Methods and compositions for enhancing immune response

Abstract

Methods and compositions for enhancing the immune response to an IRM compound by depositing within a localized tissue region an IRM depot preparation that provides an extended residence time of active IRM within the localized tissue region.

What is claimed is: 
     
         1 . A method of enhancing a subject's immune response, the method comprising: depositing within a localized tissue region of the subject an immune response modifier (IRM) depot preparation that provides an extended residence time within the localized tissue region, wherein the IRM is a TLR agonist of at least one of TLR 7 or TLR 8, and wherein the IRM is a compound of compound of following Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  has the formula alkylene-L-R 1-1 , alkenylene-L-R 1-1 , or alkynylene-L-R 1-1 , wherein:
 the alkylene, alkenylene, and alkynylene groups are optionally interrupted with 
 
 one or more —O— groups;
 L is a bond or a functional linking group selected from the group consisting of 
 
 —NH—S(O) 2 —, —NH—C(O)—, —NH—C(S)—, —NH—S(O) 2 —NR 3 —, —NH—C(O)—NR 3 —, 
 —NH—C(S)—NR 3 —, —NH—C(O)—O—, —O—, —S—, and —S(O) 2 —; and 
 R 1-1  is a linear or branched aliphatic group having at least 11 carbon atoms, optionally including one or more unsaturated carbon-carbon bonds; 
 
         R″ is selected from the group consisting of:
 hydrogen; 
 alkyl; 
 alkenyl; 
 aryl; 
 heteroaryl; 
 heterocyclyl; 
 alkylene-Y-alkyl; 
 alkylene-Y-alkenyl; 
 alkylene-Y-aryl; and 
 alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
 —OH; 
 halogen; 
 —N(R 4 ) 2 ; 
 —C(O)—C 1-10 alkyl; 
 —C(O)—O—C 1-10 alkyl; 
 —N 3 ; 
 aryl; 
 heteroaryl; 
 heterocyclyl; 
 —C(O)-aryl; and 
 —C(O)-heteroaryl; 
 
 wherein aryl is phenyl, naphthyl, biphenyl, fluorenyl or indenyl; heteroaryl is furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, or 1-oxidopyridyl; and heterocyclyl is the fully saturated or partially unsaturated derivative of any one of the above heteroaryl groups, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, or homopiperidinyl; 
 
         wherein: Y is —O— or —S(O) 0-2 —; and each R 4  is independently selected from the group consisting of hydrogen, C 1-10 alkyl, and C 2-10 alkenyl;
 R A  and R B  are taken together to form a fused benzene ring or a fused 5- to 7-membered saturated ring not containing a heteroatom, and unsubstituted or substituted by one or more R groups; 
 
         each R is independently selected from the group consisting of halogen,
 hydroxy, 
 alkyl, 
 alkenyl, 
 haloalkyl, 
 alkoxy, 
 alkylthio, and 
 —N(R 3 ) 2 ; and 
 
         each R 3  is independently selected from the group consisting of hydrogen and alkyl; 
         with the proviso that when L is —NH—S(O) 2 — and R A  and R B  join to form an unsubstituted benzene ring, R 1-1  is a linear or branched aliphatic group having greater than 16 carbon atoms, optionally including one or more unsaturated carbon-carbon bonds; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the localized tissue region the localized tissue region comprises a breast cancer tumor, a stomach cancer tumor, a lung cancer tumor, a head or neck cancer tumor, a colorectal cancer tumor, a renal cell carcinoma tumor, a pancreatic cancer tumor, a basal cell carcinoma tumor, a cervical cancer tumor, a melanoma cancer tumor, a prostate cancer tumor, ovarian cancer tumor, or a bladder cancer tumor. 
     
     
         3 . The method of  claim 1 , further comprising depositing a vaccine antigen within the localized tissue region. 
     
     
         4 . The method of  claim 3 , wherein the vaccine antigen is not physically or chemically linked to the IRM. 
     
     
         5 . The method of  claim 3 , wherein the subject's immune response to an antigen is enhanced, and wherein the antigen is an endogenous antigen. 
     
     
         6 . The method of  claim 1 , wherein the IRM depot preparation comprises the IRM compound attached to support material. 
     
     
         7 . The method of  claim 1 , wherein the IRM depot preparation comprises solid particles of IRM compound. 
     
     
         8 . The method of  claim 1 , wherein the IRM depot preparation comprises an emulsion. 
     
     
         9 . The method of  claim 1 , wherein the IRM depot preparation comprises micelles. 
     
     
         10 . The method of  claim 1 , wherein the IRM depot preparation comprises IRM within a biodegradable polymer matrix. 
     
     
         11 . The method of  claim 1 , wherein the IRM depot preparation comprises IRM compound incorporated into lipid membranes, lipid vesicles, or liposomes. 
     
     
         12 . The method of  claim 1 , wherein the IRM depot preparation provides pulsed delivery of an IRM compound. 
     
     
         13 . The method of  claim 1 , wherein the IRM depot preparation comprises an osmotically driven cylinder. 
     
     
         14 . The method of  claim 1 , wherein the IRM depot preparation is delivered within the localized tissue region using needle injection. 
     
     
         15 . The method of  claim 1 , wherein the IRM depot preparation is delivered within the localized tissue region using surgical implantation. 
     
     
         16 . The method of  claim 1 , wherein the IRM depot preparation is delivered within the localized tissue region using laparoscopic implantation. 
     
     
         17 . The method of  claim 1 , wherein the IRM depot preparation is delivered within the localized tissue region using catheter implantation. 
     
     
         18 . The method of  claim 1 , wherein the IRM depot preparation is delivered within the localized tissue region using a microneedle array. 
     
     
         19 . The method of  claim 1 , wherein the IRM depot preparation is delivered within the localized tissue region using high-velocity particle implantation. 
     
     
         20 . The method of  claim 1 , wherein the IRM depot preparation is delivered within the localized tissue region using an image guiding technique selected from ultrasound, MRI, or real-time X-ray fluoroscopy.