Treating inflammation using llp2a-bisphosphonate conjugates and mesenchymal stem cells

Abstract

The present invention provides methods of treating a subject having a primary inflammatory disease or disorder comprising administering to the subject a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug, wherein the composition comprising the LLP2A-bisphosphonate conjugate enhances the delivery of mesenchymal stem cells to a site of inflammation. Methods of enhancing an anti-inflammatory or immunomodulatory property of mesenchymal stem cells, comprising administering to a subject in need thereof the mesenchymal stem cells and a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug, are also provided.

What is claimed is: 
     
         1 . A method of treating a subject having a primary inflammatory disease or disorder selected from arthritis, inflammatory arthritis, rheumatoid arthritis, synovitis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, spondylarthritis, and osteoarthritis, the method comprising administering to the subject a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug, wherein the composition comprising the conjugate enhances the delivery of mesenchymal stem cells to a site of inflammation. 
     
     
         2 . The method of  claim 1 , wherein the composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”). 
     
     
         3 . The method of  claim 1  or  2 , further comprising administering exogenous mesenchymal stem cells. 
     
     
         4 . The method of  claim 3 , wherein the composition and the mesenchymal stem cells are administered sequentially. 
     
     
         5 . The method of  claim 3 , wherein the composition and the mesenchymal stem cells are administered concurrently. 
     
     
         6 . The method of any of  claims 3 - 5 , wherein one or both of the composition and the mesenchymal stem cells are administered locally at the site of inflammation. 
     
     
         7 . The method of any of  claims 1 - 6 , wherein the site of inflammation is a joint. 
     
     
         8 . The method of any of  claims 1 - 7 , wherein one or both of the composition and the mesenchymal stem cells are administered by injection. 
     
     
         9 . The method of any of  claims 1 - 7 , wherein one or both of the composition and the mesenchymal stem cells are administered systemically. 
     
     
         10 . The method of any of  claims 1 - 7 , wherein one or both of the composition and the mesenchymal stem cells are administered intravenously. 
     
     
         11 . The method of any of  claims 1 - 10 , wherein one or both of the composition and the mesenchymal stem cells are administered at a subtherapeutic dose. 
     
     
         12 . The method of any of  claims 1 - 11 , wherein the subject has rheumatoid arthritis or synovitis. 
     
     
         13 . A method of reducing inflammation in a subject in need thereof, the method comprising co-administering to the subject (a) a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug, and (b) mesenchymal stem cells, wherein the composition comprising the conjugate enhances the delivery of the mesenchymal stem cells to a site of inflammation. 
     
     
         14 . The method of  claim 13 , wherein the composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”). 
     
     
         15 . The method of  claim 13  or  14 , wherein the composition and the mesenchymal stem cells are administered sequentially. 
     
     
         16 . The method of  claim 13  or  14 , wherein the composition and the mesenchymal stem cells are administered concurrently. 
     
     
         17 . The method of any of  claims 13 - 16 , wherein one or both of the composition and the mesenchymal stem cells are administered locally at a site of inflammation. 
     
     
         18 . The method of  claim 17 , wherein the site of inflammation is a joint. 
     
     
         19 . The method of any of  claims 13 - 18 , wherein one or both of the composition and the mesenchymal stem cells are administered by injection. 
     
     
         20 . The method of any of  claims 13 - 18 , wherein one or both of the composition and the mesenchymal stem cells are administered systemically. 
     
     
         21 . The method of any of  claims 13 - 18 , wherein one or both of the composition and the mesenchymal stem cells are administered intravenously. 
     
     
         22 . The method of any of  claims 13 - 21 , wherein one or both of the composition and the mesenchymal stem cells are administered at a subtherapeutic dose. 
     
     
         23 . The method of any of  claims 13 - 22 , wherein the amount of mesenchymal stem cells that is administered is no more than 70% of the amount of mesenchymal stem cells that produces a significant therapeutic effect when administered alone. 
     
     
         24 . The method of any of  claims 13 - 23 , wherein the composition and the mesenchymal stem cells are administered in a series of doses separated by intervals of days or weeks. 
     
     
         25 . The method of any of  claims 13 - 24 , wherein the subject has an inflammatory disease or disorder. 
     
     
         26 . A method of treating a subject having an inflammatory disease or disorder, the method comprising co-administering to the subject (a) a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug, and (b) mesenchymal stem cells, wherein the amount of mesenchymal stem cells that is administered is a subtherapeutic dose. 
     
     
         27 . The method of  claim 26 , wherein the inflammatory disease or disorder is selected from arthritis, inflammatory arthritis, rheumatoid arthritis, synovitis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, spondylarthritis, and osteoarthritis. 
     
