Effects of a novel Nodal-targeting monoclonal antibody in melanoma

Strizzi, L.; Sandomenico, A.; Margaryan, N. V.; Foca, A.; Sanguigno, L.; Bodenstine, T. M.; Chandler, G. S.; Reed, D. W.; Gilgur, A.; Seftor, E. A.; Seftor, R. E.; Khalkhali-Ellis, Z.; Leonardi, A.; Ruvo, M.; Hendrix, M. J.

Oncotarget. 2015 Oct 16; 6(33):34071-86

Abstract

Nodal is highly expressed in various human malignancies, thus supporting the rationale for exploring Nodal as a therapeutic target. Here, we describe the effects of a novel monoclonal antibody (mAb), 3D1, raised against human Nodal. In vitro treatment of C8161 human melanoma cells with 3D1 mAb shows reductions in anchorage-independent growth and vasculogenic network formation. 3D1 treated cells also show decreases of Nodal and downstream signaling molecules, P-Smad2 and P-ERK and of P-H3 and CyclinB1, with an increase in p27. Similar effects were previously reported in human breast cancer cells where Nodal expression was generally down-regulated; following 3D1 mAb treatment, both Nodal and P-H3 levels are reduced. Noteworthy is the reduced growth of human melanoma xenografts in Nude mice treated with 3D1 mAb, where immunostaining of representative tumor sections show diminished P-Smad2 expression. Similar effects both in vitro and in vivo were observed in 3D1 treated A375SM melanoma cells harboring the active BRAF(V600E) mutation compared to treatments with IgG control or a BRAF inhibitor, dabrafenib. Finally, we describe a 3D1-based ELISA for the detection of Nodal in serum samples from cancer patients. These data suggest the potential of 3D1 mAb for selecting and targeting Nodal expressing cancers.

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