Use of dermatan sulfates and/or desulfated heparins to treat or prevent heparinoid-induced autoimmune responses

Abstract

Dermatan sulfates and/or O-desulfated heparins useful in treating and preventing heparinoid-induced autoimmune responses, in particular heparin-induced thrombocytopenia (HIT) and its associated disease states. The dermatan sulfates comprise repeating disulfated and/or trisulfated disaccharide units of L-iduronic acid and N-acetyl-D-galactosamine. The O-desulfated heparins comprise heparin molecules selectively O-desulfated at the 2-O and/or 3-O positions of the uronic acid and glucosamine saccharide residues. Particularly effective dermatan sulfate HIT antagonists have a mean molecular weight of from about 2000 to about 10,000 Daltons.

1 . A method for treating and/or preventing heparinoid-induced autoimmune responses, which comprises the step of administering to a patient or a medical device an effective amount of a dermatan sulfate in the absence of a platelet glycoprotein IIb/IIa receptor antagonist, the dermatan sulfate comprising repeating disulfated and/or trisulfated disaccharide units of L-iduronic acid and N-acetyl-D-galactosamine and having the following properties: (1) a molecular weight in the range of from about 1200 to about 35,000 Daltons; (2) a sulfur content in the range from about 6 to about 11%; (3) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 2.0; (4) a combined disulfated and trisulfated disaccharide content in the range of from about 20 to 100%; (5) less than about 20% platelet activation activity in the presence of HIT immune sera or anti-heparin/PF4 antibody; and (6) an ability to inhibit the activation of human platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT immune sera or anti-heparin/PF4 antibody.  
     
     
         2 . The method of  claim 1  wherein the dermatan sulfate has: (7) an IC 50  of less than about 250 μg/ml in the presence of added Heparin Sodium USP at 0.1 u/ml; and (8) a heparin cofactor-II activity of at least about 15 u/mg.  
     
     
         3 . The method of  claim 2  wherein the dermatan sulfate has: (2) a sulfur content of from about 8 to about 11%; (3) a sulfate/carboxyl ratio of from about 1.45 to about 2.0; (4) a combined disulfated and trisulfated disaccharide content of from about 45 to 100%; 
 (7) an IC 50  of less than about 150 μg/ml; and (8) a heparin cofactor II activity of from about 60 to about 130 u/mg.    
     
     
         4 . The method of  claim 1  wherein the dermatan sulfate comprises the 4,6-disulfated disaccharide species, the 2,4-disulfated disaccharide species, and/or the 2,4,6-trisulfated disaccharide species.  
     
     
         5 . The method of  claim 1  wherein the dermatan sulfate has a mean molecular weight of from about 2000 to about 10,000 Daltons.  
     
     
         6 . The method of  claim 5  wherein the dermatan sulfate has a ratio of the weight average mean molecular weight to the number average mean molecular weight of from about 1.2 to about 1.8.  
     
     
         7 . The method of  claim 5  wherein the dermatan sulfate has a mean molecular weight of from about 3500 to about 8500 Daltons; and a ratio of the weight average molecular weight to the number average molecular weight of from about 1.3 to about 1.6.  
     
     
         8 . The method of  claim 1  wherein the heparinoid-induced autoimmune response that is treated and/or prevented by the administration of the dermatan sulfate is heparin-induced thrombocytopenia.  
     
     
         9 . The method of  claim 1  wherein the heparinoid-induced autoimmune response that is treated and/or prevented by the administration of the dermatan sulfate is the formation and/or presence of heparin-induced immune complexes.  
     
     
         10 . The method of  claim 1  wherein the heparinoid-induced autoimmune response that is treated and/or prevented by the administration of the dermatan sulfate are activated platelets, endothelium, and/or monocytes.  
     
     
         11 . The method of  claim 1  wherein the dermatan sulfate is administered to treat and/or prevent the impairment of a medical device that is coated with a heparinoid, or interacts with or is exposed to blood.  
     
     
         12 . The method of  claim 11  wherein the medical device is provided with a source of the dermatan sulfate that is delivered to the medical device.  
     
     
         13 . The method of  claim 12  wherein the medical device is coated with the dermatan sulfate.  
     
     
         14 . The method of  claim 13  wherein the medical device is a stent, a catheter, a vascular graft, a heart-lung bypass machine, a hemodialysis unit, a drug delivery unit, an oxygenator, a filter, a membrane, or medical device circuitry.  
     
     
         15 . The method of  claim 1  wherein the heparinoid-induced autoimmune response that is treated and/or prevented by the administration of the dermatan sulfate is a vascular access obstruction.  
     
     
         16 . The method of  claim 1  wherein the dermatan sulfate is administered to a patient.  
     
     
         17 . The method of  claim 16  wherein the patient that the dermatan sulfate is administered to is a human.  
     
     
         18 . The method of  claim 1  which comprises the further step of administering an effective amount of a heparin lyase.  
     
     
         19 . The method of  claim 18  wherein the dermatan sulfate and heparin lyase are administered as separate doses.  
     
