Methods for treatment of multiple sclerosis using peptide analogs of human myelin basic protein

Abstract

The present invention is directed toward peptide analogs of human myelin basic protein. The peptide analog is at least seven amino acids long and derived from residues 83 to 99 of human myelin basic protein. The analogs are altered from the native sequence at least at positions 91, 95, or 97. Additional alterations may be made at other positions Pharmaceutical compositions containing these peptide analogs are provided. The peptide analogs are useful for treating multiple sclerosis.

What is claimed is:  
     
         1 . A method for inducing a Th2 immune response to myelin basic protein or a peptide analog thereof in a patient, comprising: 
 administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a peptide analog selected from the group consisting of: 
 (a) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 91, wherein the L-lysine at position 91 is altered to another amino acid, and one to three L-amino acids selected from the group consisting of valine at position 86, valine at position 87, histidine at position 88, threonine at position 95, threonine at position 98 and proline at position 99 are altered to an amino acid other than the amino acid present in the native protein at that position;  
 (b) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 97, wherein the L-arginine at position 97 is altered to another amino acid and one to three L-amino acids selected from the group consisting of valine at position 86, valine at position 87, histidine at position 88, threonine at position 95, threonine at position 98 and proline at position 99 are altered to an amino acid other than the amino acid present in the native protein at that position;  
 (c) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 95, wherein the L-threonine at position 95 is altered to another amino acid and one to three L-amino acids selected from the group consisting of valine at position 86, valine at position 87, histidine at position 88, threonine at position 98 and proline at position 99 are altered to an amino acid other than the amino acid present in the native protein at that position;  
 (d) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 91, wherein the L-lysine at position 91 is altered to another amino acid and the N-terminal amino acid and/or the C-terminal amino acid are altered to another amino acid, such that upon administration of the peptide analog in vivo proteolysis is reduced;  
 (e) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 95, wherein the L-lysine at position 91 is altered to another amino acid and the N-terminal amino acid and/or the C-terminal amino acid are altered to another amino acid, such that upon administration of the peptide analog in vivo proteolysis is reduced;  
 (f) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 97, wherein the L-lysine at position 91 is altered to another amino acid and the N-terminal amino acid and/or the C-terminal amino acid are altered to another amino acid, such that upon administration of the peptide analog in vivo proteolysis is reduced;  
 (g) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 91, wherein the L-lysine at position 91 is altered to another amino acid;  
 (h) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 95, wherein the L-threonine at position 95 is altered to another amino acid; and  
 (i) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 97, wherein the L-arginine at position 97 is altered to another amino acid;  
   wherein the peptide analog is administered in combination with a physiologically acceptable carrier/adjuvant or diluent.    
     
     
         2 . A method according to  claim 1 , wherein L-lysine at position 91 is altered to a non-conservative amino acid.  
     
     
         3 . A method according to  claim 1 , wherein residue 91 is altered to D-lysine.  
     
     
         4 . A method according to  claim 1 , wherein residue 91 is altered to an amino acid selected from the group consisting of arginine, asparagine, histidine, leucine, serine, glycine, glutamic acid, phenylalanine, alanine and D-lysine.  
     
     
         5 . A method according to  claim 1 , wherein residue 91 is altered to alanine and residue 87 is altered to D-valine.  
     
     
         6 . A method according to  claim 1 , wherein residue 91 is altered to alanine and residue 88 is altered to D-histidine.  
     
     
         7 . A method according to  claim 1 , wherein residue 91 is altered to alanine and residue 99 is altered to D-proline.  
     
     
         8 . A method according to  claim 1 , wherein residue 91 is altered to alanine, residue 87 is altered to D-valine, and residue 99 is altered to D-proline.  
     
     
         9 . A method according to  claim 1 , wherein residue 91 is altered to alanine, residue 88 is altered to D-histidine, and residue 99 is altered to D-proline.  
     
     
         10 . A method according to  claim 1 , wherein the L-lysine at position 91 is altered to another amino acid, and wherein residue 88 is altered to an amino acid selected from the group consisting of serine, glutamic acid, tyrosine, leucine, D-histidine, glutamine, phenylalanine and lysine.  
     
     
         11 . A method according to  claim 1 , wherein the L-arginine at position 97 is altered to a non-conservative amino acid.  
     
     
         12 . A method according to  claim 1 , wherein residue 97 is altered to D-arginine.  
     
     
         13 . A method according to  claim 1 , wherein residue 97 is altered to an amino acid selected from the group of D-alanine, D-arginine, glycine, lysine, glutamine, glutamic acid, threonine, leucine, phenylalanine, histidine and alanine.  
     
     
         14 . A method according to  claim 1 , wherein residue 97 is altered to alanine and residue 87 is altered to D-valine.  
     
     
         15 . A method according to  claim 1 , wherein residue 97 is altered to alanine and residue 88 is altered to D-histidine.  
     
     
         16 . A method according to  claim 1 , wherein residue 97 is altered to alanine and residue 99 is altered to D-proline.  
     
