Immunoconjugates targeting syndecan-1 expressing cells and use thereof

Abstract

Immunoconjugates comprising a targeting agent selectively targeting cell-surface expressed syndecan-1 and at least one effector molecule as well as in vitro and in vivo methods of using those immunocomjugates are disclosed. The effector molecule may have, in its native form, high non-selective cytotoxicity, but substantially no non-selective cytotoxicity when part of said immunoconjugate. Targeting agents include the antibody B-B4 as well as other agents that bind cell-surface expressed syndecan-1.

1 - 5 . (canceled) 
     
     
         6 . The method of  claim 26 , wherein said effector molecule of said immunoconjugate is a toxin, cytotoxic enzyme, low molecular weight cytotoxic drug, a pore-forming agent, biological response modifier, prodrug activating enzyme, an antibody, cytokine or a radionuclide. 
     
     
         7 . The method of  claim 26 , wherein said targeting agent selectively targets cell-surface expressed syndecan-1. 
     
     
         8 . The method of  claim 13 , wherein said patient suffers from an hematologic malignancy and/or a solid tumor comprising syndecan-1 expressing cells. 
     
     
         9 . The method of  claim 8 , wherein said patient suffers from one of the following: multiple myeloma, ovarian carcinoma, kidney carcinoma, gall bladder carcinoma, breast carcinoma, prostate cancer, lung cancer, colon carcinoma, Hodgkin's and non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), solid tissue sarcoma or colon carcinoma. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 26 , wherein said effector molecule exhibits, in its native form, high non-selective cytotoxicity. 
     
     
         12 . (canceled) 
     
     
         13 . A method for inhibiting, delaying and/or preventing the growth of a tumor and/or spread of malignant tumor cells in a patient in need thereof, comprising
 (a) administering to said patient one or more cancer drugs and/or radiation in an amount effective to reduce tumor load; and   (b) administering to said patient at least one immunoconjugate in a growth of a tumor and/or spreading of tumor cells inhibiting, delaying or preventing amount,   wherein said immunoconjugate selectively inhibits, delays or prevents the growth and/or spread of syndecan-1 expressing cells.   
     
     
         14 . The method of  claim 13 , wherein (a) and (b) are performed consecutively in two consecutive treatment regimes. 
     
     
         15 . The method of  claim 13 , wherein the at least one drug of (a) and the immunoconjugate of (b) are administered in a single administration step. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 26 , wherein the effector molecule is a maytansinoid. 
     
     
         19 . (canceled) 
     
     
         20 . A method for treating inhibiting, delaying and/or preventing the growth of tumor cells in a cell culture containing syndecan-1 expressing tumor cells and non-tumor cells comprising
 administering a growth of syndecan-1 expressing tumor cells inhibiting, delaying and/or Preliminary Amendment preventing effective amount of the immunoconjugate comprising:
 at least one targeting agent selectively targeting cell-surface expressed syndecan-1, 
 at least one effector molecule,
 wherein said effector molecule has, in its native form, high non-selective cytotoxicity, 
 wherein said targeting agent is functionally attached to said effector molecule to form said immunoconjugate, and 
 wherein said effector molecule has substantially no non-selective cytotoxicity when part of said immunoconjugate. 
 
   
     
     
         21 . The method of  claim 20 , wherein said effective amount induces cell death or continuous cell cycle arrest in said syndecan-1 expressing tumor cells. 
     
     
         22 . The method of  claim 20 , wherein said cells in said cell culture are obtained from a cancer patient and wherein, after administration of said effective amount of said immunoconjugate, the cells of said cell culture are reimplanted into said cancer patient. 
     
     
         23 . The method of  claim 20 , wherein the cells in said cell culture were isolated from a patient suffering from an hematologic malignancy and/or a solid tumor comprising syndecan-1 expressing cells. 
     
     
         24 . The method of  claim 23 , wherein said patient is suffering from one of the following: multiple myeloma, ovarian carcinoma, kidney carcinoma, gall bladder carcinoma, breast carcinoma, prostate cancer, lung cancer, colon carcinoma, Hodgkin's and non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), a solid tissue sarcoma or a colon carcinoma. 
     
     
         25 . The method of  claim 24 , wherein said patient is suffering from multiple myeloma. 
     
     
         26 . A method for inhibiting, delaying and/or preventing the growth of a tumor and/or spread of malignant tumor cells in a patient in need thereof, comprising
 (a) administering to said patient one or more cancer drugs and/or radiation in an amount effective to reduce tumor load; and   (b) administering to said patient at least one immunoconjugate in a growth of a tumor and/or spreading of tumor cells inhibiting, delaying or preventing amount,   wherein said immunoconjugate comprises at least one effector molecule and at least one targeting agent selectively targeting cell-surface expressed CD138 and wherein said immunoconjugate delivers said effector molecule to said CD138 expressing tumor or tumor cells and said effector molecule is released.   
     
     
         27 . The method of  claim 26 , wherein said effector molecule has a molecular weight of less than 2 kDa. 
     
     
         28 . The method of  claim 26 , wherein the targeting agent is a targeting antibody. 
     
     
         29 . The method of  claim 28 , wherein the targeting antibody binds to a linear epitope between residues 90-95 of the core protein on human CD138. 
     
     
         30 . The method of  claim 26 , wherein the effector molecule is a maytansinoid that has a molecular weight of less than 2 kDa the targeting agent is a targeting antibody that binds to a linear epitope between residues 90-95 of the core protein on human CD138.