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 . An 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.  
   
     
     
         2 . The immunoconjugate of  claim 1 , wherein the cytotoxicity of said effector molecule, in its native form, on cells targeted by said targeting agent is higher or about the same as the cytotoxicity of said immunoconjugate on said targeted cells.  
     
     
         3 . The immunoconjugate of  claim 1 , wherein said effector molecule has, in its native form, a potency of about 10 −11 -10 −8  M.  
     
     
         4 . The immunoconjugate of  claim 1 , wherein said effector molecule is a maytansinoid, a CC1065 analogue, a calicheamicin or a taxane.  
     
     
         5 . The immunoconjugate of  claim 4 , wherein said effector molecule is a maytansinoid.  
     
     
         6 . The immunoconjugate of  claim 5 , wherein said maytansinoid is DM1.  
     
     
         7 . The immunoconjugate of  claim 5 , wherein said maytansinoid is DM3.  
     
     
         8 . The immunoconjugate of  claim 5 , wherein said maytansinoid is DM4.  
     
     
         9 . The immunoconjugate of  claim 1 , wherein said effector molecule has a molecular weight of less than 5 kDa.  
     
     
         10 . The immunoconjugate of  claim 9 , wherein said effector molecule has a molecular weight of between about 600 and about 800 Da.  
     
     
         11 . The immunoconjugate of  claim 1 , wherein said targeting agent is a targeting antibody or non-immunoglobulin targeting molecule.  
     
     
         12 . The immunoconjugate of  claim 11 , wherein said targeting agent is a targeting antibody.  
     
     
         13 . The immunoconjugate of  claim 12 , wherein said targeting antibody is an antibody fragment.  
     
     
         14 . The immunoconjugate of  claim 12 , wherein said targeting antibody is derived from an antibody that internalizes poorly.  
     
     
         15 . The immunoconjugate of  claim 12 , wherein said targeting antibody is derived from the antibody B-B4.  
     
     
         16 . A pharmaceutical composition comprising an effective amount of the immunoconjugate according to  claim 1  and one or more pharmaceutically acceptable excipients.  
     
     
         17 . A kit comprising, in separate containers, pharmaceutical compositions for use in combination to inhibit, delay and/or prevent the growth of tumors and/or spread of tumor cells, wherein one container comprises an effective amount of the pharmaceutical composition of  claim 16 , and wherein, a separate container comprises a second pharmaceutical composition comprising an effective amount of an agent for the inhibition, delay and/or prevention of the growth of tumors and/or spread of tumor cells, and one or more pharmaceutically acceptable excipients.  
     
     
         18 . The kit of  claim 17 , wherein said agent in said second pharmaceutical composition is a chemotherapeutic agent or another immunoconjugate.  
     
     
         19 . 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 preventing effective amount of the immunoconjugate of  claim 1 .    
     
     
         20 . The method of  claim 19 , wherein said effective amount induces cell death or continuous cell cycle arrest in said syndecan-1 expressing tumor cells.  
     
     
         21 . The method of  claim 19 , 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.  
     
     
         22 . The method of  claim 19 , 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.  
     
     
         23 . The method of  claim 22 , 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.  
     
     
         24 . The method of  claim 23 , wherein said patient is suffering from multiple myeloma.  
     
     
         25 . A method for inhibiting, delaying and/or preventing the growth of a tumor comprising syndecan-1 expressing tumor cells and/or spread of syndecan-1 expressing tumor cells in a patient in need thereof, comprising 
 administering to said patient at least one immunoconjugate in a growth of said tumor and/or spreading of said tumor cells inhibiting or reducing amount,    wherein said immunoconjugate comprises at least one effector molecule and at least one targeting agent, and    wherein said immunoconjugate selectively inhibits, delays or prevents the growth and/or spread of syndecan-1 expressing cells.    
     
     
         26 . The method of  claim 25 , wherein said patient suffers from an hematologic malignancy and/or a solid tumor comprising syndecan-1 expressing cells.  
     
     
         27 . The method of  claim 26 , 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.  
     
     
         28 . The method of  claim 27 , wherein the disease is multiple myeloma.  
     
     
         29 . The method of  claim 25 , wherein said effector molecule exhibits, in its native form, high non-selective cytotoxicity.  
     
     
         30 . The method of  claim 25 , 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.  
     
     
         31 . 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.    
     
     
         32 . The method of  claim 31 , wherein (a) and (b) are performed consecutively in two consecutive treatment regimes.  
     
     
         33 . The method of  claim 31 , wherein the at least one drug of (a) and the immunoconjugate of (b) are administered in a single administration step.  
     
     
         34 . A method for treating a subject having a condition that would benefit from the selective suppression of myeloma cell survival, the method comprising: 
 (a) providing at least one immunoconjugate that selectively binds to syndecan-1 expressed on myeloma cells; and    (b) administering the immunoconjugate to the subject to selectively decrease survival or growth of said myeloma cells of said subject.    
     
     
         35 . The method of  claim 34 , wherein the immunoconjugate comprises a B-B4 targeting antibody.  
     
     
         36 . The method of  claim 34 , wherein the immunoconjugate comprises a maytansinoid effector molecule.  
     
     
         37 . The method of  claim 34 , wherein said selective suppression of myeloma cell survival induces growth arrest or cell death in myeloma cells.