SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38+ Hematologic Malignancies

被引：295

作者：

Deckert, Jutta ^{[1
]}

Wetzel, Marie-Cecile ^{[2
]}

Bartle, Laura M. ^{[1
]}

Skaletskaya, Anna ^{[1
]}

Goldmacher, Victor S. ^{[1
]}

Vallee, Francois ^{[3
]}

Zhou-Liu, Qing ^{[4
]}

Ferrari, Paul ^{[4
]}

Pouzieux, Stephanie ^{[3
]}

Lahoute, Charlotte ^{[2
]}

Dumontet, Charles ^{[5
,6
]}

Plesa, Adriana ^{[5
,6
]}

Chiron, Marielle ^{[2
]}

Lejeune, Pascale ^{[2
]}

Chittenden, Thomas ^{[1
]}

Park, Peter U. ^{[1
]}

Blanc, Veronique ^{[2
]}

机构：

[1] ImmunoGen Inc, Res & Dev, Waltham, MA 02451 USA

[2] Sanofi R&D, Oncol Business Div, Vitry Sur Seine, France

[3] Sanofi R&D, SCP LGCR Struct Design & Informat Struct Biol, Vitry Sur Seine, France

[4] Sanofi R&D, Biorealizat Operat & Prot Tools, Vitry Sur Seine, France

[5] Hosp Civils Lyon, Hematol Lab, Pierre Benite, France

[6] INSERM 1052 CNRS, CRCL, Lyon, France

来源：

CLINICAL CANCER RESEARCH | 2014年 / 20卷 / 17期

关键词：

ADP-RIBOSYL CYCLASE; MONOCLONAL-ANTIBODIES; EXPRESSION; MOLECULE; LEUKEMIA; THERAPY; COMPLEX; ENZYMES; DOMAIN; SITE;

D O I：

10.1158/1078-0432.CCR-14-0695

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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. (C) 2014 AACR.

引用

页码：4574 / 4583

页数：10

共 48 条

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