Targeted delivery of immunoregulatory drugs

Abstract

The present disclosure provides, inter alia, compositions comprising drug-containing polymeric particles that mimic lymphocyte migration in vivo and can specifically deliver immunosuppressive or immunoregulatory drugs to lymphoid tissues and sites of chronic inflammation where T-cell activation and T-cell mediated injury are occurring. Methods of preparing and using these drug-containing polymeric particles are also provided.

What is claimed is: 
     
         1 . A composition comprising:
 one or more drug-containing polymeric particles, each attached to a lymphocyte homing adhesion molecule or an antibody that binds a ligand of the lymphocyte homing adhesion molecule.   
     
     
         2 . The composition of  claim 1 , wherein the one or more drug-containing polymeric particles are each attached to a lymphocyte homing adhesion molecule. 
     
     
         3 . The composition of  claim 2 , wherein the lymphocyte homing adhesion molecule is selected from L-selectin, cutaneous lymphocyte antigen (CLA), α4β7 integrin, αEβ37 integrin, αLβ2 integrin, and α4β1 integrin. 
     
     
         4 . The composition of  claim 2 , wherein the lymphocyte homing adhesion molecule is L-selectin. 
     
     
         5 . The composition of  claim 1 , wherein the one or more drug-containing polymeric particles are each attached to an antibody that binds a ligand of the lymphocyte homing adhesion molecule. 
     
     
         6 . The composition of  claim 5 , wherein the ligand of the lymphocyte homing adhesion molecule is selected from peripheral lymph node addressing (PNAd), E-selectin, mucosal addressin cell adhesion molecule (MAdCAM-1), E-cadherin, intercellular adhesion molecule 1 (ICAM-1), intercellular adhesion molecule 2 (ICAM-2), vascular cell adhesion molecule 1 (VCAM-1). 
     
     
         7 . The composition of  claim 5 , wherein the antibody that binds a ligand of the lymphocyte homing adhesion molecule is an antibody that binds peripheral lymph node addressin (PNAd). 
     
     
         8 . The composition of  claim 7 , wherein the antibody that binds peripheral lymph node addressin (PNAd) is MECA-79 or S2 monoclonal antibody. 
     
     
         9 . The composition of  claim 1 , wherein the one or more drug-containing polymeric particles comprise an immunosuppressive or immunoregulatory drug. 
     
     
         10 . The composition of  claim 1 , wherein the one or more drug-containing polymeric particles are each covalently conjugated to the lymphocyte homing adhesion molecule or an antibody that binds a ligand of the lymphocyte homing adhesion molecule. 
     
     
         11 . The composition of  claim 1 , wherein the one or more drug-containing polymeric particles are each attached to the lymphocyte homing adhesion molecule or an antibody that binds a ligand of the lymphocyte homing adhesion molecule through a linker. 
     
     
         12 . The composition of  claim 11 , wherein the linker is polyethylene glycol. 
     
     
         13 . The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier. 
     
     
         14 . A method of suppressing a lymphocyte-mediated immune response in a subject, the method comprising:
 identifying a subject in need of suppressing a lymphocyte-mediated immune response; and   administering to the subject a therapeutically effective amount of a composition of any of  claims 1  to  13 .   
     
     
         15 . A method of treating or delaying progression of autoimmune diabetes in a subject, the method comprising:
 identifying a subject in need of treatment for autoimmune diabetes; and   administering to the subject a therapeutically effective amount of a composition of any of  claims 1  to  13 .   
     
     
         16 . A method of treating lymphocyte-mediated inflammation in a subject, the method comprising:
 identifying a subject in need of treatment for lymphocyte-mediated inflammation; and   administering to the subject a therapeutically effective amount of a composition of any of  claims 1  to  13 .   
     
     
         17 . A method of treating or reducing the metastasis of a PNAd-expressing malignancy in a subject, the method comprising:
 identifying a subject in need of treatment for PNAd-expressing malignancy; and   administering to the subject a therapeutically effective amount of a composition of any of  claim 4  or  7 .   
     
     
         18 . The method of  claim 17 , wherein the PNAd-expressing malignancy is lymphoma. 
     
     
         19 . A method of delivering a drug to a subject, the method comprising:
 administering a compositions of any of  claims 1 - 13  to the subject.   
     
     
         20 . A method of delivering an immunosuppressive or immunoregulatory drug to lymphoid tissues or sites of chronic inflammation in a subject, the method comprising:
 providing one or more drug-containing polymeric particles comprising the immunosuppressive or immunoregulatory drug coated with L-selectin or an antibody that binds PNAd; and   administering the one or more drug-containing polymeric particles to the subject.   
     
     
         21 . A composition of any of  claims 1  to  13  for use in suppressing a lymphocyte-mediated immune response in a subject. 
     
     
         22 . A composition of any of  claims 1  to  13  for use in treating or delaying progression of autoimmune diabetes in a subject. 
     
     
         23 . A composition of any of  claims 1  to  13  for use in treating lymphocyte-mediated inflammation in a subject. 
     
     
         24 . A composition of any of  claims 4  to  7  for use in treating or reducing the metastasis of a PNAd-expressing malignancy in a subject.