Compositions and methods for systemic inhibition of cartilage degradation

Abstract

Methods and compositions for inhibiting articular cartilage degradation. The compositions preferably include multiple chondroprotective agents, including at least one agent that promotes cartilage anabolic activity and at least one agent that inhibits cartilage catabolism. The compositions may also include one or more pain and inflammation inhibitory agents. The compositions may be administered systemically, such as to treat patients at risk of cartilage degradation at multiple joints, and suitably may be formulated in a carrier or delivery vehicle that is targeted to the joints. Alternatively the compositions may be injected or infused directly into the joint.

1 - 66 . (canceled)  
   
   
       67 . A targeted drug delivery system for the protection of cartilage, comprising a therapeutically effective amount of at least one chondroprotective agent, which is an anabolic chondroprotective agent or an inhibitor of cartilage catabolism, contained within targeted immunoparticles that are coupled to antibodies or antibody fragments that are specific to an antigenic determinant localized within the joint.  
   
   
       68 . The targeted drug delivery system of  claim 67 , wherein the targeted antigenic determinant is on or within articular cartilage.  
   
   
       69 . The targeted drug delivery system of  claim 67 , wherein the targeted antigenic determinant is on a cartilage collagen or a cartilage proteoglycan.  
   
   
       70 . The targeted drug delivery system of  claim 67 , wherein the targeted antigenic determinant is found on or within a cell, molecule or structure selected from the group consisting of collagens, including collagen Type II and the minor collagens Type V, VI, IX, X and XI; proteoglycans, including large aggregating proteoglycans, aggrecan, decorin, biglycan, fibromodulin and lumican; cartilage oligomeric matrix protein, glycoprotein-39; proteoglycan chondroitin-sulfate and glycosaminoglycans; macrophage synoviocytes and fibroblast synoviocytes; and chondrocytes.  
   
   
       71 . The targeted drug delivery system of  claim 67 , wherein the targeted antigenic determinant is on or within the synovium.  
   
   
       72 . The targeted drug delivery system of  claim 67 , wherein the targeted antigenic determinant is an epitope or neoepitope associated with the degeneration of articular cartilage.  
   
   
       73 . The targeted drug delivery system of  claim 72 , wherein the targeted epitopes or neoepitopes are immunolocalized in a superficial layer of articular cartilage in a patient diagnosed with osteoarthritis, rheumatoid arthritis, or other degenerative joint disease.  
   
   
       74 . The targeted drug delivery system of  claim 67 , wherein the targeting antibody or antibody fragment is a humanized, chimeric, or human monoclonal antibody.  
   
   
       75 . The targeted drug delivery system of  claim 67 , wherein the chondroprotective agent comprises an anabolic chondroprotective agent selected from the group consisting of interleukin (IL) agonists that promote cartilage anabolism, members of the transforming growth factor-β superfamily, including TGF-β agonists and bone morphogenetic protein (BMP) agonists, that promote cartilage anabolism, insulin-like growth factors that promote cartilage anabolism and fibroblast growth factors that promote cartilage anabolism.  
   
   
       76 . The targeted drug delivery system of  claim 67 , wherein the chondroprotective agent comprises an anabolic chondroprotective agent selected from the group consisting of IL-4, IL-10, IL-13, TGFβ1, TGFβ2, TGFβ3, BMP-2, BMP-4, BMP-6, BMP-7, IGF-1, bFGF and fragments, deletions, additions, amino acid substitutes, mutations and modifications that retain the biological characteristics of the naturally occurring agents.  
   
   
       77 . The targeted drug delivery system of  claim 67 , wherein the chondroprotective agent comprises an anabolic chondroprotective agent selected from the group consisting of: members of the transforming growth factor-β superfamily, including TGF-β agonists and bone morphogenetic protein (BMP) agonists, that promote cartilage anabolism; insulin-like growth factors that promote cartilage anabolism; and fibroblast growth factors that promote cartilage anabolism.  
   
   
       78 . The targeted drug delivery system of  claim 67 , wherein the chondroprotective agent comprises an inhibitor of cartilage catabolism selected from the group consisting of IL-1 receptor antagonists that inhibit cartilage catabolism, TNF-α receptor antagonists that inhibit cartilage catabolism, cyclooxygenase-2 specific inhibitors that inhibit cartilage catabolism, MAP kinase inhibitors that inhibit cartilage catabolism, nitric oxide synthase inhibitors that inhibit cartilage catabolism, and nuclear factor kappa B inhibitors that inhibit cartilage catabolism.  
   
   
       79 . The targeted drug delivery system of  claim 67 , wherein the chondroprotective agent comprises an inhibitor of cartilage catabolism selected from the group consisting of: inhibitors of matrix metalloproteinases that inhibit cartilage catabolism; cell adhesion molecules, including integrin agonists and integrin antagonists that inhibit cartilage catabolism; intracellular signaling inhibitors, including protein kinase C inhibitors and protein tyrosine kinase inhibitors, that inhibit cartilage catabolism; and inhibitors of SH2 domains that inhibit cartilage catabolism.  
   
   
       80 . The targeted delivery system of  claim 67 , wherein the chondroprotective agent comprises an inhibitor of cartilage catabolism selected from an IL-1 receptor antagonist that inhibits cartilage catabolism and a TNF-α receptor antagonist that inhibits cartilage catabolism.  
   
   
       81 . A targeted drug delivery system for the protection of cartilage, comprising a therapeutically effective amount of anabolic chondroprotective agent contained within a delivery vehicle that is targeted to the joint.  
   
   
       82 . A targeted drug delivery system for the protection of cartilage, comprising a therapeutically effective amount of anabolic chondroprotective agent contained within a delivery vehicle that is targeted to a molecule, cell or structure of hyaline cartilage.  
   
   
       83 . A targeted drug delivery system for the protection of cartilage, comprising a therapeutically effective amount of anabolic chondroprotective agent contained within targeted immunoparticles that are coupled to antibodies or antibody fragments that are specific to an antigenic determinant localized within the joint.  
   
   
       84 . A targeted drug delivery system for the protection of cartilage, comprising a therapeutically effective amount of at least one chondroprotective agent which is an anabolic chondroprotective agent or an inhibitor of cartilage catabolism, contained within targeted immunoparticles that are coupled to antibodies or antibody fragmenta that are specific to a neoepitope associated with the degeneration of articular cartilage.  
   
   
       85 . (canceled)  
   
   
       86 . A targeted drug delivery system for the protection of cartilage, comprising a therapeutically effective amount of at least one chondroprotective agent which is an anabolic chondroprotective agent or an inhibitor of cartilage catabolism, contained within targeted immunoparticles that are coupled to antibodies or antibody fragments that are specific to a neoepitope that appears on Type II collagen, Type II collagen fragments, aggrecan or aggrecan fragments of articular cartilage.  
   
   
       87 - 155 . (canceled)