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LRP5/6 antagonist (BI 905677)

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 co-receptors for Frizzled, the Wnt ligand receptor. BI 905677 binds to LRP5 and LRP6 with high affinity, thereby blocking the binding of Wnt ligands to LRP5/6 and Frizzled, and inhibiting Wnt ligand-/β-catenin-driven cancer proliferation, survival and immune escape.1,2

Clinical trials: 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

About BI 905677

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-spondin 3 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

Cancer cell-directed mechanism of action6

LRP5/6 antagonist cancer-cell directed mechanism of action

LRP, lipoprotein receptor-related protein

Watch the LRP5/6 antagonist mechanism of action animation

Watch the LRP5/6 antagonist mechanism of action animation

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Combination therapy

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

Immuno-modulatory mechanism of action7

LRP5/6 antagonist immuno-modulatory mechanism of action

LRP, lipoprotein receptor-related protein; PD-1, programmed cell death protein-1

BI 905681: a LRP5 antagonist

BI 905681 is a monotargeting LRP5 antagonist that blocks the binding of Wnt ligands to LRP5, thereby inhibiting Wnt ligand-/β-catenin-driven tumour cell proliferation and survival.2,10

Clinical development

BI 905667 and BI 905681 are currently undergoing clinical investigation as monotherapy in patients with advanced solid tumours who have failed on, or are not amenable to, conventional therapy, or for whom there is no therapy of proven efficacy.3,11

Solid tumours

Clinical trials of LRP5/6 and LRP5 antagonists in patients with solid tumours

AE, adverse event; LRP, low-density lipoprotein receptor-related protein; MTD, maximum tolerated dose; PK, pharmacokinetics.

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References

1

Zinzalla V, et al. Oral presentation at AACR-2019 (Abstract DDT01-01).

2

Fuerer C, et al. EMBO Reports 2008;9:134–8.

3

ClinicalTrials.gov. NCT03604445. http://clinicaltrials.gov/ct2/show/NCT03604445 (Accessed: January 2020).

4

Dahlmann M, et al. Cancers (Basel) 2016;8(6):pii:E59.

5

MacDonald BT, et al. Dev Cell 2009;17(1):9–26.

6

Zhan T, et al. Oncogene 2017;36(11):1461–73.

7

Spranger S, et al. Nature 2015: 523(7559):231–5

8

Giannakis M, et al. Nat Genet. 2014;46(12):1264.

9

Seshagiri S, et al. Nature. 2012 Aug 30;488(7413):660-4.

10

Boehringer Ingelheim. Data on file.

11

ClinicalTrials.gov. NCT04147247. http://clinicaltrials.gov/ct2/show/NCT04147247 (Accessed: January 2020).

*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: January 2020