STING agonist (BI 1387466)

STING agonist (BI 1387446)

BI 1387446: a STING agonist

BI 1387446* is a small molecule that binds to the stimulator of interferon (IFN) genes (STING).1 STING functions as a DNA sensor and induces the production of IFNβ by tumor-associated stromal cells, leading to the activation of dendritic cells (DCs), thereby driving T-cell priming and recruitment into the tumor microenvironment.2,3

Clinical trials (monotherapy and combination therapy): BI 1387446 is currently being investigated in a Phase I trial as monotherapy and in combination with ezabenlimab (BI 754091)*, a programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced solid tumors.4

Role of STING

STING is a 379-amino-acid protein that is expressed in various endothelial and epithelial cell types, as well as in hematopoietic cells, such as T cells, macrophages and DCs.5 STING is part of the innate immune response to cytosolic nucleic acids and functions as a DNA sensor and signaling molecule.6 STING is essential for controlling the transcription of numerous host defence genes, including type I IFNs and pro-inflammatory cytokines, following the recognition of cyclic dinucleotides in the cytosol of the cell.5

The production of type I IFNs leads to the activation of DCs, effective cross-priming of CD8+ T cells against tumor antigens and migration of tumor-specific CD8+ T cells into the tumor.7 Thus, therapeutic strategies that activate the STING innate immune-sensing pathway to restore type I IFN signaling may have the potential to increase tumor immunogenicity – ‘heating up’ immune cold tumors that do not respond to checkpoint inhibitor therapy due to low numbers of tumor-infiltrating lymphocytes.8

About BI 1387446

Mechanism of action

BI 1387446 induces type 1 IFN (α/β) secretion in tumor-associated DCs, leading to improved cross-priming and activation of tumor-specific cytotoxic CD8+ T cells and increased CD8+ T-cell infiltration into the tumor.1

Preclinical data have shown that BI 1387446 potently and highly selectively activates the STING pathway, resulting in dose-dependent local tumor control and the induction of a tumor-specific immune response.9

Immuno-modulatory mechanism of action1,5

STING agonist mechanism of action
CDN, cyclic dinucleotide; cGAS, cyclic GMP–AMP synthase; STING, stimulator of interferon genes.

Watch the STING agonist (BI 1387446) mechanism of action animation

Watch the STING agonist (BI 1387446) mechanism of action animation

Combination therapy

In mice, administration of BI 1387466 results in a systemic anti-tumor response, which is enhanced by combination with a PD-1 inhibitor.9

Clinical development

BI 1387466 is currently undergoing clinical investigation as a monotherapy and in combination with ezabenlimab in patients with advanced solid tumors in a Phase I study.4,10

STING agonist (BI 1387446) clinical trial

Trial number Phase Treatment Patient population Status

NCT041472344 (1426.1)

I

STING agonist

(monotherapy and in combination with

ezabenlimab [BI 754091])

Advanced solid tumors

Recruiting

A Phase I, open-label, dose-escalation study of a STING agonist (BI 1387446) with or without ezabenlimab (BI 754091) in patients with advanced solid tumors (NCT04147234)4

STING agonist: NCT04147234 (1426.1)

DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; MTD, maximum tolerated dose; OR, objective response; STING, stimulator of interferon genes.

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References

1

Boehringer Ingelheim. Data on file.

2

Woo SR. Immunity 2014;41(5):830–42.

3

Foote JB, et al. Cancer Immunol Res 2017;5(6):468–79.

4

ClinicalTrials.gov. NCT04147234. https://clinicaltrials.gov/ct2/show/NCT04147234 (Accessed: February 2021).

5

Barber GN. Nat Rev Immunol 2015;15(12):760–70.

6

Burdette DL, Vance RE. Nature Immunol 2013;14(1):19–26.

7

Corrales L. Cell Rep 2015;11(7):1018–30.

8

Jing W. J Immunother Cancer 2019;7(1):115

9

Gremel G, et al. Cancer Res 2020;80(16 Suppl.): Abstract 4522.

10

Harrington K, et al. J Immunother Cancer 2020;8(3): Abstract 408.

*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: March 2021