SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

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: Jutta Deckert, Marie-Cécile Wetzel, Laura M Bartle, Anna Skaletskaya, Victor S Goldmacher, François Vallée, Qing Zhou-Liu, Paul Ferrari, Stéphanie Pouzieux, Charlotte Lahoute, Charles Dumontet, Adriana Plesa, Marielle Chiron, Pascale Lejeune, Thomas Chittenden, Peter U Park, Véronique Blanc
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 17 Pg. 4574-83 (Sep 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24987056 (Publication Type: Journal Article)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Membrane Glycoproteins
• Rituximab
• CD38 protein, human
• ADP-ribosyl Cyclase 1
• isatuximab

Topics

• ADP-ribosyl Cyclase 1 (genetics)
• Animals
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Murine-Derived (administration & dosage)
• Antibody-Dependent Cell Cytotoxicity (drug effects)
• Cell Line, Tumor
• Drug-Related Side Effects and Adverse Reactions
• Hematologic Neoplasms (drug therapy, pathology)
• Humans
• Lymphoma, B-Cell (drug therapy, genetics, pathology)
• Membrane Glycoproteins (genetics)
• Mice
• Multiple Myeloma (drug therapy, pathology)
• Rituximab
• Xenograft Model Antitumor Assays