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CD45^neg but Not CD45^pos Human Myeloma Cells Are Sensitive to the Inhibition of IGF-1 Signaling by a Murine Anti-IGF-1R Monoclonal Antibody, mAVE1642¹

Géraldine Descamps^2,*, Soraya Wuillème-Toumi^2,*, Valérie Trichet, Corinne Venot, Laurent Debussche, Thierry Hercend, Madeleine Collette^*, Nelly Robillard, Régis Bataille^* and Martine Amiot^3,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 601, Université de Nantes, Unité de Formation et de Recherche Médecine et Techniques Médicales, LNC Label; Laboratoire d’Hématologie; EA 3822 Institut National de la Santé et de la Recherche Médicale ER17, Nantes, Cedex, France; and Sanofi-Aventis, Oncology Therapeutic Department, Vitry sur Seine, France

Insulin-like growth factor 1 (IGF-1) is a well-known growth factor for myeloma cells. Thus, therapeutic strategies targeting IGF-1R have been proposed for multiple myeloma treatment. In this study, we investigated the effect of the antagonistic anti-IGF-1R murineAVE1642 Ab (mAVE1642). We show that mAVE1642 selectively inhibits IGF-1R but not insulin signaling in human myeloma cell lines. Since we have previously shown the functional relevance of CD45 expression in the growth of myeloma cells and the association of CD45-negative (CD45^neg) status with a less favorable clinical outcome, both CD45-positive (CD45^pos) and CD45^neg myeloma cell lines were selected for our study. We found that mAVE1642 strongly inhibits the growth of CD45^neg myeloma cell lines, leading to a G₁ growth arrest, whereas it has almost no effect on the growth of CD45^pos myeloma cell lines. Furthermore, mAVE1642 binding induced a significant reduction of IGF-1R expression. We next demonstrated that the overexpression of IGF-1R in the CD45^pos myeloma cell line increased Akt phosphorylation but was not sufficient to sensitize these cells to mAVE1642. In contrast, we generated a stable CD45-silencing XG-1 cell line and showed that it became sensitive to mAVE1642. Thus, for the first time, we provided direct evidence that the expression of CD45 renders cells resistant to mAVE1642. Taken together, these results support that therapy directed against IGF-1R can be beneficial in treating CD45^neg patients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Ligue Nationale Contre le Cancer.

² G.D. and S.W.-T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Martine Amiot, Institut National de la Santé et de la Recherche Médicale,Unité 601, Département de Recherche en Cancérologie, 9, quai Moncousu 44093 Nantes, Cedex 01, France. E-mail address: mamiot{at}nantes.inserm.fr

⁴ Abbreviations used in this paper: MM, multiple myeloma; HMCL, human myeloma cell line; IGF-1, insulin-like growth factor 1; IRS, insulin receptor substrate; IR, insulin receptor; shRNA, short hairpin RNA; mAVE1642, murine AVE1642.

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