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InOncology.com

SMAC mimetic

BI 891065: A pro-apoptotic protein mimetic

BI 891065* is a second mitochondria-derived activator of caspase (SMAC) mimetic, which works by sensitising tumours to immunogenic cell death.1 It is currently undergoing clinical investigation in patients with solid tumours, including a monotherapy dose-escalation phase and in combination with the investigational programmed death-1 (PD-1) inhibitor BI 754091.*2

The role of SMAC

SMAC is a pro-apoptotic mitochondrial protein that is released into the cytosol in response to cellular stress.3

Tumour cells have evolved a variety of strategies to limit or circumvent apoptosis. Inhibitor of apoptosis (IAP) proteins are often overexpressed in cancer cell lines and their overexpression in several cancers is correlated with poor prognosis.4

SMAC binds directly to some members of the IAP family, and induces the degradation of other IAPs, both of which remove IAPs’ block on caspase-mediated cell death pathways.3

Nonclinical studies have demonstrated the anti-tumour activity of SMAC mimetics as single agents in human malignancies; however, they also suggest that the promise of SMAC mimetics may primarily reside in rational drug combinations in order to exploit synergistic lethalities.3,5,6

About BI 891065

Mechanism of action

BI 891065* is a potent SMAC mimetic with selectivity for cellular (cIAP) 1.1,2,6 In preclinical models, the SMAC mimetic BI 891065 triggers tumour cell death by degrading cIAP1. The loss of intracellular cIAP1 in the tumour cell results in activation of NF-kB signalling, stimulating NF-kB responsive genes, including tumour necrosis factor alpha (TNFα).4,6 BI 891065 also upregulates other cell death stimuli, such as Fas ligand (FasL) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL).6 These altered signalling events result in caspase-8 mediated apoptosis.3

Subsequently, the dying tumour cell releases damage-associated molecular patterns (DAMPs) and tumour antigens. The immunogenic tumour cell death induced by BI 891065 marks the first step in a set of events resulting in an anticancer immune response, a process known as the ‘first punch’.1,4,6

Preclinical models have also shown that BI 891065 directly leads to the maturation of dendritic cells in the lymph nodes surrounding the tumour, which take up and (cross-) present tumour-derived antigens. This promotes the activation and proliferation of tumour-specific T cells in the tumour microenvironment.3,6 This effect is augmented by exposure to DAMPs that have been released by dying tumour cells.6

In addition, preclinical experiments have shown that the activation of dendritic cells by administration of BI 891065 increases numbers of CD8-positive T cells within the tumour microenvironment; as in many tumours, these T cells express high levels of PD-1, indicative of functional exhaustion and an inability to suppress tumour growth.4,6 Combination with PD-1-targeted monoclonal antibody therapy has been shown to block the signalling via the PD-1 pathway and to re-activate this stalled immune response, leading to potent CD8-positive T cell-mediated tumour cell death. This is known as the ‘second punch’.1,6

Closing the cancer/immune cycle causes more DAMPs and tumour antigens to be released into the draining lymph nodes. This potentially leads to multiple iterative rounds of the cycle, and to further eradication of the tumour.6,7

Mechanism of action of SMAC mimetic in combination with a PD-1 inhibitor

Clinical Development

Preclinical data have shown tumour regression in mouse tumour models treated with SMAC mimetics and a PD-1 inhibitor.6

BI 891065 is currently being investigated in combination with the PD-1 inhibitor BI 754091 in a Phase I study in patients with solid tumours.2

Solid tumours

image

DLT, dose-limiting toxicity; DoR, duration of response; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; OR, objective response; PD-1, programmed cell death protein-1; PK/PD, pharmacokinetics/pharmacodynamics; SMAC, second mitochondria-derived activator of caspase.

References

1

Beug ST, et al. Nat Commun 2017;8:14278.

2

ClinicalTrials.gov. NCT03166631. https://clinicaltrials.gov/ct2/show/NCT03166631 (Accessed: August 2018).

3

Bai L, et al. Pharmacol Ther 2014;144(1):82–95.

4

Hargadon KM. Front Immunol 2013;4:192.

5

Wang C, Youle RJ. Annu Rev Genet 2009;43:95–118.

6

Impagnatiello MA, et al. Cancer Res 2017;77(Suppl. 13):2330.

7

Chen DS, Mellman I. Immunity 2013;39(1):1–10.

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

 

© 2018 Boehringer Ingelheim International GmbH. All rights reserved.

Last updated: October 2018