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InOncology.com

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 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 action6

LRP5/6 antagonist 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 action7

LRP5/6 antagonist immuno-modulatory mechanism of action

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

Clinical development

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

Solid tumours

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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: April 2019).

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.

*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: July 2019