     
         20 . The method of  claim 18  wherein the dermatan sulfate and heparin lyase are administered as a combined dose.  
     
     
         21 . A packaged drug product comprising a drug and instructions for administering the drug substantially in the absence of a platelet glycoprotein IIb/IIIa receptor antagonist to treat and/or prevent a heparinoid-induced autoimmune response, the drug comprising a dermatan sulfate comprising repeating disulfated and/or trisulfated disaccharide units of L-iduronic acid and N-acetyl-D-galactosamine and having the following properties: (1) a molecular weight in the range of from about 1200 to about 35,000 Daltons; (2) a sulfur content in the range from about 6 to about 11%; (3) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 2.0; (4) a combined disulfated and trisulfated disaccharide content in the range of from about 20 to 100%; (5) less than about 20% platelet activation activity in the presence of HIT immune sera or anti-heparin/PF4 antibody; and (6) an ability to inhibit the activation of human platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT immune sera or anti-heparin/PF4 antibody.  
     
     
         22 . The product of  claim 21  wherein the dermatan sulfate has a mean molecular weight of from about 2000 to about 10,000 Daltons.  
     
     
         23 . The product of  claim 21  wherein the instructions are for administering the dermatan sulfate to treat and/or prevent heparin-induced thrombocytopenia.  
     
     
         24 . The product of  claim 21  wherein the instructions are for administering the dermatan sulfate to treat and/or prevent the impairment of a medical device.  
     
     
         25 . The product of  claim 21  wherein the instructions are for administering the dermatan sulfate to treat and/or prevent a vascular access obstruction.  
     
     
         26 . The product of  claim 21  which further comprises a package that contains the drug and wherein the instructions are written or printed on the outside of the package.  
     
     
         27 . A medical device that interacts with or is exposed to blood and is provided with a source of a dermatan sulfate to be delivered to the medical device, the dermatan sulfate comprising repeating disulfated and/or trisulfated disaccharide units of L-iduronic acid and N-acetyl-D-galactosamine and having the following properties: (1) a molecular weight in the range of from about 1200 to about 35,000 Daltons; (2) a sulfur content in the range from about 6 to about 11%; (3) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 2.0; (4) a combined disulfated and trisulfated disaccharide content in the range of from about 20 to 100%; (5) less than about 20% platelet activation activity in the presence of HIT immune sera or anti-heparin/PF4 antibody; and (6) an ability to inhibit the activation of human platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT immune sera or anti-heparin/PF4 antibody.  
     
     
         28 . The medical device of  claim 27  which is a stent, a catheter, a vascular graft, a heart-lung bypass machine, a hemodialysis unit, a drug delivery unit, an oxygenator, a filter, a membrane, or medical device circuitry.  
     
     
         29 . The medical device of  claim 28  wherein the dermatan sulfate has a mean molecular weight of from about 2000 to about 10,000 Daltons.  
     
     
         30 . The medical device of  claim 29  wherein the dermatan sulfate antagonist has a mean molecular weight of from about 3500 to about 8500 Daltons; and a ratio of the weight average molecular weight to the number average molecular weight of from about 1.3 to about 1.6.  
     
     
         31 . The medical device of  claim 28  which is coated with the dermatan sulfate.  
     
     
         32 . A pharmaceutical combination, which comprises: 
 (a) a heparin lyase; and    (b) a dermatan sulfate comprising repeating disulfated and/or trisulfated disaccharide units of L-iduronic acid and N-acetyl-D-galactosamine and having the following properties: (1) a molecular weight in the range of from about 1200 to about 35,000 Daltons; (2) a sulfur content in the range from about 6 to about 11 %; (3) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 2.0; (4) a combined disulfated and trisulfated disaccharide content in the range of from about 20 to 100%; (6) less than about 20% platelet activation activity in the presence of HIT immune sera or anti-heparin/PF4 antibody; and (6) an ability to inhibit the activation of human platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT immune sera or anti-heparin/PF4 antibody.    
     
     
         33 . The combination of  claim 32  wherein the lyase is selected from the group consisting of-heparin lyase I, heparin lyase II, heparin lyase III, and mixtures thereof.  
     
     
         34 . The combination of  claim 33  wherein the dermatan sulfate has a mean molecular weight of from about 2000 to about 10,000 Daltons.  
     
     
         35 . The combination of  claim 34  wherein the dermatan sulfate has a mean molecular weight of from about 3500 to about 8500 Daltons; and a ratio of the weight average molecular weight to the number average molecular weight of from about 1.3 to about 1.6.  
     
