Methods of predicting therapeutic efficacy of treatment of a multiple sclerosis patient

Abstract

Human myelin basic protein (h-MBP) has a molecular weight of 18.5 KD and contains 170 amino acid residues. Synthetic peptides ranging in length from about 8 to 25 residues and covering the entire length of the protein have been produced. Antibodies to h-MBP (anti-MBP) were found to be neutralized by the synthetic peptides, in vitro, which span the h-MBP from about amino acid residue 61 to about amino acid residue 106. The peptides, which cover both the amino (about residues 1 to 63) and carboxy (about residues 117 to 162) terminals of h-MBP did not neutralize purified anti-MBP. Intrathecal administratin of peptide MBP(75-95), MBP(86-95), or MBP(82-98) produced complete binding-neutralization of free (F) anti-MBP with no change in bound (B) levels. A control peptide MBP35-58 had no effect on F or B anti-MBP levels. Intravenous administration of MBP(75-95), MBP(86-95), or MBP(82-98) resulted in significant decline of F and B CSF anti-MBP levels. Administration of MBP synthetic peptides to MS patients either intrathecally or intravenously did not have any adverse neurological effects and systemic complications did not occur. The MBP epitope for MS anti-MBP has been localized to an area between amino acid 86 and amino acid 95.

1 . A peptide of the formula: Asp Glu Asn Pro Val Val His Phe Phe Lys Asn Ile Val Thr Pro Arg Thr; including substitutions, additions or deletions thereof, provided that said substitutions, additions or deletions provide a peptide that is capable of neutralizing or modulating the production of anti-myelin basic protein.  
     
     
         2 . A pharmaceutical composition containing as an active ingredient a peptide of the formula: Asp Glu Asn Pro Val Val His Phe Phe Lys Asn Ile Val Thr Pro Arg Thr; including substitutions, additions or deletions thereof, provided that said substitutions, additions or deletions provide a peptide that is capable of neutralizing or modulating the production of anti-myelin basic protein, in admixture with a pharmaceutical acceptable carrier.  
     
     
         3 . A method of treating multiple sclerosis in a patient in need thereof by administering to said patient an effective amount of a peptide of the formula: Asp Glu Asn Pro Val Val His Phe Phe Lys Asn Ile Val Thr Pro Arg Thr; including substitutions, additions or deletions thereof, provided that said substitutions, additions or deletions provide a peptide that is capable of neutralizing or modulating the production of anti-myelin basic protein, in admixture with a pharmaceutical acceptable carrier.  
     
     
         4 . A method of treating multiple sclerosis in a patient in need thereof by administering to said patient an effective amount of a peptide of the formula:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   R 1 -Val-His-Phe-Phe-Lys-Asn-Ile-R 1   
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
       and salts thereof, wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, hydroxy, an amino acid residue and a polypeptide residue; provided that R 1  and R 2  are not both hydrogen or hydroxyl at the same time; including substitutions, additions or deletions thereof provided that said peptide is capable of neutralizing or modulating the production of anti-myelin basic protein, alone or in combination, in admixture with a pharmaceutical acceptable carrier; wherein said method comprises administering sequential doses of said peptide.  
     
     
         5 . The method of  claim 4 , wherein R 1  is Asn-Pro-Val- and R 2  is hydrogen or hydroxy.  
     
     
         6 . The method of  claim 4 , wherein R 1  is Pro-Val- and R 2  is -Val.  
     
     
         7 . The method of  claim 4 , wherein R 1  is Val- and R 2  is -Val-Thr.  
     
     
         8 . The method of  claim 4 , wherein R 1  is hydrogen or hydroxy and R 2  is -Val-Thr-Pro.  
     
     
         9 . The method of  claim 4 , wherein R 1  is Lys-Ser-His-Gly-Arg-Thr-Gln-Asp-Glu-Asn-Pro-Val- and R 2  is -Val-Thr.  
     
     
         10 . The method of  claim 4 , wherein R 1  is Asp-Glu-Asn-Pro-Val- and R 2  is -Val-Thr-Pro-Arg-Thr.  
     
     
         11 . The method of  claim 4 , wherein the peptide is administered intravenously, intrathecally or a combination of both.  
     
     
         12 . The method of  claim 11 , wherein the peptide is administered intravenously at a dose ranging from 1 mg/kg of body weight to 10 mg/kg of body weight.  
     
     
         13 . The method of  claim 11 , wherein the peptide is administered intrathecally at a dose ranging from 1 mg to 100 mg.  
     
     
         14 . The method of  claim 11 , wherein the peptide is administered at least daily for four to five days.  
     
     
         15 . The method of  claim 14 , wherein the peptide if further administered in an additional dose about one week after the first injections.