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InOncology.com

PD-1 inhibitor

BI 754091: A programmed cell death protein-1 inhibitor

BI 754091* is a humanised programmed cell death protein-1 (PD-1)-targeting monoclonal antibody (mAb) that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.1 In doing so, BI 754091 prevents the inactivation of immune cells by tumours, allowing them to remain active and combat tumour cells.1 BI 754091 is currently being investigated as a monotherapy in a Phase I trial in solid tumours.2 Trials in combination with BI 891065*3 (a second mitochondria-derived activator of caspase [SMAC] mimetic), BI 754111*4,5 (a lymphocyte activation gene 3 [LAG-3] inhibitor) and BI 836880*6 (a vascular endothelial growth factor/angiopoietin-2 growth factor [VEGF/Ang2] inhibitor) are also ongoing.

The role of PD-1

PD-1 is an inhibitory cell surface receptor that is activated by inflammatory signals. It has two known ligands, PD-L1 and PD-L2, which are both expressed on antigen-presenting cells (APCs). In normal tissues, binding of PD-L1 or PD-L2 to PD-1 inhibits T-cell receptor signalling, limiting T-cell function and preventing immune-mediated damage to healthy cells and tissues.7

Tumour cells can avoid destruction by host-immune surveillance. One mechanism that tumour cells use to avoid immune-mediated destruction is to upregulate PD-L1 expression, which leads to inactivation of PD-1-expressing T cells.7

Preclinical studies and clinical trials have shown that immunotherapeutic approaches using antibodies to block pathways, such as the PD-1 pathway, can facilitate the immune system’s antitumour activity in the treatment of cancers.8

About BI 754091

Mechanism of action

The PD-1 receptor is found on T cells, B cells, monocytes and natural killer cells. Activation of the PD-1 pathway, which occurs by the binding of PD-L1 or PD-L2, inactivates T cells and downregulates the expression of pro-inflammatory cytokines, making this a tumour escape pathway.7

BI 754091 is a humanised PD-1-targeting mAb that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.1 This blocks signalling downstream from PD-1, allowing T cells to remain active and carry out their role in the destruction of tumour cells by secreting molecules such as perforin and granzyme B.1,9

image

Clinical development

There are currently five clinical trials investigating BI 754091 in solid tumours:

  • One as a monotherapy2
  • One in combination with the SMAC mimetic BI 8910653
  • Two in combination with the LAG-3 inhibitor BI 7541114,5
  • One in combination with the VEGF/Ang2 inhibitor BI 8368806


Solid tumours and NSCLC

BI 754091 is currently being investigated as monotherapy and in combination therapy in solid tumours.2–6

image

*NSCLC cohort.

AE, adverse event; Ang2, angiopoietin -2; APC, antigen-presenting cell; DLT, dose-limiting toxicity; DoR, duration of response; LAG-3, a lymphocyte activation gene 3; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; OR, objective response; PD-1, programmed death-1 receptor; PD-L1, programmed death-1 receptor ligand; PFS, progression-free survival; PK/PD, pharmacokinetics/pharmacodynamics; SMAC, second mitochondria-derived activator of caspase; VEGF, vascular endothelial growth factor.

References

1
  1. Zettl M, et al. Poster presented at AACR Annual Meeting 2018; Abstract 4558.
2

ClinicalTrials.gov. NCT02952248. https://clinicaltrials.gov/ct2/show/NCT02952248 (Accessed: September 2018).

3

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

4

ClinicalTrials.gov. NCT03156114. https://clinicaltrials.gov/ct2/show/NCT03156114 (Accessed: September 2018).

5

ClinicalTrials.gov. NCT03433898. https://clinicaltrials.gov/ct2/show/NCT03433898 (Accessed: September 2018).

6

ClinicalTrials.gov. NCT03468426. https://clinicaltrials.gov/ct2/show/NCT03468426 (Accessed: September 2018).

7

McDermott DF, et al. Cancer Med 2013;2(5):662–73.

8

He J, et al. Sci Rep 2015;5:13110.

9

Martinez-Lostao L, et al. Clin Cancer Res 2015;21(22):5047–56.

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*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