     
         36 . A method for treating and/or preventing heparinoid-induced autoimmune responses, which comprises the step of administering to a patient or a medical device an effective amount of an O-desulfated heparin comprising heparin molecules selectively O-desulfated at the 2-O and/or 3-O positions of the uronic acid and glucosamine saccharide, the O-desulfated heparin having the following properties: (1) an average molecular weight in the range from about 2000 to about 14,000 Daltons; (2) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 1.5; (3) a residue on ignition in the range of from about 28 to about 41%; (4) a nitrogen content in the range of from about 1.3 to about 2.5% calculated on a dried basis; (5) a USP antifactor Xa potency of less than about 10 units/mg; (6) a USP heparin potency of less than about 10 units/mg and; (7) about 50% or greater inhibitory activity against human leukocyte elastase activity at ratios of O-desulfated heparin:elastase of from about 0.5 to about 1.0; (8) less than about 20% platelet activation activity in the presence of HIT sera or HIT antibody; and (9) an ability to inhibit the activation of platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT sera or anti-heparin/PF4 antibody.  
     
     
         37 . The method of  claim 36  wherein the heparinoid-induced autoimmune response that is treated and/or prevented by the administration of the O-desulfated heparin is heparin-induced thrombocytopenia.  
     
     
         38 . The method of  claim 36  wherein the heparinoid-induced autoimmune response that is treated and/or prevented by the administration of the O-desulfated heparin are activated platelets, endothelium, and/or monocytes.  
     
     
         39 . The method of  claim 36  wherein the O-desulfated heparin is administered to treat and/or prevent the impairment of a medical device that is coated with a heparinoid, or interacts with or is exposed to blood.  
     
     
         40 . The method of  claim 39  wherein the medical device is provided with a source of the O-desulfated heparin that is delivered to the medical device.  
     
     
         41 . The method of  claim 40  wherein the medical device is coated with the O-desulfated heparin.  
     
     
         42 . The method of  claim 36  wherein the O-desulfated heparin is administered to a patient.  
     
     
         43 . The method of  claim 42  wherein the patient that the O-desulfated heparin is administered to is a human.  
     
     
         44 . The method of  claim 36  which comprises the further step of administering an inhibitor of thrombin or activated Factor X.  
     
     
         45 . The method of  claim 44  wherein the inhibitor is DX-9065c Ltd, BAY59-7939, fondaparinux, hirudin, bivalirudin, or argatroban.  
     
     
         46 . A medical device that interacts with or is exposed to blood and is provided with a source of an O-desulfated heparin to be delivered to the medical device, the O-desulfated heparin comprising heparin molecules selectively O-desulfated at the 2-O and/or 3-O positions of the uronic acid and glucosamine saccharide, the O-desulfated heparin having the following properties: (1) an average molecular weight in the range from about 2000 to about 14,000 Daltons; (2) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 1.5; (3) a residue on ignition in the range of from about 28 to about 41%; (4) a nitrogen content in the range of from about 1.3 to about 2.5% calculated on a dried basis; (5) a USP antifactor Xa potency of less than about 10 units/mg; (6) a USP heparin potency of less than about 10 units/mg and; (7) about 50% or greater inhibitory activity against human leukocyte elastase activity at ratios of O-desulfated heparin:elastase of from about 0.5 to about 1.0; (8) less than about 20% platelet activation activity in the presence of HIT sera or HIT antibody; and (9) an ability to inhibit the activation of platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT sera or anti-heparin/PF4 antibody.  
     
     
         47 . The medical device of  claim 46  which is coated with the O-desulfated heparin.  
     
     
         48 . A pharmaceutical combination, which comprises: 
 (a) dermatan sulfate comprising repeating disulfated and/or trisulfated disaccharide units of L-iduronic acid and N-acetyl-D-galactosamine and having the following properties: (1) a molecular weight in the range of from about 1200 to about 35,000 Daltons; (2) a sulfur content in the range from about 6 to about 11%; (3) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 2.0; (4) a combined disulfated and trisulfated disaccharide content in the range of from about 20 to 100%; (5) less than about 20% platelet activation activity in the presence of HIT immune sera or anti-heparin/PF4 antibody; and (6) an ability to inhibit the activation of human platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT immune sera or anti- heparin/PF4 antibody; and    (b) an O-desulfated heparin comprising heparin molecules selectively O-desulfated at the 2-O and/or 3-O positions of the uronic acid and glucosamine saccharide, the O-desulfated heparin having the following properties: (1) an average molecular weight in the range from about 2000 to about 14,000 Daltons; (2) a sulfate/carboxylate ratio (S/C) in the range of from about 1.2 to about 1.5; (3) a residue on ignition in the range of from about 28 to about 41%; (4) a nitrogen content in the range of from about 1.3 to about 2.5% calculated on a dried basis; (5) a USP antifactor Xa potency of less than about 10 units/mg; (6) a USP heparin potency of less than about 10 units/mg and; (7) about 50% or greater inhibitory activity against human leukocyte elastase activity at ratios of O-desulfated heparin:elastase of from about 0.5 to about 1.0; (8) less than about 20% platelet activation activity in the presence of HIT sera or HIT antibody; and (9) an ability to inhibit the activation of platelets caused by HIT reactive sulfated glycosaminoglycans in the presence of either HIT sera or anti-heparin/PF4 antibody.