Methods of treating inflammatory and autoimmune diseases with natalizumab

Abstract

Natalizumab is a safe and efficacious treatment for inflammatory and autoimmune diseases, such as multiple sclerosis, Crohn's Disease, and rheumatoid arthritis. Chain swapping between natalizumab and IgG4 molecules acts to reduce the level of bivalent natalizumab present following administration of natalizumab, and thus to lower the activity of natalizumab in the patient. Differences in IgG4 levels across patients or within a single patient across time may change the pharmacokinetic profile of natalizumab. Patients with lower levels of IgG4 may experience higher nadir levels of natalizumab during a dosing period. Monitoring IgG4 and/or bivalent natalizumab levels, and determining a dose or dosage period based on the monitoring may improve the safety and/or efficacy of natalizumab therapy.

1 . A method of treating a patient with an inflammatory or autoimmune disease with natalizumab comprising: 
 (a) administering a dose of natalizumab for a first dosage period;    (b) monitoring the amount of bivalent natalizumab in the patient's plasma or serum during the first dosage period;    (c) determining a second dose of natalizumab based on the level of bivalent natalizumab observed; and    (d) administering a second dose of natalizumab for a second dosage period;    wherein the second dose improves the safety and/or efficacy of the treatment during the second dosage period.    
   
   
       2 . The method of  claim 1 , wherein if the monitoring shows that the amount of bivalent natalizumab in the patient's plasma or serum remains above a predetermined level during the first dosage period, and wherein the corrected dose of natalizumab administered over the second dosage period is designed to achieve a reduction of the natalizumab level during the second dosage period to below the predetermined level during at least a portion of the second dosage period.  
   
   
       3 . The method of  claim 2 , wherein the second dose is lower than the first dose.  
   
   
       4 . The method of  claim 2 , wherein the second dosage period is longer than the first dosage period.  
   
   
       5 . The method of  claim 2 , wherein the corrected dose is lower than the first dose, and wherein the second dosage period is longer than the first dosage period.  
   
   
       6 . The method of  claim 2 , wherein the first dose is 300 mg administered by IV infusion and the first dosage period is four weeks.  
   
   
       7 . The method of  claim 6 , wherein the predetermined level is about 1 μg/ml, and wherein the second dose is less than 300 mg administered by IV infusion and the second dosage period is more than four weeks.  
   
   
       8 . The method of  claim 6 , wherein the predetermined level is about 0.5 μg/ml, and wherein the second dose is less than 300 mg administered by IV infusion and the second dosage period is more than four weeks.  
   
   
       9 . The method of  claim 6 , wherein the predetermined level is about 0.1 μg/ml, and wherein the second dose is less than 300 mg administered by IV infusion and the second dosage period is more than four weeks.  
   
   
       10 . The method of  claim 1 , wherein the amount of bivalent natalizumab in the patient's plasma or serum falls below a predetermined level during the first dosage period within a predetermined time after administration of the first dose, and wherein the second dose of natalizumab administered over the second dosage period is designed to maintain the natalizumab level above the predetermined level.  
   
   
       11 . The method of  claim 1 , wherein the disease is multiple sclerosis.  
   
   
       12 . The method of  claim 1 , wherein the disease is inflammatory bowel disease or rheumatoid arthritis.  
   
   
       13 . The method of  claim 1 , further comprising monitoring the patient for indicators of serious infection and/or treating the patient with prophylaxis designed to reduce the risk of developing serious infection.  
   
   
       14 . The method of  claim 1 , further comprising monitoring the patient for indicators of progressive multifocal leukoencephalopathy.  
   
   
       15 . The method of  claim 14 , wherein the monitoring detects JCV in the patient's urine, blood, and/or cerebrospinal fluid.  
   
   
       16 . The method of  claim 14 , wherein the monitoring comprises testing for clinical and/or radiologic symptoms of progressive multifocal leukoencephalopathy.  
   
   
       17 . The method of  claim 14 , further comprising, in the presence of indicators of progressive multifocal leukoencephalopathy, providing at least one treatment selected from intravenous immunoglobulin therapy, plasmapheresis, and antiviral therapy.  
   
   
       18 . The method of  claim 14 , wherein the patient is not treated simultaneously with natalizumab and an immunosuppressive or antineoplastic agent.  
   
   
       19 . A method of treating a patient with an inflammatory or autoimmune disease with natalizumab comprising: 
 (a) determining the amount of IgG4 in the patient's plasma or serum;    (b) determining a dose and dosage period of natalizumab based on the amount of IgG4 in the patient's plasma or serum; and    (c) administering the dose of natalizumab to the patient over the dosage period;    wherein the dose and dosage period improve the safety and/or efficacy of the treatment compared to the safety and/or efficacy provided by the standard dose and dosage period of natalizumab.    
   
   
       20 . The method of  claim 19 , wherein the standard dose is 300 mg by IV infusion and the standard dosage period is every four weeks.  
   
