Immunoconjugates targeting cd138 and uses thereof

Abstract

Disclosed are immunoconjugates having in particular specificity for CD138 expressed on target cells and which display homogenous targeting. The immunoconjugates may be sterially hindered and/or contain a cleavable linker.

1 .- 15 . (canceled) 
     
     
         16 . A method of treating multiple myeloma in a subject, comprising:
 providing a immunoconjugate comprising a targeting antibody and an effector molecule, wherein the effector is linked to the targeting antibody via a cleavable linker, and wherein said immunoconjugate target CD138 expressing cells, wherein said targeting antibody comprises:
 heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and 
 light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively, and 
 heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and 
 light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively and 
   administering to said subject said immunoconjugate in an amount effective to treat multiple myeloma.   
     
     
         17 . The method of  claim 16 , wherein said cleavable linker comprises a disulfite bond. 
     
     
         18 . A method for immunoconjugate mediated drug delivery comprising:
 providing a immunoconjugate comprising a targeting antibody and an effector molecule, wherein the effector is linked to the targeting antibody via a cleavable linker, and wherein said immunoconjugate targets CD138 expressing cells, wherein said targeting antibody comprises:
 heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and 
 light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively, and 
 heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and 
 light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively of claim  15 , and 
   administering said immunoconjugate in a therapeutically effective amount, wherein said IgG4 isotype alleviates ADCC, complement dependent cytotoxicity and/or Fc-mediated targeting of hepatic FcR.   
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 18 , wherein said cleavable linker comprises a disulfite bond. 
     
     
         21 . The method of  claim 16 , wherein the cleavable linker is a SPDB (N-succinimidyl-4-(2-pyridyldithio) butyrate) linker. 
     
     
         22 . The method of  claim 18 , wherein the cleavable linker is a SPDB (N-succinimidyl-4-(2-pyridyldithio) butyrate) linker. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . A method for inhibiting, delaying and/or preventing the growth of a tumor comprising CD138 tumor cells and/or spread of tumor cells of such a tumor in a patient in need thereof, comprising
 administering to said patient at least one immunoconjugate comprising a targeting antibody and an effector molecule, wherein the effector is linked to the targeting antibody via a cleavable linker, and wherein said immunoconjugate targets CD138 expressing cells, wherein said targeting antibody comprises:
 heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and 
 light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively, and 
 heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and
 light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively in a growth of said tumor and/or spreading of said tumor cells inhibiting or reducing amount, 
 wherein said immunoconjugate inhibits, delays or prevents the growth and/or spread of said tumor cells. 
 
   
     
     
         26 . The method of  claim 25 , wherein said patient suffers from a hematologic malignancy and/or a solid tumor comprising CD138 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 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. 
     
     
         30 . The method of  claim 25 , wherein said immunoconjugate is administered in a single dose of 5 mg/m 2  to about 300 mg/m 2 . 
     
     
         31 . The method of  claim 25 , wherein said immunoconjugate is administered in at least two doses of about 5 mg/m 2  to about 300 mg/m 2 , optionally at hourly, daily, weekly intervals or combinations thereof. 
     
     
         32 . 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 at least one immunoconjugate comprising a targeting antibody and an effector molecule, wherein the effector is linked to the targeting antibody via cleavable linker, and wherein said immunoconjugate targets CD138 expressing cells, wherein said targeting antibody comprises:
 heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and 
 light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively, and 
 heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and
 light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively in a growth of a tumor and/or spreading of tumor cells inhibiting, delaying or preventing amount; and 
 
   (b) administering to said patient one or more cytotoxic agent and/or radiation in an amount effective to reduce tumor load,
 wherein said immunoconjugate inhibits, delays or prevents the growth and/or spread of tumor cells comprising CD138 expressing cells. 
   
     
     
         33 . The method of  claim 32 , wherein (a) and (b) are performed consecutively in two consecutive treatment regimes. 
     
     
         34 . The method of  claim 32 , wherein the immunoconjugate of (a) and the at least one cytotoxic agent of (b) are co-administered. 
     
     
         35 . The method of  claim 32 , wherein the cytotoxic agent is mephalan, vincristine, doxorubicin, dexamethasone, cyclophosphamide, etoposide, cytarabine, cisplatin, thalidomide, prednisone, thalidomide, bortezomib, lenalidomide, sorafenib, romidepsin or combinations thereof. 
     
