BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Antitumor Activity In Vivo in Hematologic Malignancies
2012; American Association for Cancer Research; Volume: 19; Issue: 2 Linguagem: Inglês
10.1158/1078-0432.ccr-12-2333
ISSN1557-3265
AutoresMichelle Kuhne, Tanya Mulvey, Blake Belanger, Sharline Chen, Chin Pan, Colin Chong, Fei Cao, Wafa Niekro, Tom Kempe, Karla A. Henning, Lewis Cohen, Alan J. Korman, Pina M. Cardarelli,
Tópico(s)interferon and immune responses
ResumoCXCR4 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.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.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.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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