Wnt Signaling (LRP5/6 antagonist)

Wnt Signaling (LRP5/6 antagonist)

LRP5/6-antagonist (BI 905677)

BI 905677: Blocking Wnt Signaling (LRP5/6 antagonist)

BI 905677* is a humanized biparatopic nanobody® comprising two blocking domains for lipoprotein receptor-related proteins (LRP) 5 and 6. BI 905677 binds to LRP5 and LRP6 with high affinity, and prevents them from activating the Wnt signaling pathway that drives cancer proliferation, survival and immune escape.1,2

Clinical trials (monotherapy): BI 905677 is currently undergoing investigation as a monotherapy in a Phase I trial in patients with advanced solid tumors.3

Role of LRP5/6 and Wnt signaling

Wnt/β-catenin signaling activation was shown to drive resistance to checkpoint inhibitors through loss of DC function and T cell exclusion, which is blocked by BI 905677. This inhibits Wnt ligand/β-catenin-driven tumor cell proliferation and survival.2,4

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.7,8 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 action5

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 action8

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 Wnt Signaling (LRP5/6 antagonist) include: BI 1401-0001.

Wnt Signaling (LRP5/6 antagonist) (BI 905677) clinical trials

Trial number Phase Treatment Patient population Status

NCT036044453 (1401.1)

I

Wnt Signaling (LRP5/6 antagonist) [BI 905677]

Advanced, unresectable, and/or metastatic solid tumors

Recruiting

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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: September 2021).

4

Boehringer Ingelheim. Data on file.

5

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

6

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

7

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

8

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: September 2021