Compositions and methods for cancer immunotherapy

Abstract

Provided is a cancer therapeutic agent comprising a cancer targeting molecule linked to a liver-expressed chemokine (LEC). In one embodiment, the cancer targeting molecule is an antibody that targets cancer cells or tumors in vivo. The cancer targeting molecule is associated non-covalently or covalently with LEC. The cancer therapeutic agents of the invention are useful for the treatment of cancer in an individual by reducing the size of a tumor or inhibiting the growth of cancer cells in an individual and/or by inhibiting the development of metastasis. The effectiveness of the therapy using the LEC cancer therapeutic agents can be increased by reducing the activity of immunoregulatory T cells and/or by adoptively transferring immune T cells.

1 . A method of reducing the size of a tumor or inhibiting the growth of cancer cells in an individual, comprising administering to the individual an effective amount of a cancer targeting molecule linked to a liver-expressed chemokine (LEC) in an amount effective to function as a chemoattractant for monocytes, lymphocytes, or polymorphonuclear leukocytes with the proviso that cancer targeting moiety linked to the LEC does not act as a primary chemotactic factor for dendric cells. 
     
     
         2 - 10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the targeting molecule is an antibody. 
     
     
         12 . The method of  claim 11 , wherein the antibody is specific for a tumor cell-surface antigen. 
     
     
         13 . The method of  claim 11 , wherein said antibody is specific for a stromal component of a tumor. 
     
     
         14 . The method of  claim 11  wherein said antibody is specific for an intracellular antigen. 
     
     
         15 . The method of  claim 11 , wherein the antibody is specific for an intranuclear antigen. 
     
     
         16 . The method of  claim 11 , wherein the antibody is a murine, chimeric, humanized, or human form of murine antibody TNT-1, TNT-2, TNT-3 or NHS76. 
     
     
         17 . The method of  claim 1  or  11 , wherein said cancer targeting molecule and LEC are covalently linked. 
     
     
         18 . The method of  claim 1  or  11 , wherein the cancer targeting molecule is a protein linked to LEC by genetic fusion. 
     
     
         19 . The method of  claim 1  or  11 , wherein the LEC is fused at its C-terminus to the N-terminus of said cancer targeting molecule. 
     
     
         20 . The method of  claim 1 , wherein the cancer targeting molecule is an antibody and wherein LEC is fused to the N-terminus of the light or heavy chain of said antibody or wherein LEC is fused to the N-terminus of the light and the heavy chain of said antibody. 
     
     
         21 . The method of  claim 1  or  11 , wherein said the LEC has an amino acid sequence which has at least 95% sequence identity with SEQ ID NO: 3. 
     
     
         22 . The method of  claim 1  or  11 , wherein said the LEC has an amino acid sequence which has at least 98% sequence identity with SEQ ID NO: 3. 
     
     
         23 . The method of  claim 1  or  11 , wherein the LEC has the amino acid sequence shown in SEQ ID NO: 3. 
     
     
         24 . A method of reducing the size of a tumor or inhibiting the growth of cancer cells in an individual, consisting of administering an effective amount of a cancer therapeutic agent comprising a cancer targeting molecule linked to a liver-expressed chemokine (LEC) to the individual, wherein said cancer therapeutic agent can target to metastatic cancer in vivo cancer cells or tumor in vivo and said LEC functions as a chemoattractant for monocytes, lymphocytes, or polymorphonuclear leukocytes. 
     
     
         25 - 33 . (canceled) 
     
     
         34 . The method of  claim 24 , wherein the targeting molecule is an antibody. 
     
     
         35 . The method of  claim 34 , wherein the antibody is specific for a tumor cell-surface antigen. 
     
     
         36 . The method of  claim 34 , wherein said antibody is specific for a stromal component of a tumor. 
     
     
         37 . The method of  claim 34 , wherein said antibody is specific for an intracellular antigen. 
     
     
         38 . The method of  claim 34 , wherein said antibody is specific for an intranuclear antigen. 
     
     
         39 . The method of  claim 34 , wherein said antibody is a murine, chimeric, humanized, or human form of murine antibody TNT-1, TNT-2, TNT-3 or NHS76. 
     
     
         40 . The method of  claim 24  or  34 , wherein said cancer targeting molecule and LEC are covalently linked. 
     
     
         41 . The method of  claim 24  or  34 , wherein said cancer targeting molecule is a protein linked to LEC by genetic fusion. 
     
     
         42 . The method of  claim 24  or  34 , wherein LEC is fused at its C-terminus to the N-terminus of said cancer targeting molecule. 
     
     
         43 . The method of  claim 24 , wherein the cancer targeting molecule is an antibody and wherein LEC is fused to the N-terminus of the light or heavy chain of said antibody or wherein LEC is fused to the N-terminus of the light and the heavy chain of said antibody. 
     
     
         44 . The method of  claim 24  or  34 , wherein said LEC has an amino acid sequence which has at least 95% sequence identity with SEQ ID NO: 3. 
     
     
         45 . The method of  claim 24  or  34 , wherein said LEC has an amino acid sequence which has at east 98% sequence identity with SEQ ID NO: 3. 
     
     
         46 . The method of  claim 24  or  34 , wherein said LEC has the amino acid sequence shown in SEQ ID NO: 3.