     
         28 . The method of  claim 27 , wherein the inflammatory disease or disorder is rheumatoid arthritis or synovitis. 
     
     
         29 . The method of any of  claims 26 - 28 , wherein the composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”). 
     
     
         30 . The method of any of  claims 26 - 29 , wherein the composition and the mesenchymal stem cells are administered sequentially. 
     
     
         31 . The method of any of  claims 26 - 29 , wherein the composition and the mesenchymal stem cells are administered concurrently. 
     
     
         32 . The method of any of  claims 26 - 31 , wherein one or both of the composition and the mesenchymal stem cells are administered locally at a site of inflammation. 
     
     
         33 . The method of  claim 32 , wherein the site of inflammation is a joint. 
     
     
         34 . The method of any of  claims 26 - 33 , wherein one or both of the composition and the mesenchymal stem cells are administered by injection. 
     
     
         35 . The method of any of  claims 26 - 33 , wherein one or both of the composition and the mesenchymal stem cells are administered systemically. 
     
     
         36 . The method of any of  claims 26 - 33 , wherein one or both of the composition and the mesenchymal stem cells are administered intravenously. 
     
     
         37 . The method of any of  claims 26 - 36 , wherein the amount of mesenchymal stem cells that is administered is no more than 70% of the amount of mesenchymal stem cells that produces a significant therapeutic effect when administered alone. 
     
     
         38 . The method of any of  claims 26 - 37 , wherein the composition and the mesenchymal stem cells are administered in a series of doses separated by intervals of days or weeks. 
     
     
         39 . A method of enhancing an anti-inflammatory or immunomodulatory property of mesenchymal stem cells, comprising administering to a subject in need thereof the mesenchymal stem cells and a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug. 
     
     
         40 . The method of  claim 39 , wherein the composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”). 
     
     
         41 . The method of  claim 39  or  40 , wherein the mesenchymal stem cells are administered in an amount that is not sufficient to significantly reduce inflammation or have a significant immunomodulatory effect in a subject administered mesenchymal stem cells in the absence of the composition comprising the conjugate. 
     
     
         42 . The method of any of  claims 39 - 41 , wherein the subject has an inflammatory disease or disorder selected from arthritis, inflammatory arthritis, rheumatoid arthritis, synovitis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, spondylarthritis, and osteoarthritis. 
     
     
         43 . The method of any of  claims 39 - 42 , wherein the composition and the mesenchymal stem cells are administered sequentially. 
     
     
         44 . The method of any of  claims 39 - 42 , wherein the composition and the mesenchymal stem cells are administered concurrently. 
     
     
         45 . The method of any of  claims 39 - 44 , wherein one or both of the composition and the mesenchymal stem cells are administered locally at a site of inflammation. 
     
     
         46 . The method of  claim 45 , wherein the site of inflammation is a joint. 
     
     
         47 . The method of any of  claims 39 - 46 , wherein one or both of the composition and the mesenchymal stem cells are administered by injection. 
     
     
         48 . The method of any of  claims 39 - 46 , wherein one or both of the composition and the mesenchymal stem cells are administered systemically. 
     
     
         49 . The method of any of  claims 39 - 46 , wherein one or both of the composition and the mesenchymal stem cells are administered intravenously. 
     
     
         50 . The method of any of  claims 39 - 49 , wherein the composition and the mesenchymal stem cells are administered in a series of doses separated by intervals of days or weeks. 
     
     
         51 . The method of any of  claims 39 - 50 , wherein one or both of the composition and the mesenchymal stem cells are administered at a subtherapeutic dose. 
     
     
         52 . A method of reducing one or more signs or symptoms of arthritis pain in a subject, the method comprising administering to the subject a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug. 
     
     
         53 . The method of  claim 52 , wherein the arthritis is inflammatory arthritis or rheumatoid arthritis. 
     
     
         54 . The method of  claim 52  or  53 , wherein the composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”). 
     
     
         55 . The method of any of  claims 52 - 54 , further comprising administering exogenous mesenchymal stem cells. 
     
     
         56 . A method of reducing, slowing, or inhibiting cartilage and/or bone destruction resulting from inflammation in arthritis, the method comprising administering to the subject a composition comprising a conjugate of an LLP2A peptidomimetic ligand and a bisphosphonate drug. 
     
     
         57 . The method of  claim 56 , wherein the arthritis is inflammatory arthritis or rheumatoid arthritis. 
     
     
         58 . The method of  claim 56  or  57 , wherein the composition comprises a conjugate of LLP2A and Alendronate (“LLP2A-Ale”). 
     
     
         59 . The method of any of  claims 56 - 58 , further comprising administering exogenous mesenchymal stem cells.