Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin® protein MP0250: a preclinical study
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Luigia Rao1,*, Kim De Veirman2,*, Donato Giannico1, Ilaria Saltarella1, Vanessa Desantis1, Maria Antonia Frassanito1, Antonio Giovanni Solimando1, Domenico Ribatti3, Marcella Prete1, Andreas Harstrick4, Ulrike Fiedler4, Hendrik De Raeve5, Vito Racanelli1, Karin Vanderkerken2,* and Angelo Vacca1,*
1Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
2Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
3Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, National Cancer Institute "Giovanni Paolo II", Bari, Italy
4Molecular Partners AG, Zürich-Schlieren, Switzerland
5Department of Pathology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
*These authors contributed equally to this work
Angelo Vacca, email: email@example.com
Karin Vanderkerken, email: firstname.lastname@example.org
Keywords: multiple myeloma; angiogenesis; DARPin; dual inhibitor; syngeneic mouse model
Received: November 11, 2017 Accepted: January 25, 2018 Published: January 30, 2018
The investigational drug MP0250 is a multi-specific DARPin® molecule that simultaneously binds and neutralizes VEGF and HGF with high specificity and affinity. Here we studied the antiangiogenic effects of the MP0250 in multiple myeloma (MM). In endothelial cells (EC) isolated from bone marrow (BM) of MM patients (MMEC) MP0250 reduces VEGFR2 and cMet phosphorylation and affects their downstream signaling cascades. MP0250 influences the secretory profile of MMEC and inhibits their in vitro angiogenic activities (spontaneous and chemotactic migration, adhesion, spreading and capillarogenesis). Compared to anti-VEGF or anti-HGF neutralizing mAbs, MP0250 strongly reduces capillary network formation and vessel-sprouting in a Matrigel angiogenesis assay. MP0250 potentiates the effect of bortezomib in the same in vitro setting. It significantly reduces the number of newly formed vessels in the choriollantoic membrane assay (CAM) and the Matrigel plug assay. In the syngeneic 5T33MM tumor model, MP0250 decreases the microvessel density (MVD) and the combination MP0250/bortezomib lowers the percentage of idiotype positive cells and the serum levels of M-protein. Overall results define MP0250 as a strong antiangiogenic agent with potential as a novel combination drug for treatment of MM patients.
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