title: 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.
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.
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Kashyap
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Harrison
authors.initials: H
authors.lastname: Jones
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Carlos I
authors.initials: CI
authors.lastname: Amaya-Chanaga
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Choi
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Melo-Cardenas
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Amine
authors.initials: A
authors.lastname: Ale-Ali
authors.affiliation: Bristol-Myers Squibb, Department of Cell Biology and Physiology, Redwood City, CA, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Kuhne
authors.affiliation: Department of Early Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sabbatini
authors.affiliation: Department of Early Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Cohen
authors.affiliation: Department of Early Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Suresh G
authors.initials: SG
authors.lastname: Shelat
authors.affiliation: CLL Research Consortium, La Jolla, CA, USA.
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.|CLL Research Consortium, La Jolla, CA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Bristol-Myers Squibb, Department of Cell Biology and Physiology, Redwood City, CA, USA.
authors.forename: Pina M
authors.initials: PM
authors.lastname: Cardarelli
authors.affiliation: UCSD-Moores Cancer Center, La Jolla, CA, USA.|CLL Research Consortium, La Jolla, CA, USA.
authors.forename: Januario E
authors.initials: JE
authors.lastname: Castro
mesh_terms: D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001596:Benzylamines; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000378:metabolism; D000080027:Cyclams; D004789:Enzyme Activation / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D050113:Imino Furanoses / Q000494:pharmacology*; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear; D011744:Pyrimidinones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D050113:Imino Furanoses; D011744:Pyrimidinones; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000593472:ulodesine; C088327:plerixafor
keywords: BMS-936564; CXCR4; Ulocuplumab; chronic lymphocytic leukemia; reactive oxygen species