Publicaciones científicas

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

15-may-2019 | Revista: Clínical Cancer Research

Moreno L (1), Perez C (1), Zabaleta A (1), Manrique I (1), Alignani D (1), Ajona D (1,2,3), Blanco L (1), Lasa M (1), Maiso P (1), Rodriguez I (1), Garate S (1), Jelinek T (1), Segura V (1), Moreno C (1), Merino J (1), Rodriguez-Otero P (1), Panizo C (1), Prosper F (1), San-Miguel JF (1), Paiva B (4).


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.


We performed a comprehensive analysis of the MoA of isatuximab.


Isatuximab induces internalization of CD38 but not its significant release from MM cell 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 CD38hi MM cells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38lo and CD38hi tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38hi 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 CD38hi B-lymphocyte precursors and natural killer (NK) lymphocytes ex vivo-the latter through activation followed by exhaustion and eventually phagocytosis.


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 CD38lo MM patients.See related commentary by Malavasi and Faini, p. 2946.

CITA DEL ARTÍCULO  Clin Cancer Res. 2019 May 15;25(10):3176-3187. doi: 10.1158/1078-0432.CCR-18-1597. Epub 2019 Jan 28

Nuestros autores

Investigadora predoctoral del Grupo de Mieloma Múltiple del Cima Universidad de Navarra
Dra. Cristina Pérez Ruiz
Graduada Adscrito a Proyecto Grupo de Investigación en Mieloma Múltiple
Dra. Aintzane Zabaleta Azpiroz
Investigadora postdoctoral del Grupo de Mieloma Múltiple del Cima Universidad de Navarra
Dra. Irene Manrique Saenz de Tejada
Diego Alignani
Técnico Superior de Investigación Plataforma de Citometría
Dr. Daniel Ajona Martínez-Polo
Marta Lasa, investigadora del Grupo de Mieloma Múltiple del Cima Universidad de Navarra
Dra. Marta Lasa Ventura
Colaborador de Investigación Grupo de Investigación en Mieloma Múltiple
Sonia Gárate Luzuriaga
Técnico de laboratorio Plataforma de Citometría