CD11 B[low] MACROPHAGES AND CONDITIONED MEDIA THEREOF FOR TREATING CANCER AND/OR FIBROSIS

Abstract

A conditioned cell culture medium of CD11b low human macrophages or a biologically active fraction thereof can be prepared by a method that includes (i) culturing a population of human mononuclear cells of the monocyte/macrophage lineage for 5-7 days, so as to induce differentiation of the mononuclear cells to macrophages; (ii) incubating the macrophages obtained in (i) with apoptotic cells or in the presence of a pro-resolving lipid mediator to reduce the CD11b expression, thus obtaining a culture of CD11b low macrophages; and (iii) collecting the conditioned cell culture medium of CD11b low macrophages. Pharmaceutical compositions containing the CD11b low macrophages conditioned medium or a culture of CD11b low macrophages can be used in the treatment of cancer or fibrosis.

What is claimed is: 
     
         1 . A conditioned cell culture medium of CD11b low  human macrophages or a biologically active fraction thereof. 
     
     
         2 . A method for preparing the conditioned cell culture medium of CD11b low  human macrophages of  claim 1 , the method comprising:
 (i) culturing a population of human mononuclear cells of the monocyte/macrophage lineage for 5-7 days, so as to induce differentiation of said mononuclear cells to macrophages;   (ii) incubating the macrophages obtained in said (i) with apoptotic cells or in presence of a pro-resolving lipid mediator to reduce a CD11b expression, thus obtaining a culture of CD11b low  macrophages; and   (iii) collecting the conditioned cell culture medium of CD11b low  macrophages.   
     
     
         3 . The method according to  claim 2 , wherein said human mononuclear cells of the monocyte/macrophage lineage are human monocytes. 
     
     
         4 . The method according to  claim 3 , wherein the human monocytes are derived from peripheral blood mononuclear cells of an individual. 
     
     
         5 . The method according to  claim 2 , wherein the incubation of the macrophages in said (ii) is carried out in presence of apoptotic cells. 
     
     
         6 . The method according to  claim 5 , wherein a ratio of said macrophages to apoptotic cells is between 1:1 and 1:1.5. 
     
     
         7 . The method according to  claim 2 , wherein the incubation of the macrophages in said (ii) is carried out in presence of a pro-resolving lipid mediator selected from the group consisting of a lipoxin (LX), a resolvin (Rv), a protectin (PD), a maresin (MaR), and a glucorticoid. 
     
     
         8 . The method according to  claim 7 , wherein said lipoxin is LXB 4  or 15-epi-LXA 4 , said resolvin is RvD1 or RvD2, said protectin is PD1, and said glucorticoid is dexamethasone. 
     
     
         9 . A conditioned cell culture medium of CD11b low  macrophages produced according to  claim 2 . 
     
     
         10 . An active agent selected from the group consisting of (i) a conditioned cell culture medium of CD11b low  macrophages; (ii) a biologically active fraction thereof; (iii) a pharmaceutical composition comprising said (i) or (ii) and a pharmaceutically active carrier, an excipient or a diluent; (iv) a culture of human CD11b low  macrophages; or (v) a pharmaceutical composition comprising said (iv) and a pharmaceutically active carrier, an excipient or a diluent, for use in treatment of a cancer or a fibrosis. 
     
     
         11 . The conditioned cell culture medium of CD11b low  macrophages or the pharmaceutical composition comprising it according to  claim 10 , for use in treatment of the cancer. 
     
     
         12 . The conditioned cell culture medium of CD11b low  macrophages or the pharmaceutical composition comprising it according to  claim 11 , wherein said treatment of the cancer comprises preventing or delaying a cancer recurrence or an occurrence of metastasis or inhibiting a cancer metastasis. 
     
     
         13 . The conditioned cell culture medium of CD11b low  macrophages or the pharmaceutical composition comprising it according to  claim 10 , wherein said cancer is selected from the group consisting of breast, prostate, esophageal, skin, lung, head and neck, colon and liver cancer. 
     
     
         14 . The conditioned cell culture medium of CD11b low  macrophages or the pharmaceutical composition comprising it according to  claim 10 , wherein said treatment of fibrosis comprises preventing or inhibiting the fibrosis. 
     
     
         15 . The conditioned cell culture medium of CD11b low  macrophages or the pharmaceutical composition comprising it according to  claim 14 , wherein said fibrosis is associated with cancer. 
     
     
         16 . The conditioned cell culture medium of CD11b low  macrophages or the pharmaceutical composition comprising it according to  claim 14 , wherein said fibrosis is associated with a disease or a condition selected from the group consisting of acute lung injury, Alzheimer's disease, chronic diabetic wounds, chronic granulomatous disease (CGD), chronic obstructive pulmonary disease (COPD), constrictive pericarditis, Dupuytren's disease, emphysema, hypertrophic burn scars, keloid, liver cirrhosis, plantar fibromatosis, retinal detachment inflammation, scleroderma, cystic fibrosis, endometrial fibrosis, idiopathic pulmonary fibrosis, myocardial fibrosis, nephrogenic fibrosis, pancreatic fibrosis, perineural fibrosis, renal interstitial fibrosis, secondary fibrosis in the gastrointestinal tract or fibrosis resulting after surgery. 
     
     
         17 . A pharmaceutical composition comprising an active agent selected from the group consisting of (i) a conditioned cell culture medium of CD11b low  macrophages; (ii) a biologically active fraction thereof; (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically active carrier, an excipient or a diluent; (iv) a culture of human CD11b low  macrophages; or (v) a pharmaceutical composition comprising (iv) and a pharmaceutically active carrier, an excipient or a diluent. 
     
     
         18 . A method for preparing a culture of CD11blow macrophages, the method comprising:
 (i) culturing a population of mononuclear cells of the monocyte/macrophage lineage for 5-7 days, so as to induce differentiation of said mononuclear cells to macrophages; and   (ii) incubating the macrophages obtained in said (i) with apoptotic cells or in presence of a pro-resolving lipid mediator to reduce the CD11b expression, thus obtaining a culture of CD11b low  macrophages.   
     
     
         19 . A method for treating a cancer comprising administering to a subject in need an effective amount of an active agent selected from the group consisting of:
 (i) a conditioned cell culture medium of CD11b low  macrophages;   (ii) a biologically active fraction thereof;   (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically active carrier, an excipient or a diluent;   (iv) a culture of human CD11b low  macrophages; and   (v) a pharmaceutical composition comprising (iv) and a pharmaceutically active carrier, an excipient or a diluent, wherein said treatment comprises preventing or delaying a cancer recurrence or an occurrence of metastasis or inhibiting a cancer metastasis.   
     
     
         20 . The method according to  claim 19 , wherein said treating cancer, preventing or delaying the cancer recurrence or occurrence of metastasis, or inhibiting cancer metastasis comprises preventing or inhibiting an outbreak of dormant cancer cells. 
     
     
         21 . The method according to  claim 19 , wherein said subject in need is in cancer remission. 
     
     
         22 . The method according to  claim 19 , wherein said administering is performed in combination with additional one or more anti-cancer agents or treatments. 
     
     
         23 . A method for treating a fibrosis comprising administering to a subject in need an effective amount of an active agent selected from the group consisting of:
 (i) a conditioned cell culture medium of CD11b low  macrophages;   (ii) a biologically active fraction thereof;   (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically active carrier, an excipient or a diluent;   (iv) a culture of human CD11b low  macrophages; and   (v) a pharmaceutical composition comprising (iv) and a pharmaceutically active carrier, an excipient or a diluent, wherein said treatment fibrosis comprises preventing or inhibiting fibrosis.