title: BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Cell Biology and Physiology, BDC, Bristol-Myers Squibb, Lawrenceville, New Jersey, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Kuhne
authors.forename: Tanya
authors.initials: T
authors.lastname: Mulvey
authors.forename: Blake
authors.initials: B
authors.lastname: Belanger
authors.forename: Sharline
authors.initials: S
authors.lastname: Chen
authors.forename: Chin
authors.initials: C
authors.lastname: Pan
authors.forename: Colin
authors.initials: C
authors.lastname: Chong
authors.forename: Fei
authors.initials: F
authors.lastname: Cao
authors.forename: Wafa
authors.initials: W
authors.lastname: Niekro
authors.forename: Tom
authors.initials: T
authors.lastname: Kempe
authors.forename: Karla A
authors.initials: KA
authors.lastname: Henning
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Cohen
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.forename: Pina M
authors.initials: PM
authors.lastname: Cardarelli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008024:Ligands; D051379:Mice; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D008024:Ligands; D019718:Receptors, CXCR4; C581980:ulocuplumab; D002118:Calcium