2. Academic Validation
  3. Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

  • Oncoimmunology. 2018 Jul 23;7(10):e1486948. doi: 10.1080/2162402X.2018.1486948.
Jayeeta Ghose 1,  Domenico Viola 2 3,  Cesar Terrazas 4,  Enrico Caserta 2 3,  Estelle Troadec 2 3,  Jihane Khalife 2 4,  Emine Gulsen Gunes 2 5,  James Sanchez 3,  Tinisha McDonald 6,  Guido Marcucci 2 3,  Balveen Kaur 7,  Michael Rosenzweig 3,  Jonathan Keats 8,  Steven Rosen 3,  Amrita Krishnan 3,  Abhay R Satoskar 4,  Craig C Hofmeister 9,  Flavia Pichiorri 2 3
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA.
  • 2 Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 3 Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, USA.
  • 4 Division of Experimental Pathology, Department of Microbiology, The Ohio State University Medical Center, Columbus, OH, USA.
  • 5 Toni Stephenson Lymphoma Center, Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, CA, USA.
  • 6 Liquid Tissue Bank Shared Resource, City of Hope, Duarte, CA, USA.
  • 7 Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 8 Translational Genomics Research Institute, Phoenix, AZ.
  • 9 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
PMID: 30288349 DOI: 10.1080/2162402X.2018.1486948
Abstract

Daratumumab (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.

Keywords

CD38; bone marrow stromal cells; bortezomib; daratumumab; internalization; loss of adhesion; multiple myeloma; plasma cells; sensitivity.

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