Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells.
We tested the in vitro and in vivo antitumor activity of the maytansinoid DM1 (N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine), a potent antimicrotubule agent, covalently linked to the murine monoclonal antibody (mAb) B-B4 targeting syndecan-1 (CD138). We evaluated the in vitro activity of B-B4-DM1 against a panel of CD138(+) and CD138(-) cell lines, as well as CD138(+) patient multiple myeloma (MM) cells. Treatment with B-B4-DM1 selectively decreased growth and survival of MM cell lines, patient MM cells, and MM cells adherent to bone marrow stromal cells. We further examined the activity of B-B4-DM1 in 3 human MM models in mice: (1) severe combined immunodeficient (SCID) mice bearing subcutaneous xenografts; (2) SCID mice bearing green fluorescent protein-positive (GFP(+)) xenografts; and (3) SCID mice implanted with human fetal bone (SCID-hu) and subsequently injected with patient MM cells. Tumor regression and inhibition of tumor growth, improvement in overall survival, and reduction in levels of circulating human paraprotein were observed in mice treated with B-B4-DM1. Although immunohistochemical analysis demonstrates restricted CD138 expression in human tissues, the lack of B-B4 reactivity with mouse tissues precludes evaluation of its toxicity in these models. In conclusion, B-B4-DM1 is a potent anti-MM agent that kills cells in an antigen-dependent manner in vitro and mediates in vivo antitumor activity at doses that are well tolerated, providing the rationale for clinical trials of this immunoconjugate in MM.
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
Pierfrancesco
P
Tassone
Victor S
VS
Goldmacher
Paola
P
Neri
Antonella
A
Gozzini
Masood A
MA
Shammas
Kathleen R
KR
Whiteman
Linda L
LL
Hylander-Gans
Daniel R
DR
Carrasco
Teru
T
Hideshima
Reshma
R
Shringarpure
Jialan
J
Shi
Charles K
CK
Allam
John
J
Wijdenes
Salvatore
S
Venuta
Nikhil C
NC
Munshi
Kenneth C
KC
Anderson
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008453:Maytansine / Q000494:pharmacology* / Q000627:therapeutic use; D008562:Membrane Glycoproteins; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation; D011509:Proteoglycans; D015996:Survival Rate; D053668:Syndecan-1; D053667:Syndecans; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D008453:Maytansine