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Research Articles: Therapeutics, Targets, and Development

Antibody targeting of B-cell maturation antigen on malignant plasma cells

Seattle Genetics, Inc., Bothell, Washington

Requests for reprints: Maureen C. Ryan, Seattle Genetics, Inc., 21823 30th Drive Southeast, Bothell, WA 98021. Phone: 425-527-4652; Fax: 425-527-4609. E-mail: mryan{at}seagen.com

Abstract

B-cell maturation antigen (BCMA) is expressed on normal and malignant plasma cells and represents a potential target for therapeutic intervention. BCMA binds to two ligands that promote tumor cell survival, a proliferation inducing ligand (APRIL) and B-cell activating factor. To selectively target BCMA for plasma cell malignancies, we developed antibodies with ligand blocking activity that could promote cytotoxicity of multiple myeloma (MM) cell lines as naked antibodies or as antibody-drug conjugates. We show that SG1, an inhibitory BCMA antibody, blocks APRIL–dependent activation of nuclear factor-B in a dose-dependent manner in vitro. Cytotoxicity of SG1 was assessed as a naked antibody after chimerization with and without Fc mutations that enhance FcRIIIA binding. The Fc mutations increased the antibody-dependent cell-mediated cytotoxicity potency of BCMA antibodies against MM lines by 100-fold with a 2-fold increase in maximal lysis. As an alternative therapeutic strategy, anti-BCMA antibodies were endowed with direct cytotoxic activity by conjugation to the cytotoxic drug, monomethyl auristatin F. The most potent BCMA antibody-drug conjugate displayed IC₅₀ values of 130 pmol/L for three different MM lines. Hence, BCMA antibodies show cytotoxic activity both as naked IgG and as drug conjugates and warrant further evaluation as therapeutic candidates for plasma cell malignancies. [Mol Cancer Ther 2007;6(11):3009–18]

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.

Note: Current address for D. Peckham: Amgen, Inc., Seattle, Washington. Current address for C.F. McDonagh: Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts. Current address for R.F. Zabinski: deCODE Biostructures, Inc., Bainbridge Island, Washington.

¹ I. Grewal, unpublished data.

² K. Kim, unpublished observations.

Received 7/11/07; revised 9/11/07; accepted 10/ 1/07.