     
         36 . The method of  claim 32 , wherein the cytotoxic agent is antibody based. 
     
     
         37 . A method for treating a subject having a condition that would benefit from the suppression of myeloma cell survival, the method comprising:
 (a) providing at least one immunoconjugate comprising a targeting antibody and an effector molecule, wherein the effector is linked to the targeting antibody via a cleavable linker, and wherein said immunoconjugate targets CD138 expressing cells, wherein said targeting antibody comprises:
 heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and 
 light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively, and 
 heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and 
 light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively; and 
   (b) administering the immunoconjugate to the subject to selectively decrease survival or growth of said myeloma cells of said subject.   
     
     
         38 . A pharmaceutical composition comprising the immunoconjugate comprising a targeting antibody and an effector molecule, wherein the effector is linked to the targeting antibody via a cleavable linker, and wherein said immunoconjugate targets CD138 expressing cells, wherein said targeting antibody comprises:
 heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and   light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively, and   heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and   light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively, and one or more pharmaceutically acceptable excipients and further comprising at least one cytotoxic agent.   
     
     
         39 . (canceled) 
     
     
         40 . The pharmaceutical composition of  claim 38 , wherein the cytotoxic agent is mephalan, vincristine, doxorubicin, dexamethasone, cyclophosphamide, etoposide, cytarabine, cisplatin, thalidomide, prednisone, thalidomide, bortezomib, lenalidomide, sorafenib, romidepsin or combinations thereof. 
     
     
         41 . The pharmaceutical composition of  claim 38 , wherein the cytotoxic agent is antibody based. 
     
     
         42 . 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 immunoconjugate of the pharmaceutical composition of  claim 38 , and wherein, a separate container comprises a second pharmaceutical composition comprising an effective amount of said cytotoxic 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. 
     
     
         43 . The kit of  claim 42 , wherein said agent in said second pharmaceutical composition is a selected from the group consisting of mephalan, vincristine, doxorubicin, dexamethasone, cyclophosphamide, etoposide, cytarabine, cisplatin, thalidomide, prednisone, thalidomide, bortezomib, lenalidomide sorafenib, romidepsin and combinations thereof or is antibody based. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 16 , wherein said effector molecule is sterically hindered and a growth of a tumor inhibiting activity of an unhindered counterpart of the immunoconjugate comprising a non-cleavable linker exceeds that of the growth of a tumor inhibiting activity of its unhindered counterpart comprising a cleavable linker, by at least about 5%, at least about 10%, up to about 15%. 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 16 , wherein said effector molecule is DM4. 
     
     
         48 . (canceled) 
     
     
         49 . A method of  claim 16 , wherein said effector molecule is sterically hindered and wherein the immunoconjugate is administered to said subject in multiple doses, wherein the so administered immunoconjugate provides a growth of a tumor inhibiting activity that exceeds that of its unhindered counterpart by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or more. 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . The method of  claim 49 , wherein said multiple doses are administered at intervals of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 hours, 1, 2, 3, 4, 5, 6, 7 days, 1, 2, 3, 4, 5, 6, 7 or 8 weeks. 
     
     
         53 . (canceled) 
     
     
         54 . A method for diminishing an amount of cells in direct or indirect contact with CD138 expressing tumor cells in a subject in need thereof comprising:
 administering to said subject at least one immunoconjugate comprising a targeting antibody and an effector molecule, wherein the effector is linked to the targeting antibody via a cleavable linker, and wherein said immunoconjugate targets CD138 expressing cells, wherein said targeting antibody comprises:
 heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and 
 light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively, and 
 heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and 
 light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively in an amount effective to diminish the amount of said cells in direct or indirect contact with said CD138 expressing tumor cells. 
   
     
     
         55 . The method of  claim 54 , wherein said cells in direct or indirect contact with CD138 expressing tumor cells consist of cells expressing CD138 heterogeneously, non CD138 expressing cells and/or cells being inaccessible to an effective amount of said at least one immunoconjugate. 
     
     
         56 . The method of  claim 54 , wherein said cells are cells in direct contact with or attached to CD138 expressing tumor cells. 
     
     
         57 . (canceled)