Abstract IA13: Inhibiting the Wnt pathway with selective anti-Frizzled synthetic antibodies

Secreted Wnt glycoproteins regulate intracellular signaling pathways important for embryonic development and adult tissue homeostasis. Misregulation of Wnt signalling is frequent in human cancers. Wnt ligands are recognized at the surface of cells by various receptor complexes that are differentially expressed and determine context-dependent cellular responses. In humans, 16 Wnt ligands interact directly with 10 Frizzled seven transmembrane proteins through their extracellular cysteine rich domain (CRD). Wnts also interact with various co-receptors, such as LRP5/6, ROR1/2, RYK, PTK7, which engage different downstream signaling pathways. While genetic analysis of mouse knockouts has revealed specific roles for different Wnt receptors and co-receptors during embryonic development, relatively little is known about their respective functions during adult tissue homeostasis or in the initiation and progression of human diseases such as cancer. There is a paucity of reagents allowing the selective and temporal pharmacological inhibition of Wnt receptors. We are employing phage-display technology to identify high affinity synthetic blocking monoclonal antibodies (mAbs) against all human Wnt receptors. To date we have isolated a collection of anti-receptor antibodies exhibiting unique selectivity and functionality profiles. Our lead anti-Frizzled mAbs targeting a subset of Frizzled proteins inhibit Wnt-promoted activation of the TopFlash reporter with low nanomolar potency. These mAb...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Signaling Pathways: Wnt: Oral Presentations - Invited Abstracts Source Type: research