     
         17 . A method according to  claim 1 , wherein residue 97 is altered to alanine, residue 87 is altered to D-histidine and residue 99 is altered to D-proline.  
     
     
         18 . A method according to  claim 1 , wherein residue 97 is altered to alanine, residue 88 is altered to D-histidine and residue 99 is altered to D-proline.  
     
     
         19 . A method according to  claim 1 , wherein the L-arginine at position 97 is altered to another amino acid, and wherein residue 88 is altered to an amino acid selected from the group consisting of serine, glutamic acid, tyrosine, leucine, D-histidine, glutamine, phenylalanine and lysine.  
     
     
         20 . A method according to  claim 1 , wherein the L-threonine at position 95 is altered to a non-conservative amino.  
     
     
         21 . A method according to  claim 1 , wherein residue 95 is altered to D-threonine.  
     
     
         22 . A method according to  claim 1 , wherein residue 95 is altered to an amino acid selected from the group consisting of alanine, D-threonine, glycine, isoleucine, tyrosine, glutamine, serine, lysine, glutamic acid and histidine.  
     
     
         23 . A method according to  claim 1 , wherein residue 95 is altered to alanine and residue 87 is altered to D-valine.  
     
     
         24 . A method according to  claim 1 , wherein residue 95 is altered to alanine and residue 88 is altered to D-histidine.  
     
     
         25 . A method according to  claim 1 , wherein residue 95 is altered to alanine and residue 99 is altered to D-proline.  
     
     
         26 . A method according to  claim 1 , wherein residue 95 is altered to alanine, residue 87 is altered to D-valine, and residue 99 is altered to D-proline.  
     
     
         27 . A method according to  claim 1 , wherein residue 95 is altered to alanine, residue 88 is altered to D-histidine, and residue 99 is altered to D-proline.  
     
     
         28 . A method according to  claim 1 , wherein the N-terminal and/or C-terminal amino acids are D-amino acids.  
     
     
         29 . A method according to  claim 1 , wherein the peptide analog comprises seven to seventeen amino acids.  
     
     
         30 . A method according to  claim 29 , wherein the peptide further comprises one to three additional altered residues selected from residues 83-90, 92-96, 98 and 99 to another amino acid.  
     
     
         31 . A method according to  claim 1 , wherein residue 91 is alanine, residue 88 is D-histidine and residue 99 is D-proline.  
     
     
         32 . A method according to  claim 1 , wherein residue 91 is alanine, residue 87 is D-valine and residue 99 is D-proline.  
     
     
         33 . A method according to  claim 1 , wherein residue 91 is alanine and residue 88 is D-histidine.  
     
     
         34 . A method according to  claim 1 , wherein residue 91 is alanine and residue 87 is D-valine.  
     
     
         35 . A method according to  claim 1 , wherein residue 91 is alanine and residue 99 is D-proline.  
     
     
         36 . A method according to  claim 1 , wherein residue 95 is alanine, residue 87 is D-valine, and residue 99 is D-proline.  
     
     
         37 . A method according to  claim 1 , wherein residue 95 is alanine, residue 88 is D-histidine and residue 99 is D-proline.  
     
     
         38 . A method according to  claim 1 , wherein residue 95 is alanine and residue 88 is D-histidine.  
     
     
         39 . A method according to  claim 1 , wherein residue 95 is alanine and residue 99 is D-proline.  
     
     
         40 . A method according to  claim 1 , wherein residue 95 is alanine and residue 87 is D-histidine.  
     
     
         41 . A method according to  claim 1 , wherein residue 97 is alanine, residue 87 is D-valine, and residue 99 is D-proline.  
     
     
         42 . A method according to  claim 1 , wherein residue 97 is alanine, residue 88 is D-histidine and residue 99 is D-proline.  
     
     
         43 . A method according to  claim 1 , wherein residue 97 is alanine and residue 87 is D-valine.  
     
     
         44 . A method according to  claim 1 , wherein residue 97 is alanine and residue 88 is D-histidine.  
     
     
         45 . A method according to  claim 1 , wherein residue 97 is alanine and residue 99 is D-proline.  
     
     
         46 . A method for inducing a Th2 immune response to myelin basic protein or a peptide analog thereof in a patient, comprising: 
 administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a peptide analog, wherein the peptide analog comprises at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 91, wherein the L-lysine at position 91 is altered to another amino acid, and two to four additional L-amino acids selected from residues 83 to 90 and 92 to 99 are altered to an amino acid other than the amino acid present in the native protein at that position,    wherein the peptide analog is administered in combination with a physiologically acceptable carrier or diluent.    
     
     
         47 . A method according to  claim 46 , wherein L-lysine at position 91 is altered to alanine.  
     
     
         48 . A method according to  claim 46 , wherein the phenylalanine at position 89 is substituted with another amino acid.  
     
     
         49 . A method according to  claim 46 , wherein the N-terminal amino acid and/or the C-terminal amino acid are altered to another amino acid.  
     
     
         50 . A method according to  claim 46 , wherein the N-terminal and/or C-terminal amino acids are altered to a D-amino acid.  
     
