAGGT 
               
               
                   
                   
               
               
                   
                 AGCTGGGTCAGAAGAGATGAATTAATTGGTCCTAGCGCGA 
               
               
                   
                   
               
               
                   
                 CTTGACTGTTTGCTAAGCTTGGTACCGAGCTCGGATCC.  
               
               
                   
                   
               
            
           
         
       
     
     As used herein, the term “about” when combined with a value refers to plus and minus 10% of the reference value. For example, a length of about 1,000 nanometers (nm) refers to a length of 1,000 nm±100 nm. 
     It is noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a polynucleotide” includes a plurality of such polynucleotides and reference to “the polypeptide” includes reference to one or more polypeptides and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements or use of a “negative” limitation. 
     In those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” 
     It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the invention are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein. 
     Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples. 
     EXAMPLES 
     Generally, the nomenclature used herein, and the laboratory procedures utilized in the present invention include chemical, molecular, biochemical, and cell biology techniques. Such techniques are thoroughly explained in the literature. See, for example, “Molecular Cloning: A laboratory Manual” Sambrook et al., (1989); “Current Protocols in Molecular Biology” Volumes I-III Ausubel, R. M., ed. (1994); “Cell Biology: A Laboratory Handbook”, Volumes I-III Cellis, J. E., ed. (1994); The Organic Chemistry of Biological Pathways by John McMurry and Tadhg Begley (Roberts and Company, 2005); Organic Chemistry of Enzyme-Catalyzed Reactions by Richard Silverman (Academic Press, 2002); Organic Chemistry (6 th  Edition) by Leroy “Skip” G Wade; Organic Chemistry by T. W. Graham Solomons and, Craig Fryhle. 
     Materials and Methods 
     Cloning Procedure 
     Recombinant lentiviral particles were generated by transfecting a lentiviral expression plasmid into lentiviral packaging cells. The lentiviral expression plasmid contained a PD-L1 signaling or pathway responsive element, including all other elements required for packaging, transduction and stable integration of the viral expression construct into genomic DNA, which further enable expression of elements carried by the vector. Further, the expression plasmid contained a reporter gene, e.g., eGFP, the expression of which is indicative of activation of the above-mentioned PD-L1 signaling responsive element. 
     Generation of Expressing Cells 
     Transfection 
     The chosen tumor cells for the viral infection were LivMet cells. LivMet cells are a pancreatic tumor cell line derived from KrasG12D/+ transgenic mice which developed tumor of pancreatic ductal adenocarcinoma (PDA). The LivMet cell line was derived from a liver metastasis that occurred in these transgenic mice. 
     Two days before infection, 1×10 5  LivMet cells were seeded in a 48 well plate in 600 μl DMEM supplemented with 10% heat-inactivated fetal bovine serum so that the cells were 70-80% confluent in the moment of infection. The cells were incubated at 37° C. with 5% CO 2 . 1.5 μl of 2.82 μl 10 8  TU/ml titer lentivirus particles were added into the culture following changing the medium to 200 μl DMEM containing 1% heat-inactivated fetal bovine serum. Culture was incubated in 37° C. with 5% CO 2  for 4 hours and 400 μl of 10% heat-inactivated fetal bovine serum DMEM was added. 
     Two (2) days after infection, 3 μg/ml of puromycin was used to select the infected cells according to the puromycin survival tests on LivMet cells ( FIG.  12   ). 
     In order to obtain 1 clone, the inventors performed a single cell cloning by seeding 0.5 cell per well in ten 96-well plates. Then, using a light microscope, the inventors chose the clones that expressed the least eGFP and checked these clones for PD-L1 protein expression after IFN-γ stimulation via fluorescence activated cell sorting (FACS). The clone that had the highest eGFP MFI only after IFN-γ stimulation (LPA) was chosen ( FIG.  13   ). 
     Expression Analysis 
     1×10 5  LPA cells were seeded in 4×96 well plates one day before treatment. Each well was treated with 10 mM of a different FDA approved drug. DiscoveryProbe™ FDA-approved Drug Library was purchased from ApexBio company. Two (2) plates were treated with IFN-γ, and 2 were not. One plate of each was measured for eGFP MFI in FACS 24 hours after treatment and the other was tested 48 hours after treatment. Each plate had 8 wells of CTRL: 2×LivMet, 2×LivMet+IFN-γ, 2×LPA, and 2×LPA-γ. 
     Validation of drugs that upregulated or downregulated eGFP expression in this screening was performed on LivMet cells. 1×10 5  LivMet cells were seeded in two 96 well plates one day before treatment. Each well was treated with a chosen drug and cells were stained with anti PD-L1 antibody, 24 hr and 48 hr after treatment with or without IFN-γ. Supernatant of each well was further tested via ELISA for CXCL10 expression. 