   
       21 . The method of  claim 20 , wherein the amount of IgG4 in the patient's blood is below 200 μg/ml and the determined dose of natalizumab is below 300 mg by IV infusion.  
   
   
       22 . The method of  claim 20 , wherein the amount of IgG4 in the patient's blood is below 200 ug/ml and the determined dosage period is longer than four weeks.  
   
   
       23 . The method of  20 , wherein the amount of IgG4 in the patient's blood is below 200 μg/ml, the determined dose of natalizumab is below 300 mg by IV infusion, and the determined dosage period is longer than four weeks.  
   
   
       24 . The method of  claim 20 , wherein the amount of IgG4 in the patient's blood is below 100 μg/ml and the determined dose of natalizumab is below 300 mg by IV infusion.  
   
   
       25 . The method of  claim 20 , wherein the amount of IgG4 in the patient's blood is below 100 ug/ml and the determined dosage period is longer than four weeks.  
   
   
       26 . The method of  claim 20 , wherein the amount of IgG4 in the patient's blood is below 100 μg/ml, the determined dose of natalizumab is below 300 mg by IV infusion, and the determined dosage period is longer than four weeks.  
   
   
       27 . The method of  claim 19 , wherein the disease is multiple sclerosis.  
   
   
       28 . The method of  claim 19 , wherein the disease is inflammatory bowel disease or rheumatoid arthritis.  
   
   
       29 . The method of  claim 19 , further comprising monitoring the patient for indicators of serious infection and/or treating the patient with prophylaxis designed to reduce the risk of developing serious infection.  
   
   
       30 . The method of  claim 19 , further comprising monitoring the patient for indications of progressive multifocal leukoencephalopathy.  
   
   
       31 . The method of  claim 30 , wherein the monitoring detects JCV in the patient's urine, blood, and/or cerebrospinal fluid.  
   
   
       32 . The method of  claim 30 , wherein the monitoring comprises testing for clinical and/or radiologic symptoms of progressive multifocal leukoencephalopathy.  
   
   
       33 . The method of  claim 30 , further comprising, in the presence of indicators of progressive multifocal leukoencephalopathy, providing at least one treatment selected from intravenous immunoglobulin therapy, plasmapheresis, and antiviral therapy.  
   
   
       34 . The method of  claim 30 , wherein the patient is not treated simultaneously with natalizumab and an immunosuppressive or antineoplastic agent.  
   
   
       35 . A method of using natalizumab to treat a patient with an inflammatory or autoimmune disease comprising: 
 (a) determining the amount of IgG4 in the patient's plasma or serum;    (b) administering a dose of natalizumab for a first dosage period;    (c) monitoring the level of bivalent natalizumab in the patient's plasma or serum during the first dosage period;    (d) determining a second dose and dosage period of natalizumab based on the amount of IgG4 in the patient's plasma or serum and on the level of bivalent natalizumab in the patient's plasma or serum; and    (e) administering the second dose of natalizumab for the second dosage period;    wherein the second dose and dosage period improve the safety and/or efficacy of the treatment.    
   
   
       36 . The method of  claim 35 , wherein if the monitoring shows that the amount of bivalent natalizumab in the patient's plasma or serum remains above a predetermined level during the first dosage period, and wherein the second dose of natalizumab administered over the second dosage period is designed to achieve a reduction of the natalizumab level during the second dosage period to below the predetermined level during at least a portion of the second dosage period.  
   
   
       37 . The method of  claim 36 , wherein the first dose of natalizumab is 300 mg administered by IV infusion for a first dosage period of four weeks.  
   
   
       38 . The method of  claim 37 , wherein the predetermined level is about 1 μg/ml.  
   
   
       39 . The method of  claim 37 , wherein the predetermined level is about 0.5 μg/ml.  
   
   
       40 . The method of  claim 37 , wherein the predetermined level is about 0.1 μg/ml.  
   
   
       41 . The method of  claim 37 , wherein the corrected dose is lower than the first dose, or the second dosage period is longer than the first dosage period, or the corrected dose is lower than the first dose and the second dosage period is longer than the first dosage period.  
   
   
       42 . The method of  claim 35 , wherein the amount of bivalent natalizumab in the patient's plasma or serum falls below a predetermined level during the first dosage period within a predetermined time after administration of the first dose, and wherein the second dose of natalizumab administered over the second dosage period is designed to maintain the natalizumab level above the predetermined level at least up to the predetermined time after administration of the second dose during the second dosage period.  
   
   
       43 . The method of  claim 36 , further comprising monitoring the patient for indicators of serious infection.  
   
   
       44 . The method of  claim 43 , wherein the serious infection is progressive multifocal leukoencephalopathy.  
   
   
       45 . The method of  claim 36 , further comprising treating the patient with prophylaxis designed to reduce the risk of developing serious infection.  
   
   
       46 . The method of  claim 45 , wherein the serious infection is progressive multifocal leukoencephalopathy.  
   
   
       47 . The method of  claim 37 , wherein the amount of IgG4 in the patient's blood is below 200 μg/ml and the determined dose of natalizumab is below 300 mg by IV infusion.  
   
