Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program.

Abstract

BACKGROUND:

IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent).

PROCEDURES:

IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated.

RESULTS:

Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models.

CONCLUSIONS:

IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined.

• Authors: Andrew C Wood, John M Maris, Richard Gorlick, E Anders Kolb, Stephen T Keir, C Patrick Reynolds, Min H Kang, Jianrong Wu, Raushan T Kurmasheva, Kathleen Whiteman, Peter J Houghton, Malcolm A Smith
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 60 Issue 11 Pg. 1860-7 (Nov 2013) ISSN: 1545-5017 [Electronic] United States
• PMID: 23798344 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• lorvotuzumab mertansine
• Maytansine

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Female
• Humans
• Immunohistochemistry
• Maytansine (analogs & derivatives, pharmacology)
• Mice
• Mice, SCID
• Neoplasms, Experimental (drug therapy)
• Xenograft Model Antitumor Assays