       FIGS.  1 A- 1 B  include vertical bar graphs showing the expression levels of PD-L1 ( 1 A) and CXCL10 ( 1 B) in LivMet cells in the absence (UT) or presence of interferon γ (IFN-γ). 
       FIG.  2    includes a graph showing the upregulating effect of IFN-γ and compound 18 on the expression of GFP in LPA cells. 
       FIGS.  3 A- 3 B  include graphs showing the down-regulating effect of IFN-γ and compound 62 on the expression of GFP in LPA cells. ( 3 A) a graph of a FACS analysis. ( 3 B) a vertical bar graph showing the FITC MFI of the different experimental groups. 
       FIGS.  4 A- 4 B  include graphs showing a validation of the upregulating effect of IFN-γ and compound 18 on the expression of PD-L1 in LivMet cells. ( 4 A) a graph of a FACS analysis. ( 3 B) a vertical bar graph showing the PE MFI of the different experimental groups. 
       FIG.  5    includes a graph showing a validation of the down-regulating effect of IFN-γ and compound 62 on the expression of PD-L1 in LivMet cells. 
       FIG.  6    includes a graph showing the effect of IFN-γ and a series of compounds (1-529) on the expression of GFP in LPA cells. 
       FIG.  7    includes a graph showing the effect of IFN-γ and compound 18 (which stimulates overexpression of PD-L1) on CXCL10 expression in LPA cells (Upregulation, minor down regulation). 
       FIG.  8    includes a graph showing the effect of IFN-γ and compound 62 (which inhibits expression of PD-L1) on CXCL10 expression in LPA cells (Upregulation, minor downregulation). 
       FIG.  9    includes a graph showing the effect of IFN-γ and compound 6 (which stimulates overexpression of PD-L1) on CXCL10 expression in LPA cells (Upregulation, Downregulation). 
       FIG.  10    includes a graph showing the effect of IFN-γ and compound 52 (which inhibits expression of PD-L1) on CXCL10 expression in LPA cells (Downregulation, Downregulation). 
       FIG.  11    includes a schematic non-limiting set up of lentivirus production and infection of target cells. 
       FIG.  12    includes a plot showing the survival % of LivMet cells according to their reaction to different concentrations of puromycin. 
       FIG.  13    includes a graph showing the fluorescent intensity of eGFP in LivMet and LPA cells, untreated and treated with IFNγ. 
     Drugs that either reduced or enhanced GFP expression were then validated for their effect on the expression of IFN-g inducible genes in-vitro in mouse LivMet cells, thereafter in human primary lung cells and in-vivo in a mouse Delayed-type hypersensitivity (DTH) model. 
     Human Primary lung cells were isolated from normal lung biopsies and culture for five days. Then, cells were stimulated with IFN-g and were treated separately with each one the candidate drugs. 48 hours later, immune CD45+ cells and epithelial (EPCAM+) cells were identified via flow cytometry and IFN-g dependent expression of PDL-1 and IP-10 were measured via FACS and ELISA, respectively. Drugs that affected human primary lung cells were further tested in-vivo in a mouse DTH model. 
     Mouse DTH in-vivo assay is an inflammatory model which is known as type IV hypersensitivity reactions and is mediated by soluble antigens primarily involving CD4+ or CD8+ T cell activation. This assay is characterized by the release of mediators from activated T cells. The T cells then activate local endothelial cells and recruit macrophages, which results in local inflammation and swelling. In this assay, female BALB/c mice were sensitized on the shaved abdominal skin with 100 μl of 2% oxazalone dissolved in acetone/olive oil [4:1 (vol/vol)] applied topically (day 0). DTH sensitivity was elicited 6 days later by challenging the mice with 20 μl of 0.5% oxazalone in acetone/olive oil, 10 μl administered topically to each side of the right ear. Control group was subcutaneously injected with Dexamethasone 100 μg/mouse in a total volume of 200 μl. 24 hr after challenge the swelling of the right ear was measured using a Micrometer, digital caliper (Mitutoyo Corp, Tokyo, Japan). The swelling of the left ear was served as control and the readout of this experiment model was the delta between the right and left ear ( FIG.  15 E ). 
     Generally, drugs that showed a pro-inflammatory effect in this assay, are directed to treating or preventing graft versus host disease (GVHD), or cancer progression and can be further tested for their anti-tumor properties alone or with a combination with immunotherapy compound, whereas drugs that showed anti-inflammatory effect in this assay, are directed to treating or preventing an autoimmune disease or condition, inflammation, or viral infection. 
     Specifically, Penfluridol had a pro-inflammatory effect in this model, while Deferasirox had an anti-inflammatory effect ( FIGS.  15 C- 15 D ). 
     Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.