   
       48 . The method of  claim 37 , wherein the amount of IgG4 in the patient's blood is below 200 ug/ml and the determined dosage period is longer than four weeks.  
   
   
       49 . The method of  claim 37 , wherein the amount of IgG4 in the patient's blood is below 200 μg/ml, the determined dose of natalizumab is below 300 mg by IV infusion, and the determined dosage period is longer than four weeks.  
   
   
       50 . The method of  claim 37 , wherein the amount of IgG4 in the patient's blood is below 100 μg/ml and the determined dose of natalizumab is below 300 mg by IV infusion.  
   
   
       51 . The method of  claim 37 , wherein the amount of IgG4 in the patient's blood is below 100 ug/ml and the determined dosage period is longer than four weeks.  
   
   
       52 . The method of  claim 37 , wherein the amount of IgG4 in the patient's blood is below 100 μg/ml, the determined dose of natalizumab is below 300 mg by IV infusion, and the determined dosage period is longer than four weeks.  
   
   
       53 . The method of  claim 37 , wherein the standard dose of natalizumab is 300 mg IV infusion and the standard dosage period is four weeks.  
   
   
       54 . A method of using natalizumab to treat a patient with an inflammatory or autoimmune disease comprising: 
 (a) determining the amount of IgG4 in the patient's plasma or serum prior to initiating treatment;    (b) initiating treatment of the patient with natalizumab in the event the amount of IgG4 in the patients plasma or serum is above a predefined threshold; and    (c) initiating treatment of the patient with natalizumab with increased monitoring for indicators of progressive multifocal leukoencephalopathy and/or opportunistic infections in the event the amount of IgG4 in the patients plasma or serum is at or below a predefined threshold;    wherein determining of the amount of IgG4 in the patient's plasma or serum improves the safety and/or efficacy of the treatment.    
   
   
       55 . The method of  claim 54 , wherein in the event the amount of IgG4 in the patients plasma or serum is at or below a second predefined threshold, treatment is not initiated.  
   
   
       56 . The method of  claim 54 , wherein treatment is initiated if the amount of IgG4 in the patient's blood is about 200 μg/ml or higher.  
   
   
       57 . The method of  claim 54 , wherein treatment is initiated if the amount of IgG4 in the patient's blood is about 100 μg/ml or higher.  
   
   
       58 . The method of  claim 54 , further comprising 
 (d) determining the amount of IgG4 in the patient's plasma or serum during treatment; and    (e) terminating treatment in the event the amount of IgG4 is the patients plasma or serum is below a predefined threshold.    
   
   
       59 . The method of  claim 54 , further comprising 
 (d) monitoring the amount of bivalent natalizumab in the patient's plasma or serum during treatment; and    (e) terminating treatment in the event the amount of bivalent natalizumab is above a predefined threshold.    
   
   
       60 . The method of  claim 58 , further comprising 
 (f) monitoring the amount of bivalent natalizumab in the patient's plasma or serum during treatment; and    (g) terminating treatment in the event the amount of bivalent natalizumab is above a predefined threshold.    
   
   
       61 . A method of treating a patient with an inflammatory or autoimmune disease with natalizumab comprising: 
 (a) administering a dose of natalizumab for a first dosage period;    (b) monitoring the amount of bivalent natalizumab in the patient's plasma or serum during the first dosage period;    (c) determining a second dose of natalizumab based on the level of bivalent natalizumab observed;    (d) administering a second dose of natalizumab for a second dosage period; and    (e) administering the second dose of natalizumab for one or more subsequent second dosage periods;    wherein the second dose improves the safety and/or efficacy of the treatment during the second dosage period.    
   
   
       62 . A method of treating a patient with an inflammatory or autoimmune disease with natalizumab comprising: 
 (a) determining the amount of IgG4 in the patient's plasma or serum;    (b) determining a dose and dosage period of natalizumab based on the amount of IgG4 in the patient's plasma or serum;    (c) administering the dose of natalizumab to the patient over the dosage period; and    (d) administering the dose of natalizumab to the patient over one or more subsequent dosage periods;    wherein the dose and dosage period improve the safety and/or efficacy of the treatment compared to the safety and/or efficacy provided by the standard dose and dosage period of natalizumab.    
   
   
       63 . A method of using natalizumab to treat a patient with an inflammatory or autoimmune disease comprising: 
 (a) determining the amount of IgG4 in the patient's plasma or serum;    (b) administering a dose of natalizumab for a first dosage period;    (c) monitoring the level of bivalent natalizumab in the patient's plasma or serum during the first dosage period;    (d) determining a second dose and dosage period of natalizumab based on the amount of IgG4 in the patient's plasma or serum and on the level of bivalent natalizumab in the patient's plasma or serum;    (e) administering the second dose of natalizumab for the second dosage period; and    (f) administering the second dose of natalizumab for one or more subsequent second dosage periods;    wherein the second dose and dosage period improve the safety and/or efficacy of the treatment.