Oncotarget

Research Papers:

Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway

Manoj K. Kashyap, Deepak Kumar, Harrison Jones, Carlos I. Amaya-Chanaga, Michael Y. Choi, Johanna Melo-Cardenas, Amine Ale-Ali, Michelle R. Kuhne, Peter Sabbatini, Lewis J. Cohen, Suresh G. Shelat, Laura Z. Rassenti, Thomas J. Kipps, Pina M. Cardarelli and Januario E. Castro _

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Oncotarget. 2016; 7:2809-2822. https://doi.org/10.18632/oncotarget.6465

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Abstract

Manoj K. Kashyap1, Deepak Kumar1, Harrison Jones1, Carlos I. Amaya-Chanaga1, Michael Y. Choi1, Johanna Melo-Cardenas1, Amine Ale-Ali1, Michelle R. Kuhne3, Peter Sabbatini4, Lewis J. Cohen4, Suresh G. Shelat4, Laura Z. Rassenti2, Thomas J. Kipps1,2, Pina M. Cardarelli3 and Januario E. Castro1,2

1 UCSD-Moores Cancer Center, La Jolla, CA, USA

2 CLL Research Consortium, La Jolla, CA, USA

3 Bristol-Myers Squibb, Department of Cell Biology and Physiology, Redwood City, CA, USA

4 Department of Early Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA

Correspondence to:

Januario E. Castro, email:

Pina M. Cardarelli, email:

Keywords: Ulocuplumab, BMS-936564, reactive oxygen species, chronic lymphocytic leukemia, CXCR4

Received: October 05, 2015 Accepted: October 22, 2015 Published: December 04, 2015

Abstract

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma – CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor - Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies.


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