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.