CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro

Author(s):Show less -

Hansen, Hinrich P. ^[1] ; Trad, Ahmad ^[2] ; Dams, Maria ^[1] ; Zigrino, Paola ^[3] ; Moss, Marcia ^[4] ; Tator, Maximilian ^[1] ; Schoen, Gisela ^[1] ; Grenzi, Patricia C. ^[1] ; Bachurski, Daniel ^[1] ; Aquino, Bruno ^[5] ; Duerkop, Horst ^[6] ; Reiners, Katrin S. ^[1] ; von Bergwelt-Baildon, Michael ^[1] ; Hallek, Michael ^[1] ; Groetzinger, Joachim ^[2] ; Engert, Andreas ^[1] ; Paes Leme, Adriana F. ^[5] ; von Strandmann, Elke Pogge ^[1]

Affiliation

^[1] Univ Cologne, Dept Internal Med 1, D-50931 Cologne - Germany

^[2] Univ Kiel, Dept Biochem, Kiel - Germany

^[3] Univ Cologne, Dept Dermatol, Cologne - Germany

^[4] BioZyme Inc, Apex, NC - USA

^[5] CNPEM, LNBio, Brazilian Biosci Natl Lab, Campinas, SP - Brazil

^[6] Pathodiagnost Berlin, Berlin - Germany

• Document type: Journal article
• Source: ONCOTARGET; v. 7, n. 21, p. 30523-30535, MAY 24 2016.
• Web of Science Citations: 10

Abstract

The goal of targeted immunotherapy in cancer is to damage both malignant and tumor-supporting cells of the microenvironment but spare unaffected tissue. The malignant cells in classical Hodgkin lymphoma (cHL) selectively express CD30. They release this receptor on extracellular vesicles (EVs) for the tumor-supporting communication with CD30 ligand (CD30L)-positive bystander cells. Here, we investigated how CD30-positive EVs influence the efficacy of the CD30 antibody drug conjugate (ADC) Brentuximab Vedotin (SGN-35). The malignant cells and the EVs expressed the active sheddase ADAM10. ADAM10 cleaved and released the CD30 ectodomain (sCD30), causing a gradual depletion of SGN-35 binding sites on EVs and creating a soluble competitor of the ADC therapy. In a 3D semi-solid tumor microenvironment model, the EVs were retained in the matrix whereas sCD30 penetrated readily into the surrounding culture medium. This resulted in a lowered ratio of EV-associated CD30 (CD30EV) to sCD30 in the surrounding medium in comparison to non-embedded cultures. A low percentage of CD30EV was also detected in the plasma of cHL patients, supporting the clinical relevance of the model. The adherence of CD30EV but not sCD30 to CD30-(/)CD30L(+) mast cells and eosinophils allowed the indirect binding of SGN-35. Moreover, SGN-35 damaged CD30-negative cells, provided they were loaded with CD30(+) EVs. (AU)

• FAPESP's process: 09/54067-3 - Acquisition of a mass spectrometer coupled to a liquid chromatography system for increasing the capacity to meet the needs of users and for making new technologies available in the Laboratory of Mass Spectrometry
• Grantee: Adriana Franco Paes Leme
• Support Opportunities: Multi-user Equipment Program