BI 905677* is a humanized biparatopic nanobody® comprising two blocking domains for lipoprotein receptor-related proteins (LRP) 5 and 6, which are co-receptors for Frizzled, the Wnt ligand receptor. BI 905677 binds to LRP5 and LRP6 with high affinity, thereby blocking the binding of Wnt to LRP5/6 and Frizzled, and inhibiting Wnt ligand-/β-catenin-driven cancer proliferation, survival and immune escape.1,2
The related compound BI 905681*, an LRP5 antagonist, is also undergoing clinical investigation.
Clinical trials (monotherapy): BI 905677 is currently undergoing investigation as a monotherapy in a Phase I trial in patients with solid tumors.3
Wnt/β-catenin signaling has been shown to play a key role in tumorigenesis4–6 and resistance to immunotherapy.7 Wnt ligand-mediated signals are transduced by the serpentine receptor Frizzled (Fzd), and are closely related to single-span transmembrane proteins LRP5 and LRP6.4,5 This trimeric complex of Fzd-Wnt-LRP5/6 blocks the degradation of β-catenin and allows stabilized β-catenin to enter the nucleus to act as a transcriptional activator of Wnt target genes.1,4–6
Aberrant Wnt/β-catenin signaling has been shown to play a key role in tumor development. Mutations in upstream and downstream regulators of Wnt/β-catenin signaling have been identified that result in constitutively activated β-catenin and the upregulation of genes involved in tumor proliferation.6
Wnt/β-catenin signaling activation has also been shown to drive resistance to checkpoint inhibitors via inhibition of dendritic cell (DC) function and T-cell infiltration in tumors.7
Mechanism of action
BI 905677 binds to LRP5/6 with high affinity, preventing the binding of Wnt ligands to LRP5/6 and blocking Wnt/β-catenin signaling that promotes tumor cell proliferation and survival.1,2
RNF43 inactivating mutations and R-spondin 3 fusion transcripts are genomic alterations that are known to drive ligand-dependent Wnt/β-catenin signaling activation in some solid tumors.8,9 Preclinical data have shown that BI 905677 potently and selectively blocks ligand-dependent Wnt signaling and induces tumor growth inhibition in RNF43 mutation-positive and R-spondin 3 fusion-positive tumors.1
BI 905677 has also shown immuno-modulatory activity through induction of DC activation and T-cell infiltration in tumor tissues, leading to tumor regression when combined with an anti-programmed cell death protein-1 (PD-1) immune checkpoint inhibitor in syngeneic tumor models.1
BI 905667 is currently undergoing clinical investigation as a monotherapy in patients with advanced solid tumors who have failed on, or are not amenable to, conventional therapy, or for whom there is no therapy of proven efficacy.3
|Trial number||Phase||Treatment||Patient population||Status|
LRP5/6 antagonist (BI 905677)
Advanced, unresectable solid tumors
Zinzalla V, et al. Oral presentation at AACR-2019 (Abstract DDT01-01).
Fuerer C, et al. EMBO Reports 2008;9:134–8.
ClinicalTrials.gov. NCT03604445. http://clinicaltrials.gov/ct2/show/NCT03604445 (Accessed: February 2021).
Dahlmann M, et al. Cancers (Basel) 2016;8(6):pii:E59.
MacDonald BT, et al. Dev Cell 2009;17(1):9–26.
Zhan T, et al. Oncogene 2017;36(11):1461–73.
Spranger S, et al. Nature 2015: 523(7559):231–5
Giannakis M, et al. Nat Genet. 2014;46(12):1264.
Seshagiri S, et al. Nature. 2012 Aug 30;488(7413):660-4.
Boehringer Ingelheim. Data on file.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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Page last updated: March 2021
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