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Anti‐c‐ MET Nanobody ® – a new potential drug in multiple myeloma treatment
Author(s) -
Slørdahl Tobias Schmidt,
Denayer Tinneke,
Moen Siv Helen,
Standal Therese,
Børset Magne,
Ververken Cedric,
Rø Torstein Baade
Publication year - 2013
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12185
Subject(s) - hepatocyte growth factor , c met , autocrine signalling , chemistry , microbiology and biotechnology , protein kinase b , cancer research , phosphorylation , biology , biochemistry , receptor
Background c‐ MET is the tyrosine kinase receptor of the hepatocyte growth factor ( HGF ). HGF ‐c‐ MET signaling is involved in many human malignancies, including multiple myeloma ( MM ). Recently, multiple agents have been developed directed to interfere at different levels in HGF ‐c‐ MET signaling pathway. Nanobodies ® are therapeutic proteins based on the smallest functional fragments of heavy‐chain‐only antibodies. In this study, we wanted to determine the anticancer effect of a novel anti‐c‐ MET Nanobody in MM . Methods We examined the effects of an anti‐c‐ MET Nanobody on thymidine incorporation, migration, adhesion of MM cells, and osteoblastogenesis in vitro . Furthermore, we investigated the effects of the Nanobody on HGF ‐dependent c‐ MET signaling by Western blotting. Results We show that the anti‐c‐ MET Nanobody effectively inhibited thymidine incorporation of ANBL ‐6 MM cells via inhibition of an HGF autocrine growth loop and thymidine incorporation in INA ‐6 MM cells induced by exogenous HGF . HGF ‐induced migration and adhesion of INA ‐6 were completely and specifically blocked by the Nanobody. Furthermore, the Nanobody abolished the inhibiting effect of HGF on bone morphogenetic protein‐2‐induced alkaline phosphatase activity and the mineralization of human mesenchymal stem cells. Finally, we show that the Nanobody reduced phosphorylation of tyrosine residues in c‐ MET , MAPK , and Akt. We also compared the Nanobody with anti‐c‐ MET monoclonal antibodies and revealed the similar or better effect. Conclusions The anti‐c‐ MET Nanobody inhibited MM cell migration, thymidine incorporation, and adhesion, and blocked the HGF ‐mediated inhibition of osteoblastogenesis. The anti‐c‐ MET Nanobody might represent a novel therapeutic agent in the treatment of MM and other cancers driven by HGF ‐c‐ MET signaling.