Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells

Abstract

IntroductionFollowing the discovery of monoclonal antibody (mAb) technology, 1 numerous attempts have been made to use mAbs targeted to cancer-associated antigens for the treatment of human cancer. Of many mAbs tested, several were found to be therapeutically active, either as naked antibodies or as immunoconjugates of radionuclides. [2][3][4] Conjugates of antibodies with cytotoxic agents have also been explored as anticancer agents 2,3 as a means of improving the selectivity of cytotoxic drugs by targeting them to antigens preferentially expressed on the surface of malignant cells. Gemtuzumab ozogamicin (Mylotarg), a conjugate of anti-CD33 humanized monoclonal antibody with a highly cytotoxic DNA-damaging agent calicheamicin, has recently been approved by the FDA as the first drug of this type for clinical treatment of myeloid leukemia. [5][6][7] Immunoconjugates of the highly potent cytotoxic drug maytansine derivative DM1 (N 2Ј -deacetyl-N 2Ј -(3-mercapto-1-oxopropyl)-maytansine) are also being evaluated as antigen-targeted anticancer agents. 8 Maytansine 9 is a natural product originally derived from the Ethiopian shrub Maytenus serrata. This drug inhibits tubulin polymerization, 9-11 resulting in mitotic block and cell death. The cytotoxicity of maytansine is 200-to 1000-fold higher than that of anticancer drugs in clinical use that affect tubulin polymerization, such as Vinca alkaloids or taxol. However, clinical trials of maytansine indicated that it lacked a therapeutic window, due to high systemic toxicity. DM1 is 3-to 10-fold more cytotoxic than maytansine, and can be converted into a prodrug by linking it via disulfide bond to a mAb directed against a tumorassociated antigen. Such a conjugate (tumor-activated prodrug or TAP) is not cytotoxic in the blood compartment, since it is activated only upon binding to target cells, with subsequent release of the drug. 12 Several mAb-DM1 conjugates have been developed, 13 and, to date, huC242-DM1 and huN901-DM1 have been evaluated in clinical trials. These conjugates were well tolerated, did not induce any detectable immune response, and had a long circulation time. [14][15][16] The murine IgG1 mAb B-B4 binds to a linear epitope between residues 90 to 95 of the core protein on human syndecan-1 (CD138), a member of the family of transmembrane heparan sulfate proteoglycans. 17,18 This antigen was originally described as a membrane proteoglycan present on cells of epithelial origin, and was subsequently found on hematopoietic cells. 19 In the normal human hematopoietic compartment, CD138 expression is restricted to plasma cells 17,20 ; in particular, CD34 ϩ stem and progenitor cells do not express CD138. 17 In malignant hematopoiesis, CD138 is highly expressed on the majority of multiple myeloma (MM) cells, many Hodgkin lymphomas with classic Reed-Sternberg cells, 17,20 From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA; the VA Boston Healthcare System, Harvard Medical School, Boston, MA; the University of "Magna Graecia," Ca...

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

“…Accordingly, therapeutic antibodies against a variety of myeloma antigens, such as CD40, 8 CD56, 9 CD138, 10 and CD20, 11 have been developed; however, none of these therapeutics has, so far, proven to be clinically effective and alternative myeloma surface molecules are urgently needed as potential targets.…”

Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma

“…The unconjugated B-B4 antibody alone had little activity. 15 The immunoconjugate also suppressed tumor growth in myeloma mouse models. 15 The anti-CD138 antibody nBT062 is a murine/human chimeric form of B-B4.…”

“…15 The immunoconjugate also suppressed tumor growth in myeloma mouse models. 15 The anti-CD138 antibody nBT062 is a murine/human chimeric form of B-B4. Three immunoconjugates of nBT062 with DM1 or DM4 were developed, which also showed potent antimyeloma activities in vitro as well as in vivo in myeloma mouse models.…”

“…13 and medullary region. 14,15 It functions as a receptor for the extracellular matrix molecules collagen and fibronectin. CD138 also binds via its heparan sulfate chains to various soluble extracellular molecules, including hepatocyte growth factor and fibroblast growth factor.…”

Flow cytometric immunophenotypic characteristics of plasma cell leukemia

“…Besides their immunophenotypic marker function, these antigens contribute relevant processes for cell survival, participate in lytic bone lesion formation, and mediate the action of novel anti-myeloma drugs and resistance to treatment [1][2][3][4][5][6][7][8][9][10][11][12].…”