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A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment

¹ Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences; ² Division of Transfusion Medicine, Tokushima University Hospital, Tokushima, Japan; and ³ Genome Antibody Research Department, ⁴ Pharmaceutical Research Department III, and ⁵ Product Planning Department, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan

Requests for reprints: Shuji Ozaki, Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Phone: 81-88-633-7120; Fax: 81-88-633-7121; E-mail: ozakishu{at}clin.med.tokushima-u.ac.jp.

Cross-linked human leukocyte antigen (HLA) class I molecules have been shown to mediate cell death in neoplastic lymphoid cells. However, clinical application of an anti-HLA class I antibody is limited by possible side effects due to widespread expression of HLA class I molecules in normal tissues. To reduce the unwanted Fc-mediated functions of the therapeutic antibody, we have developed a recombinant single-chain Fv diabody (2D7-DB) specific to the 2 domain of HLA-A. Here, we show that 2D7-DB specifically induces multiple myeloma cell death in the bone marrow environment. Both multiple myeloma cell lines and primary multiple myeloma cells expressed HLA-A at higher levels than normal myeloid cells, lymphocytes, or hematopoietic stem cells. 2D7-DB rapidly induced Rho activation and robust actin aggregation that led to caspase-independent death in multiple myeloma cells. This cell death was completely blocked by Rho GTPase inhibitors, suggesting that Rho-induced actin aggregation is crucial for mediating multiple myeloma cell death. Conversely, 2D7-DB neither triggered Rho-mediated actin aggregation nor induced cell death in normal bone marrow cells despite the expression of HLA-A. Treatment with IFNs, melphalan, or bortezomib enhanced multiple myeloma cell death induced by 2D7-DB. Furthermore, administration of 2D7-DB resulted in significant tumor regression in a xenograft model of human multiple myeloma. These results indicate that 2D7-DB acts on multiple myeloma cells differently from other bone marrow cells and thus provide the basis for a novel HLA class I–targeting therapy against multiple myeloma. [Cancer Res 2007;67(3):1184–92]