title: SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies.
abstract: OBJECTIVE
  The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984.
  
  
  METHODS
  Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice.
  
  
  RESULTS
  We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38+ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent proapoptotic activity against CD38+ human primary multiple myeloma cells.
  
  
  CONCLUSIONS
  These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in phase I clinical trials in patients with CD38+ B-cell malignancies.
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts. jutta.deckert@immunogen.com.
authors.forename: Jutta
authors.initials: J
authors.lastname: Deckert
authors.affiliation: Oncology Business Division, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Wetzel
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bartle
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Anna
authors.initials: A
authors.lastname: Skaletskaya
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Goldmacher
authors.affiliation: SCP LGCR/Structure Design & Informatics/Structural Biology, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: François
authors.initials: F
authors.lastname: Vallée
authors.affiliation: Biorealization/Operations and Protein Tools, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou-Liu
authors.affiliation: Biorealization/Operations and Protein Tools, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Ferrari
authors.affiliation: SCP LGCR/Structure Design & Informatics/Structural Biology, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pouzieux
authors.affiliation: Oncology Business Division, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lahoute
authors.affiliation: Hematology Laboratory, Hospices Civils de Lyon, Pierre Bénite, France and CRCL, INSERM 1052-CNRS 5286, Lyon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.affiliation: Hematology Laboratory, Hospices Civils de Lyon, Pierre Bénite, France and CRCL, INSERM 1052-CNRS 5286, Lyon, France.
authors.forename: Adriana
authors.initials: A
authors.lastname: Plesa
authors.affiliation: Oncology Business Division, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Chiron
authors.affiliation: Oncology Business Division, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Lejeune
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chittenden
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Peter U
authors.initials: PU
authors.lastname: Park
authors.affiliation: Oncology Business Division, Sanofi R&D, Vitry-sur-Seine, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Blanc
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D045744:Cell Line, Tumor; D064420:Drug-Related Side Effects and Adverse Reactions; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D008562:Membrane Glycoproteins; D000069283:Rituximab; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; C000599209:isatuximab