In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells.
HuN901 is a humanized monoclonal antibody that binds with high affinity to CD56, the neuronal cell adhesion molecule. HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing tumors. Based on gene expression profiles of primary multiple myeloma (MM) cells showing expression of CD56 in 10 out of 15 patients (66.6%) and flow cytometric profiles of MM (CD38(bright)CD45(lo)) cells showing CD56 expression in 22 out of 28 patients (79%), we assessed the efficacy of huN901-DM1 for the treatment of MM. We first examined the in vitro cytotoxicity and specificity of huN901-DM1 on a panel of CD56(+) and CD56(-) MM cell lines, as well as a CD56(-) Waldenstrom's macroglobulinemia cell line. HuN901-DM1 treatment selectively decreased survival of CD56(+) MM cell lines and depleted CD56(+) MM cells from mixed cultures with a CD56(-) cell line or adherent bone marrow stromal cells. In vivo antitumor activity of huN901-DM1 was then studied in a tumor xenograft model using a CD56(+) OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.
Tassone
Pierfrancesco
P
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02115, USA.
Gozzini
Antonella
A
Goldmacher
Victor
V
Shammas
Masood A
MA
Whiteman
Kathleen R
KR
Carrasco
Daniel R
DR
Li
Cheng
C
Allam
Charles K
CK
Venuta
Salvatore
S
Anderson
Kenneth C
KC
Munshi
Nikhil C
NC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D019002:CD56 Antigen / Q000096:biosynthesis / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D019002:CD56 Antigen; D000922:Immunotoxins; C488736:N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)maytansine; D019006:Neural Cell Adhesion Molecules; D008453:Maytansine