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InOncology.com

SMAC mimetic (BI 891065)

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 in combination with the investigational programmed death-1 (PD-1) inhibitor BI 754091.*2

The role of SMAC

Inhibitor of apoptosis (IAP) proteins are often overexpressed in cancer cell lines and their overexpression in several cancers is correlated with poor prognosis.3

SMAC, a pro-apoptotic mitochondrial protein that is released into the cytosol in response to cellular stress, binds directly to some members of the IAP family, and induces the degradation of other IAPs.4

Preclinical studies have demonstrated the antitumour activity of SMAC mimetics as single agents in human malignancies, and suggest potential synergistic value of their use in combination, for example, with immunotherapy.4–6

BI 891065’s mechanism of action

BI 891065* is a potent SMAC mimetic with selectivity for cellular IAP (cIAP) 1.1,2,6 In preclinical models, BI 891065 has been shown to trigger tumour cell death by degrading cIAP1. The loss of intracellular cIAP1 in the tumour cell results in activation of NF-kB signalling, which stimulates NF-kB responsive genes such as 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 and immunogenic tumour cell death,4 the first step in a set of events resulting in an anticancer immune response, a process known as the ‘First Punch’.1,3,6

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,4,6 an effect that is augmented by exposure to damage-associated molecular patterns (DAMPs) released by dying tumour cells.6

These T cells in the tumour microenvironment have been shown to express high levels of PD-1 and often exhibit an ‘exhausted’ phenotype, with an inability to control tumour growth.3,6 Using BI 891065 in combination with BI 754091, which blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, has the potential to re-activate this stalled immune response, leading to potent CD8-positive T-cell mediated eradication of tumour cells: the ‘Second Punch’ of the immune response.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

Combination PD-1 inhibitor and SMAC mimetic: mechanism of action

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 involving patients with solid tumours (dose escalation phase), and in non-small cell lung cancer (NSCLC) and other solid tumours (dose expansion phase).2

 Solid tumours and NSCLC

image

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

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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

Hargadon KM. Front Immunol 2013;4:192.

4

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

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.

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PAge last updated: May 2019