The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications

• Published in: British journal of haematology 2011-11, Vol.155 (4), p.438-448
• Main Authors: Podar, Klaus, Zimmerhackl, Alexander, Fulciniti, Mariateresa, Tonon, Giovanni, Hainz, Ursula, Tai, Yu‐Tzu, Vallet, Sonia, Halama, Niels, Jäger, Dirk, Olson, Dian L., Sattler, Martin, Chauhan, Dharminder, Anderson, Kenneth C.
• Format: Article
• Language: English
• Subjects: adhesion; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; bone marrow microenvironment; Cell Adhesion - drug effects; cell adhesion‐mediated drug resistance; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Cell Movement - drug effects; Disease Models, Animal; Endothelial Cells - drug effects; Endothelial Cells - pathology; Fibronectins - metabolism; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunohistochemistry; Immunopathology; Integrin alpha4 - biosynthesis; integrin‐α4; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Mice; Mice, SCID; multiple myeloma; Multiple Myeloma - blood supply; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Natalizumab; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Signal Transduction - drug effects; Tumor Microenvironment; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2011.08864.x

Summary Recent advances regarding the introduction of anti‐adhesion strategies as a novel therapeutic concept in oncology hold great promise. Here we evaluated the therapeutic potential of the new‐in‐class‐molecule selective‐adhesion‐molecule (SAM) inhibitor Natalizumab, a recombinant humanized IgG4 monoclonal antibody, which binds integrin‐α4, in multiple myeloma (MM). Natalizumab, but not a control antibody, inhibited adhesion of MM cells to non‐cellular and cellular components of the microenvironment as well as disrupted the binding of already adherent MM cells. Consequently, Natalizumab blocked both the proliferative effect of MM‐bone marrow (BM) stromal cell interaction on tumour cells, and vascular endothelial growth factor (VEGF)‐induced angiogenesis in the BM milieu. Moreover, Natalizumab also blocked VEGF‐ and insulin‐like growth factor 1 (IGF‐1)‐induced signalling sequelae triggering MM cell migration. In agreement with our in vitro results, Natalizumab inhibited tumour growth, VEGF secretion, and angiogenesis in a human severe combined immunodeficiency murine model of human MM in the human BM microenvironment. Importantly, Natalizumab not only blocked tumour cell adhesion, but also chemosensitized MM cells to bortezomib, in an in vitro therapeutically representative human MM‐stroma cell co‐culture system model. Our data therefore provide the rationale for the clinical evaluation of Natalizumab, preferably in combination with novel agents (e.g. bortezomib) to enhance MM cytotoxicity and improve patient outcome.