Immunoregulation by anti-ilts antibodies and ilts-binding antibody fragments

Abstract

Disclosed herein are methods of using anti-ILT5 antibodies and ILT5-binding fragments thereof to induce an immunostimulatory effect in a T cell when such a T cell is contacted with an antigen presenting cell (APC) that has been previously contacted with the anti-ILT5 antibody or ILT5-binding fragment. Also disclosed herein are methods of using anti-ILT5 antibodies and ILT5-binding fragments thereof to inhibit a response in a T cell (e.g., a proliferative response) when such a T cell is concomitantly contacted, or has previously been contacted, with an APC, which APC is simultaneously contacted with the anti-ILT5 antibody or ILT5-binding fragment. Also disclosed herein are methods of using anti-ILT5 antibodies and ILT5-binding fragments thereof for the treatment of various diseases and for use as immunostimulatory adjuvants.

1 . A method of inducing a response in a T cell, the method comprising contacting the T cell with an APC that has been contacted with or is in contact with a monovalent anti-ILT5 antibody or an ILT5-binding fragment of the antibody. 
     
     
         2 . The method of  claim 1 , wherein the response is a proliferative response. 
     
     
         3 . The method of  claim 1 , wherein the level of the response is proportional to the amount of antibody or fragment with which the APC is contacted. 
     
     
         4 . The method of  claim 1 , wherein the response does not require recognition of a MHC molecule by a T cell receptor. 
     
     
         5 . A method of inducing a naive T cell to express NKG2D on its surface, comprising contacting the T cell with an APC that has been contacted with an anti-ILT5 antibody or an ILT5-binding fragment of the antibody. 
     
     
         6 . A method of inducing a T cell to upregulate expression of a T cell receptor:CD3 complex, comprising contacting the T cell with an APC that has been contacted with an anti-ILT5 antibody or an ILT5-binding fragment of the antibody. 
     
     
         7 . A method of inducing a T cell to secrete Fas ligand, comprising contacting the T cell with an APC that has been contacted with an anti-ILT5 antibody or an ILT5-binding fragment of the antibody. 
     
     
         8 . A method of endowing a T cell with cytotoxic potential, comprising contacting the T cell with an APC that has been contacted with an anti-ILT5 antibody or an ILT5-binding fragment of the antibody. 
     
     
         9 . The method of  claim 8 , further comprising contacting the T cell with an antigen from a tumor cell or from a cell that is infected with a bacterium, a virus, a fungus, a protozoan, or a parasite; wherein the T cell becomes cytotoxic when it binds or recognizes the antigen on a cell. 
     
     
         10 . The method of  claim 1 , wherein the contacting is done in vitro. 
     
     
         11 . The method of  claim 1 , wherein the contacting is done in vivo. 
     
     
         12 . The method of  claim 1 , wherein the T cell is a CD4+ T cell. 
     
     
         13 . The method of  claim 1 , wherein the T cell is a CD8+ T cell. 
     
     
         14 . A method of inducing or enhancing an immune response in a subject, the method comprising administering to the subject an anti-ILT5 antibody or an ILT5-binding fragment of the antibody. 
     
     
         15 . The method of  claim 14 , wherein the response does not require recognition of a MHC molecule by a T cell receptor. 
     
     
         16 . The method of  claim 14 , wherein the method induces a response in a T cell in the subject. 
     
     
         17 . The method  claim 14 , wherein a T cell in the subject is endowed with cytotoxic potential upon contact with an APC that has been contacted with or is in contact with the administered anti-ILT5 antibody or the ILT5-binding fragment of the antibody. 
     
     
         18 . The method of  claim 17 , wherein the T cell or its progeny, having gained cytotoxic potential, becomes cytotoxic when it binds or recognizes an antigen. 
     
     
         19 . The method of  claim 18 , wherein the antigen is selected from one or both of an exogenous antigen and an endogenous antigen. 
     
     
         20 . The method of  claim 19 , wherein the exogenous antigen is selected from the group consisting of: a tumor antigen, a viral antigen, a bacterial antigen, a fungal antigen, a protozoan antigen, and a parasite antigen. 
     
     
         21 . The method of  claim 20 , wherein the exogenous antigen is administered to the subject. 
     
     
         22 . The method of  claim 21 , wherein the anti-ILT5 antibody or the ILT5-binding fragment of the antibody is administered at least once before, together with, or very close in time to the administration of the exogenous antigen. 
     
