In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells.

Abstract

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.

• Authors: Pierfrancesco Tassone, Antonella Gozzini, Victor Goldmacher, Masood A Shammas, Kathleen R Whiteman, Daniel R Carrasco, Cheng Li, Charles K Allam, Salvatore Venuta, Kenneth C Anderson, Nikhil C Munshi
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 13 Pg. 4629-36 (Jul 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15231675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• CD56 Antigen
• Immunotoxins
• N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)maytansine
• Neural Cell Adhesion Molecules
• Maytansine

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, metabolism, pharmacology)
• CD56 Antigen (biosynthesis, metabolism)
• Cell Adhesion (physiology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Humans
• Immunotoxins (metabolism, pharmacology)
• Male
• Maytansine (administration & dosage, analogs & derivatives, pharmacology)
• Mice
• Mice, SCID
• Multiple Myeloma (drug therapy, immunology, metabolism)
• Neural Cell Adhesion Molecules (biosynthesis, metabolism)
• Xenograft Model Antitumor Assays