Methods and agents for improving targeting of CD138 expressing tumor cells
Disclosed are immunoconjugates having specificity for CD138 that diminish adhesion of CD138 expressing tumor cells to stroma cells and methods of using the same. This diminished adhesion renders the tumor cells not only susceptible to the immunoconjugate, but also to other agents, in particular cytotoxic agents.
1. A method for destroying multiple myeloma cells and diminishing adhesion of stroma cells to CD138 expressing multiple myeloma cells in multiple myeloma cells of a subject in need thereof comprising:
(i) administering to said multiple myeloma cells, in a first administration, an immunoconjugate targeting said CD138 expressing multiple myeloma cells said immunoconjugate comprising a chimeric CD138 antibody comprising an antigen binding region which comprises
(a) a light chain variable region comprising amino acid residues 24-34 (CDR1), residues 50-56 (CDR2) and residues 89-97 (CDR3) of SEQ ID NO: 2, and
(b) a heavy chain variable region comprising amino acid residues 31-35 (CDR1), residues 51-68 (CDR2) and residues 99-111 (CDR3) of SEQ ID No: 1
and at least one maytansinoid effector molecule, wherein said effector molecule and said chimeric CD138 antibody are attached to each other via a cleavable linker,
(ii) waiting for 12 hours to 6 days during which
the immunoconjugate:
(a) destroys multiple myeloma cells, and
(b) prevents, at least in part, multiple myeloma cells from adhering to bone marrow stromal cells (BMSCs) thus overcoming cell adhesion-mediated drug resistance (CAM-DR), and
(iii) administering to said multiple myeloma cells, in an administration subsequent to the first administration in (i) and subsequent to (ii), a further cytotoxic agent that is not said immunoconjugate
wherein said diminished adhesion results in alleviation of adhesion mediated drug resistance against said further cytotoxic agent.
2. The method of claim 1 , wherein the cleavable linker contains a disulfide bond.
3. The method of claim 2 , wherein the linker is SPP or SPDB.
4. The method of claim 1 , wherein the adhesion is diminished by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or more.
5. The method of claim 1 , wherein said cytotoxic agent is mephalan, vincristine, doxorubicin, dexamethasone, cyclophosphamide, etoposide, cytarabine, cisplatin, thalidomide, prednisone, thalidomide, bortezomib, lenalidomide, sorafenib, romidepsin or combinations thereof.
6. The method of claim 1 , wherein said maytansinoid effector molecule is sterically hindered.
7. The method of claim 1 , wherein the maytansinoid effector molecule is DM1, DM3, or DM4.
8. The method of claim 7 , wherein said effector molecule is DM4.
9. The method of claim 1 , wherein said chimeric CD138 antibody comprises:
SEQ ID NO:1 and SEQ ID NO:2.
10. The method of claim 1 , wherein the cleavable linker is cleaved releasing the effector molecule and wherein the adhesion of the stroma cells to CD138 expressing tumor cells is diminished by diffusion of said effector molecules to said stroma cells.