     
         51 . A method according to  claim 50 , wherein the N-terminal amino acid is residue 83 of human myelin basic protein.  
     
     
         52 . A method according to  claim 46 , wherein at least one of the additional L-amino acids selected from residues 83 to 90 and 92 to 99 is substituted with a charged amino acid.  
     
     
         53 . A method according to  claim 46 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-leucine, and L-lysine at position 91 is altered to L-alanine.  
     
     
         54 . A method according to  claim 46 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein L-glutamic acid at position 83 is altered to D-alanine, L-phenylalanine at position 89 is altered to L-alanine and L-lysine at position 91 is altered to L-alanine.  
     
     
         55 . A method according to  claim 46 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-alanine, and L-lysine at position 91 is altered to L-alanine.  
     
     
         56 . A method according to  claim 46 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-alanine, L-lysine at position 91 is altered to L-alanine, and L-threonine and position 98 is altered to D-alanine.  
     
     
         57 . A method according to  claim 46 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-leucine, L-lysine at position 91 is altered to L-alanine, and L-threonine at position 98 is altered to D-alanine.  
     
     
         58 . A method according to  claim 46 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-lysine at position 91 and the L-phenylalanine at position 89 are altered to other amino acids.  
     
     
         59 . A method according to  claim 1  or  claim 47 , wherein the pharmaceutical composition further comprises an adjuvant.  
     
     
         60 . A method according to  claim 59 , wherein the adjuvant is alum.  
     
     
         61 . A method for inducing a Th2 immune response to myelin basic protein or a peptide analog thereof in a patient, comprising: 
 administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a peptide analog comprising the sequence D-Ala-Lys-Pro-Val-Val-His-Leu-Phe-Ala-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro (SEQ ID NO: 7).    
     
     
         62 . A method for inducing a persistent systemic immune response to myelin basic protein or a peptide analog thereof in a patient, comprising: 
 administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a peptide analog selected from the group consisting of 
 (a) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 91, wherein the L-lysine at position 91 is altered to another amino acid, and one to three L-amino acids selected from the group consisting of valine at position 86, valine at position 87, histidine at position 88, threonine at position 95, threonine at position 98 and proline at position 99 are altered to an amino acid other than the amino acid present in the native protein at that position;  
 (b) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 97, wherein the L-arginine at position 97 is altered to another amino acid and one to three L-amino acids selected from the group consisting of valine at position 86, valine at position 87, histidine at position 88, threonine at position 95, threonine at position 98 and proline at position 99 are altered to an amino acid other than the amino acid present in the native protein at that position;  
 (c) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 95, wherein the L-threonine at position 95 is altered to another amino acid and one to three L-amino acids selected from the group consisting of valine at position 86, valine at position 87, histidine at position 88, threonine at position 98 and proline at position 99 are altered to an amino acid other than the amino acid present in the native protein at that position;  
 (d) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 91, wherein the L-lysine at position 91 is altered to another amino acid and the N-terminal amino acid and/or the C-terminal amino acid are altered to another amino acid, such that upon administration of the peptide analog in vivo proteolysis is reduced;  
 (e) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 95, wherein the L-lysine at position 91 is altered to another amino acid and the N-terminal amino acid and/or the C-terminal amino acid are altered to another amino acid, such that upon administration of the peptide analog in vivo proteolysis is reduced;  
 (f) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 97, wherein the L-lysine at position 91 is altered to another amino acid and the N-terminal amino acid and/or the C-terminal amino acid are altered to another amino acid, such that upon administration of the peptide analog in vivo proteolysis is reduced;  
 (g) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 91, wherein the L-lysine at position 91 is altered to another amino acid;  
 (h) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 95, wherein the L-threonine at position 95 is altered to another amino acid; and  
 (i) peptide analogs comprising at least seven amino acids selected from residues 83 to 99 of human myelin basic protein, including residue 97, wherein the L-arginine at position 97 is altered to another amino acid;  
   wherein the peptide analog is administered in combination with a physiologically acceptable carrier or diluent.    
     
     
         63 . A method according to  claim 62 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-leucine, and L-lysine at position 91 is altered to L-alanine.  
     
     
         64 . A method according to  claim 62 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein L-glutamic acid at position 83 is altered to D-alanine, L-phenylalanine at position 89 is altered to L-alanine and L-lysine at position 91 is altered to L-alanine.  
     
     
         65 . A method according to  claim 62 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-alanine, and L-lysine at position 91 is altered to L-alanine.  
     
     
         66 . A method according to  claim 62 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-alanine, L-lysine at position 91 is altered to L-alanine, and L-threonine and position 98 is altered to D-alanine.  
     
     
         67 . A method according to  claim 62 , wherein the peptide analog comprises residues 83 to 99 of human myelin basic protein, wherein the L-glutamic acid at position 83 is altered to D-alanine, L-asparagine at position 84 is altered to L-lysine, L-phenylalanine at position 89 is altered to L-leucine, L-lysine at position 91 is altered to L-alanine, and L-threonine at position 98 is altered to D-alanine.