Abstract DDT01-01: BI 905677: A first-in-class LRP5/6 antagonist targeting Wnt-driven proliferation and immune escape

Abstract

Abstract Aberrant Wnt/β-catenin signalling has been shown to play a key role in tumorigenesis and resistance to immunotherapy in several tumor indications. Wnt ligand-mediated signals are transduced by two distinct receptor types, the serpentine receptor Frizzled (FZD) and the closely related single-span transmembrane proteins LRP5 and LRP6. Formation of the FZD-Wnt-LRP5/6 trimeric complex induces phosphorylation of LRP5 or LRP6 intracellular domains leading to inactivation of the β-catenin degradation complex, allowing stabilized β-catenin to enter the nucleus, bind to the TCF transcription factors, and act as a transcriptional activator of Wnt target genes. We have developed a first-in-class LRP5/6 antagonist, a bi-paratopic antibody comprising two modules binding to distinct epitopes of LRP5 (or LRP6). BI 905677 is a highly potent blocker of signalling induced by the Wnt family of ligands and shows anti-tumor activity in cancer models harbouring genomic alterations in upstream regulators of the Wnt pathway, such as RNF43 mutations or RSPO fusions. Furthermore, BI 905677 in combination with an anti-PD-1 immune checkpoint inhibitor induces dendritic cell activation and T cell infiltration in tumor tissues leading to complete responses in syngeneic tumor models. A Phase I clinical trial is underway in patients with advanced cancer to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and efficacy of BI 905677 (NCT03604445). Citation Format: Vittoria Zinzalla, Barbara Drobits-Handl, Alexander Savchenko, Jörg Rinnenthal, Markus Johann Bauer, Michael Sanderson, Sophia Maria Blake, Norbert Schweifer, Robert Gerhardus Jacob Vries, Hans Clevers, Norbert Kraut. BI 905677: A first-in-class LRP5/6 antagonist targeting Wnt-driven proliferation and immune escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr DDT01-01.