Treatment of a disease of the gastrointestinal tract with a tlr modulator

Abstract

This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with a TLR agonist.

1 - 383 . (canceled) 
     
     
         384 . A method of treating a disease of the gastrointestinal (GI) tract in a subject, the method comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a TLR modulator and delivering the therapeutically effective amount of the TLR modulator at a desired location in the GI tract of the subject, wherein the therapeutically effective amount of the TLR modulator is less than an amount that is effective when the TLR modulator is administered systemically. 
     
     
         385 . The method of  claim 384 , wherein the delivery of the therapeutically effective amount of the TLR modulator at the desired location in the GI tract provides a concentration of the TLR modulator in the plasma of the subject that is less than 1 μg/ml. 
     
     
         386 . The method of  claim 384 , wherein the delivery of the therapeutically effective amount of the TLR modulator at the desired location in the GI tract provides a concentration of the TLR modulator in the plasma of the subject that is less than 0.3 μg/ml. 
     
     
         387 . The method of  claim 384 , wherein the delivery of the therapeutically effective amount of the TLR modulator at the desired location in the GI tract provides a concentration of the TLR modulator in the plasma of the subject that is less than 0.1 μg/ml. 
     
     
         388 . The method of  claim 384 , wherein the delivery of the therapeutically effective amount of the TLR modulator at the desired location in the GI tract provides a concentration of the TLR modulator in the plasma of the subject that is less than 0.01 μg/ml. 
     
     
         389 . The method of  claim 384 , wherein the concentration of the TLR modulator delivered at the desired location in the gastrointestinal tract is 10%, 25%, 50%, 75%, 100%, 200%, 300%, 400%, 500%, 1000%, 2000% greater than the concentration of the TLR modulator in the plasma. 
     
     
         390 . The method of  claim 389 , wherein the concentration of the TLR modulator delivered at the desired location in the gastrointestinal tract is measured from a sample comprising GI tissue. 
     
     
         391 . The method of  claim 384 , wherein the delivery of the therapeutically effective amount of the TLR modulator results in modulation of one or more inflammatory markers in the GI tract selected from the group consisting of interferon-K, IL-1J, IL-6, IL-22, IL-17A, TNFa, IL-2, and combinations thereof. 
     
     
         392 . The method of  claim 384 , wherein the pharmaceutical composition is administered in an ingestible device. 
     
     
         393 . The method of  claim 391 , wherein the therapeutically effective amount of the TLR modulator is topically delivered at a desired location in the GI tract of the subject. 
     
     
         394 . The method of  claim 391 , wherein the level of TLR modulator in plasma in a subject at a time point following oral administration of the device is lower than the level of the TLR modulator in plasma in a subject at substantially the same time point following systemic administration of an equal amount of the TLR modulator. 
     
     
         395 . The method of  claim 384 , wherein the desired location is proximate to one or more sites of disease. 
     
     
         396 . The method of  claim 395 , wherein the TLR modulator is delivered 100 cm or less from the one or more sites of disease. 
     
     
         397 . The method of  claim 384 , wherein the TLR modulator is delivered at the cecum, the ascending colon, or the distal portion of the ileum. 
     
     
         398 . The method of  claim 384 , wherein the disease of the GI tract is an inflammatory bowel disease. 
     
     
         399 . The method of  claim 384 , wherein the TLR modulator is selected from the group consisting of Pam2CSK4, rintatolimod, Poly-ICLC, RGC100, IPH-3102, Ampligen poly(I):poly(C12U), IPH-31XX, MCT-465-dsRNA, lipopolysaccharide (LPS), monophosphoryl lipid A, AS15, aminoalkyl glucosaminide 4-phosphate, picibanil,  Spirulina  complex polysaccharide, Chitohexaose, E5564, CRX-675, CRX-527, Flagellin, ANA975, ANA773, Imidazoquinoline, Resiquimod, motolimod (VTX-2337), GS-9620, SC1, Gardiquimod, CL097, Loxoribine, VTX-294, IMO-9200, IPH-32XX, PF-3512676, IMO-2055, DIMS0150 (cobitolimod), CpG7909, IMO-9200, AVE0675, Amplivax, HSP22, CRX-527, IAXO-102, CRX-52624, E5531, ODN 2088, ODN 4084-F, ODN INH-1, ODN INH-18, ODN TTAGGG (A151), G-ODN, CpG-ODN c41, COV08-0064, ODN 1585, ODN 1826, ODN 2395, IRS869, IMO-3100, TTAGGG, CpG ODN 2088, and generic equivalents thereof. 
     
     
         400 . The method of  claim 384 , wherein the pharmaceutical composition further comprises a liquid medium. 
     
     
         401 . The method of  claim 384 , wherein the pharmaceutical composition is a solution. 
     
     
         402 . The method of  claim 384 , wherein the pharmaceutical composition is a suspension. 
     
     
         403 . The method of  claim 384 , wherein delivery of the therapeutically effective amount of the TLR modulator at the desired location in the GI tract does not comprise releasing more than 10% of the TLR modulator at a location that is not proximate to a site of disease.