Publicaciones científicas

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

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).

(1) Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain.
(2) Solid Tumors Program, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00443, Pamplona, Spain.
(3) Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
(4) Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Spain.

Revista: Clínical Cancer Research

Fecha: 15-may-2019

Inmunología e Inmunoterapia Hematología y Hemoterapia

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 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.

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 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

tal vezLE INTERESE

¿QUÉ TECNOLOGÍA UTILIZAMOS?

La Clínica es el hospital privado con mayor dotación tecnológica de España, todo en un único centro.

Imagen de un PET, tecnología de vanguardia en la Clínica Universidad de Navarra

NUESTROS
PROFESIONALES

Los profesionales de la Clínica realizan una labor continuada de investigación y formación, siempre en beneficio del paciente.

Imagen profesionales de la Clínica Universidad de Navarra

POR QUÉ VENIR
A LA CLÍNICA

Conozca por qué somos diferentes a otros centros sanitarios. Calidad, rapidez, comodidad y resultados.

Imagen del edificio de la Clínica Universidad de Navarra