Sensitization of Immune System Against Haptenized Melanoma Antigens

Abstract

The invention is based on the observation that certain phenols, monophenols or benzenediols, can be metabolized into reactive quinones, in particular ortho-quinones and related reactive intermediates, which is brought about by oxidation of monophenols and benzenediols by proteins exhibiting tyrosinase activity, such as human tyrosinase and the related proteins TRP1 and TRP2. Although the substances and the produced reactive intermediates are toxic and can induce cell death, it is more relevant according to this invention that they function as haptens that become covalently bound to the tyrosinase enzymes, in particular to histidine moieties, in or near the catalytic site of proteins exhibiting tyrosinase activity, such as tyrosinase, TRP1 and TRP2. An immune response is then to be mounted against these haptenized auto-antigens, in order to treat melanocytic malignancies, in particular melanomas. This is brought about by topical administration of the phenol compounds that can function as tyrosinase substrate analogues. The invention hence provides medicaments for and methods of treating melanomas.

1 - 15 . (canceled) 
     
     
         16 . A method for treating maliginancies exhibiting tyrosinase enzyme activity, comprising topically administering to said maliginancies an effective amount of a monophenol or benzenediol compound capable of reacting with and modifying tyrosinase proteins. 
     
     
         17 . The method according to claim  1 , wherein the compound is selected from the group consisting of monophenols and benzenediols, phenol, catechol, hydroquinone, 4-tertiary butylphenol, 4-tertiary amylphenol, 4-tertiarybutylcatechol, monomethyl ether of hydroquinone, monoethyl ether of hydroquinone, 4-tertiary amylphenol, monobenzyl ether of hydroquinone, 4-phenylphenol, 4-octylphenol, 4-nonylphenol, 4-isopropylcatechol, 4-methylcatechol, p-cresol, 1,2-benzenediol, butylated hydroxyanisole, butylated hydroxytoluene, 4-S-cysteaminylphenol, and N-acetyl-4-S-cysteaminylphenol. 
     
     
         18 . The method according to  claim 16 , wherein two or more monophenol or benzenediol compounds are combined in the medicament. 
     
     
         19 . The method according to  claim 16 , further comprising the use of immune modifying compounds or immunogenic adjuvants to stimulate a local inflammatory response. 
     
     
         20 . A pharmaceutically acceptable composition comprising at least one monophenol or benzenediol compound capable of modifying tyrosinase proteins, and optionally one or more compounds selected from the group consisting of immune modifying compounds and pharmaceutical excipients. 
     
     
         21 . A pharmaceutically acceptable composition comprising at least one monophenol or benzenediol compound capable of modifying tyrosinase protein, and optionally one or more compounds capable of inhibiting regulatory T cells. 
     
     
         22 . The composition according to  claim 20 , wherein the composition is in a form for transdermal delivery and the excipients comprise at least a skin permeation enhancer or a release controlling polymer, matrix, coating or membrane. 
     
     
         23 . The composition according to  claim 20  wherein the composition is in a form for injection directly into the lesion. 
     
     
         24 . The composition according to  claim 20 , wherein the immune modifier is selected from the group consisting of imiquimod, resiquimod, interleukins, interferons, and TLR activating adjuvants. 
     
     
         25 . The composition according to  claim 21 , wherein the inhibitor of regulatory T cells is selected from the group consisting of fludarabine and cyclophosphamide. 
     
     
         26 . An isolated and inactivated tyrosinase protein or a fragment thereof, reacted with and covalently modified by a monophenol or benzenediol compound. 
     
     
         27 . A method for inducing an immune response against tyrosinase displaying cells or malignancies, comprising: administering to said cells an effective amount of an isolated tyrosinase protein or a fragment thereof, reacted with and covalently modified by a monophenol or benzenediol compound. 
     
     
         28 . A T-cell receptor capable of recognizing a modified tyrosinase protein or fragment thereof as defined in  claim 26 . 
     
     
         29 . A T-cell comprising the T cell receptor as defined in  claim 28 . 
     
     
         30 . A method for the treatment of malignancies expressing tyrosinase, comprising treating said malignancy with an effective amount of T-cells according to  claim 29 .