     
         23 . The method of  claim 21 , wherein the anti-ILT5 antibody or the ILT5-binding fragment of the antibody is administered at least once after, together with, or very close in time to the administration of the exogenous antigen. 
     
     
         24 . The method of  claim 21 , wherein the anti-ILT5 antibody or the ILT5-binding fragment of the antibody is administered separately from the administration of the exogenous antigen. 
     
     
         25 . The method of  claim 18 , wherein the antigen is a cellular antigen. 
     
     
         26 . The method of  claim 25 , wherein the subject has a tumor. 
     
     
         27 . The method of  claim 26 , wherein the cellular antigen comprises an endogenous antigen. 
     
     
         28 . The method of  claim 27 , further comprising administering to the subject a therapy, wherein the therapy inhibits or prevents the function of cells, causes destruction of cells, or both. 
     
     
         29 . The method of  claim 28 , wherein the therapy induces or enhances release of the endogenous antigen. 
     
     
         30 . The method of  claim 28 , wherein the therapy is administered at least once after, together with, or very close in time to administration of the anti-ILT5 antibody or the ILT5-binding fragment. 
     
     
         31 . The method of  claim 29 , wherein the therapy is administered at least once before, together with, or very close in time to administration of the anti-ILT5 antibody or the ILT5-binding fragment. 
     
     
         32 . The method of  claim 28 , wherein the anti-ILT5 antibody or the ILT5-binding fragment of the antibody is administered separately from the administration of the therapy. 
     
     
         33 . The method of  claim 27 , wherein the method results in one or more of:
 inhibition of tumor growth, reduction in tumor size, reduction in the number of tumors, a decrease in tumor burden, prolonging survival of the subject.   
     
     
         34 . The method of  claim 25 , wherein the subject has a viral infection. 
     
     
         35 . The method of  claim 18 , wherein the T cell becomes cytotoxic when it binds or recognizes the antigen on a cell. 
     
     
         36 . The method of  claim 17 , wherein the T cell is a CD4+ T cell. 
     
     
         37 . The method of  claim 17 , wherein the T cell is a CD8+ T cell. 
     
     
         38 . The method of  claim 17 , wherein the method induces a response in the T cell. 
     
     
         39 . A method of inhibiting a response in a T cell, the method comprising contacting the T cell with an antigen at the same time as or very close in time to contacting the T cell with an APC that has been contacted with a crosslinked anti-ILT5 antibody or a crosslinked ILT5-binding fragment of the antibody. 
     
     
         40 . The method of  claim 39 , wherein a proliferative response is inhibited. 
     
     
         41 . The method of  claim 39 , wherein the level inhibition of the response is proportional to the amount of antibody or fragment with which the APC is contacted. 
     
     
         42 . The method of  claim 39 , wherein the inhibition occurs when the antibody or fragment crosslinks or hypercrosslinks ILT5. 
     
     
         43 . The method of  claim 39 , wherein the contacting is done in vitro. 
     
     
         44 . The method of  claim 39 , wherein the contacting is done in vivo. 
     
     
         45 . The method of  claim 39 , wherein the T cell is a CD4+ T cell. 
     
     
         46 . The method of  claim 39 , wherein the T cell is a CD8+ T cell. 
     
     
         47 . A method of inducing tolerance in a subject, comprising administering to the subject a crosslinked anti-ILT5 antibody or a crosslinked ILT5-binding fragment of the antibody such that the antibody or fragment binds an APC, wherein a T cell in the subject that has previously bound or recognized an antigen is tolerized upon contact with the APC. 
     
     
         48 . The method of  claim 47 , wherein the subject has a disease. 
     
     
         49 . The method of  claim 48 , wherein the disease is an immune-related disease. 
     
     
         50 . The method of  claim 1 , wherein the anti-ILT5 antibody or ILT5-binding fragment binds human ILT5. 
     
     
         51 . The method of  claim 1 , wherein the anti-ILT5 antibody or ILT5-binding fragment is chimeric. 
     
     
         52 . The method of  claim 1 , wherein the anti-ILT5 antibody or ILT5-binding fragment is humanized. 
     
     
         53 . The method of  claim 1 , wherein the ILT5-binding fragment comprises a Fab fragment, a F(ab′) 2  fragment, or a scFv fragment.