Cancer Therapy: Preclinical BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Antitumor Activity In Vivo in Hematologic Malignancies

Purpose:CXCR4has been identified as a prognosticmarker for acutemyeloid leukemia (AML) and other malignancies. We describe the development and characterization of a fully human antibody to CXCR4 and its application for therapy of AML, non–Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and multiple myeloma. Experimental Design: Human transgenic mice were immunized with CXCR4-expressing cells, and antibodies reactivewithCXCR4were analyzed for apoptosis induction and ability to interferewithCXCL12induced migration and calcium flux. In vivo efficacy was determined in multiple AML, NHL, and multiple myeloma xenograft tumors in severe combined immunodeficient mice. Results: BMS-936564/MDX-1338 is a fully human IgG4 monoclonal antibody that specifically recognizes human CXCR4. In vitro studies show that MDX-1338 binds to CXCR4-expressing cells with low nanomolar affinity, blocks CXCL12 binding to CXCR4-expressing cells, and inhibits CXCL12induced migration and calcium flux with low nanomolar EC50 values. When given as monotherapy, MDX-1338 exhibits antitumor activity in established tumors including AML, NHL, and multiple myeloma xenograft models. In addition, we show that MDX-1338 induced apoptosis on a panel of cell lines and propose that antibody-induced apoptosis is one of the mechanisms of tumor growth