Effective inhibition of Bone Morphogenetic Protein function by highly specific llama-derived antibodies (original) (raw)

Molecular cancer therapeutics, 2015

Abstract

Bone Morphogenetic Proteins (BMPs) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, since most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here we describe the generation of three types of llama-derived heavy chain variable domains (VHHs) which selectively bind to either BMP4, to BMP2 and 4, or to BMP2,4,5 and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signalling. Epitope binning and docking modelling have shed light into the basis for their BMP-specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organo...

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