The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

被引：169

作者：

Moreno, Laura ^{[1
]}

Perez, Cristina ^{[1
]}

Zabaleta, Aintzane ^{[1
]}

Manrique, Irene ^{[1
]}

Alignani, Diego ^{[1
]}

Ajona, Daniel ^{[1
,2
,3
]}

Blanco, Laura ^{[1
]}

Lasa, Marta ^{[1
]}

Maiso, Patricia ^{[1
]}

Rodriguez, Idoia ^{[1
]}

Garate, Sonia ^{[1
]}

Jelinek, Tomas ^{[1
]}

Segura, Victor ^{[1
]}

Moreno, Cristina ^{[1
]}

Merino, Juana ^{[1
]}

Rodriguez-Otero, Paula ^{[1
]}

Panizo, Carlos ^{[1
]}

Prosper, Felipe ^{[1
]}

San-Miguel, Jesus F. ^{[1
]}

Paiva, Bruno ^{[1
]}

机构：

[1] Clin Univ Navarra, CIMA, Inst Invest Sanitaria Navarra IDISNA, CIBER ONC CB16 12 00369 & CB16 12 00489, Pamplona, Spain

[2] Inst Invest Sanitaria Navarra IDISNA, CIMA, Solid Tumors Program, CIBER ONC CB16 12 00443, Pamplona, Spain

[3] Univ Navarra, Sch Sci, Dept Biochem & Genet, Pamplona, Spain

来源：

CLINICAL CANCER RESEARCH | 2019年 / 25卷 / 10期

基金：

欧洲研究理事会;

关键词：

MINIMAL RESIDUAL DISEASE; CD38; EXPRESSION; DARATUMUMAB MONOTHERAPY; ANTITUMOR-ACTIVITY; TUMOR-CELLS; HUMAN B; LENALIDOMIDE; DEXAMETHASONE; COMPLEMENT; IMMUNOTHERAPY;

D O I：

10.1158/1078-0432.CCR-18-1597

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAb) is required to understand which patients with multiple myeloma (MM) benefit the most from a given mAb, alone or in combination therapy. Although there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce. Experimental Design: We performed a comprehensive analysis of the MoA of isatuximab. Results: Isatuximab induces internalization of CD38 but not its significant release from MMcell surface. In addition, we uncovered an association between levels of CD38 expression and different MoA: (i) Isatuximab was unable to induce direct apoptosis on MM cells with CD38 levels closer to those in patients with MM, (ii) isatuximab sensitized CD38(hi) MMcells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38(lo) and CD38(hi) tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38(hi) MM cells, whereas (v) complement-dependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38(hi) B-lymphocyte precursors and natural killer (NK) lymphocytes ex vivo-the latter through activation followed by exhaustion and eventually phagocytosis. Conclusions: This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma cell protection, augmenting NK lymphocyte-mediated ADCC, or facilitating ADCP in CD38(lo) MM patients.

引用

页码：3176 / 3187

页数：12

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