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BI 905677: an LRP5/6 antagonist
BI 905677* is a humanised biparatopic nanobody® comprising two blocking domains for lipoprotein receptor-related proteins (LRP) 5 and 6, which are the Wnt ligand co-receptors. It binds to LRP5 and LRP6 with high affinity, thereby blocking binding of Wnt ligands to LRP5/6 and inhibiting Wnt ligand-/β-catenin-driven cancer proliferation, survival and immune escape.1,2
BI 905677 is currently undergoing investigation as a monotherapy in a Phase I trial in patients with solid tumours.3
Role of LRP5/6 and the Wnt signalling pathway
Wnt/β-catenin signalling 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 stabilised β-catenin to enter the nucleus to act as a transcriptional activator of Wnt target genes.1,4–6
Aberrant Wnt/β-catenin signalling has been shown to play a key role in tumour development. Mutations in upstream and downstream regulators of Wnt/β-catenin signalling have been identified that result in constitutively activated β-catenin and the upregulation of genes involved in tumour proliferation.6
Wnt/β-catenin signalling activation has also been shown to drive resistance to checkpoint inhibitors via inhibition of dendritic cell (DC) function and T-cell infiltration in tumours.7
BI 905677’s mechanism of action
Cancer-cell directed 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 signalling that promotes tumour cell proliferation and survival.1,2
RNF43 inactivating mutations and R-spondin3 fusion transcripts are genomic alterations known to drive ligand-dependent Wnt/β-catenin signalling activation in some solid tumours.8,9 Preclinical data have shown that BI 905677 potently and selectively blocks ligand-dependent Wnt signalling and induces tumour growth inhibition in RNF43 mutation-positive and R-spondin 3 fusion-positive tumours.1
BI 905677’s cancer cell-directed mechanism of action
LRP, lipoprotein receptor-related protein.
Immuno-modulatory mechanism of action
BI 905677 has also shown immuno-modulatory activity through induction of DC activation and T-cell infiltration in tumour tissues, leading to tumour regression when combined with an anti-programmed cell death protein-1 (PD-1) immune checkpoint inhibitor in syngeneic tumour models.1
BI 905677’s immuno-modulatory mechanism of action
LRP, lipoprotein receptor-related protein; PD-1, programmed cell death protein-1.
BI 905667 is currently undergoing clinical investigation as a monotherapy in a Phase I trial involving patients with advanced solid tumours who are not amenable to standard therapy, have failed conventional therapy, or in whom there is no therapy of proven efficacy.3
AE, adverse event; LRP, low-density lipoprotein receptor-related protein; MTD, maximum tolerated dose; PK, pharmacokinetics.
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: April 2019).
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.
*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: April 2019
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