Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

Jayeeta Ghose,Domenico Viola,Cesar Terrazas,Enrico Caserta,Estelle Troadec,Jihane Khalife,Emine Gulsen Gunes,James Sanchez,Tinisha Mcdonald,Guido Marcucci,Balveen Kaur,Michael Rosenzweig,Jonathan Keats,Steven Rosen,Amrita Krishnan,Abhay R Satoskar,Craig C Hofmeister,Flavia Pichiorri

doi:10.1080/2162402x.2018.1486948

Abstract

ABSTRACTDaratumumab (Dara), a human immunoglobulin G1 kappa (IgG1κ) monoclonal anti-CD38 antibody, has been approved by the U.S. Food and Drug Administration for the treatment of relapsed multiple myeloma (MM) as a single agent as well as in combination with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI). Although the scientific rationale behind the use of Dara in combination with IMiDs has been extensively explored, the molecular mechanisms underlying Dara-PI regimens have not yet been investigated. Here, we demonstrate that CD38 on the surface of MM cells is rapidly internalized after Dara treatment; we also show that Dara treatment impairs MM cell adhesion, an effect that can be rescued by using the endocytosis inhibitor Dynasore. Finally, we show that Dara potentiates bortezomib (BTZ) killing of MM cells in vitro and in vivo, independent of its function as an immune activator. In conclusion, our data show that Dara impairs MM cell adhesion, which results in an increased sensitivity of MM to proteasome inhibition.

Highlights

Multiple myeloma (MM) is a hematologic malignancy in which plasma cells (PCs) tend to proliferate and accumulate in the bone marrow (BM).[1,2] MM is the second most common hematologic disease, affecting approximately 83,000 US citizens, with 30,330 new cases diagnosed per year in the country.[3]
We show that the CD38 surface receptor can be internalized in CD138+ plasma cells (MM-PCs) by antibody binding via endocytosis, leading to loss of adhesion from bone marrow stromal cells (BMSCs) thereby sensitizing MM cells to proteasome inhibitors (PI) treatment in vitro and in vivo
Since our data confirmed that CD38 is highly expressed in CD138+ MM-PCs, and because previously published studies have shown that the human CD38 molecule is internalized by endocytosis in a number of leukemia- and lymphoma-derived cell lines,[16] we decided to investigate whether CD38 on the surface of MM cells is internalized by antibody-mediated binding

Summary

Introduction

Multiple myeloma (MM) is a hematologic malignancy in which plasma cells (PCs) tend to proliferate and accumulate in the bone marrow (BM).[1,2] MM is the second most common hematologic disease, affecting approximately 83,000 US citizens, with 30,330 new cases diagnosed per year in the country.[3]. In support of its function as an ectoenzyme, it has been previously reported that a fraction of the entire CD38 surface molecule can be internalized by endocytosis in a number of leukemia- and lymphoma-derived cell lines.[15,16] CD38 interacts with its known ligand

Methods

Results

Conclusion