BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies

  • Clin Cancer Res. 2013 Jan 15;19(2):357-66. doi: 10.1158/1078-0432.CCR-12-2333.
Michelle R Kuhne  1 ,  Tanya Mulvey ,  Blake Belanger ,  Sharline Chen ,  Chin Pan ,  Colin Chong ,  Fei Cao ,  Wafa Niekro ,  Tom Kempe ,  Karla A Henning ,  Lewis J Cohen ,  Alan J Korman ,  Pina M Cardarelli
Affiliations
  • 1. Department of Cell Biology and Physiology, BDC, Bristol-Myers Squibb, Lawrenceville, New Jersey, USA.
PMID: 23213054 DOI: 10.1158/1078-0432.CCR-12-2333
Abstract

Purpose: CXCR4 has been identified as a prognostic marker for acute myeloid 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 reactive with CXCR4 were analyzed for Apoptosis induction and ability to interfere with CXCL12-induced 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 IgG(4) 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 CXCL12-induced migration and calcium flux with low nanomolar EC(50) 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 inhibition.

Conclusions: BMS-936564/MDX-1338 is a potent CXCR4 Antagonist which is efficacious as monotherapy in tumor-bearing mice and is currently in phase I for the treatment of relapsed/refractory AML, NHL, CLL, and multiple myeloma.

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