LRP5/6 antagonist (BI 905677)

LRP5/6-antagonist (BI 905677)

BI 905677: a LRP5/6 antagonist

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

Role of LRP5/6 and Wnt signaling

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

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 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

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

Combination therapy

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

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 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

More information about Boehringer Ingelheim oncology clinical trials can be found on the MyStudyWindow website. Relevant trials for our LRP5/6 antagonist include: BI 1401-0001.

LRP5/6 antagonist (BI 905677) clinical trials

Trial number Phase Treatment Patient population Status

NCT036044453

(1401.1)

I

LRP5/6 antagonist (BI 905677)

Advanced, unresectable solid tumors

Recruiting

Trial number

I

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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: February 2021).

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.

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

© 2021 Boehringer Ingelheim International GmbH. All rights reserved.

Page last updated: March 2021