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InOncology.com

BI 754091

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BI 754091* is a programmed death-1 (PD-1) monoclonal antibody (mAb) that allows immune cells to remain active in combatting tumour cells. It is currently being investigated in Phase I trials in solid tumours as a monotherapy1 and in combination with BI 8910652* (SMAC mimetic) and  BI 7541113* (LAG3 mAb) are also in preparation.

About BI 754091

BI 754091’s mechanism of action

BI 754091 is a PD-1 monoclonal antibody (mAb) that binds to the PD-1 receptor, found on T-cells, B-cells, monocytes and natural killer (NK) cells, thereby blocking activation of downstream signalling and a tumour escape pathway. Activation of the PD-1 pathway inhibits T-cell immune response and downregulates the expression of proinflammatory cytokines and anti-apoptotic molecules.4

PD-1 mAb mechanism of action

The role of PD-1

PD-1 is a cell surface receptor that is activated by inflammatory signals limiting the scale and duration of an inflammatory response. The PD-1 surface protein is a transmembrane immunoglobulin that 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 and downregulates expression of specific anti-apoptotic molecules to limit T cell function and prevent immune mediated damage to healthy cells and tissues.4

Tumour cells need to avoid apoptotic destruction by host immune surveillance. One mechanism tumour cells use to do this is to upregulate PD-L1 expression which leads to inactivation of the PD-1-expressing T-cells and allows tumours to escape immune-mediated destruction.4,5 Previous experimental studies and clinical trials have shown that immunotherapeutic approaches using antagonistic antibodies to block checkpoint pathways can release cancer inhibition and facilitate antitumor activity to treat cancers.5

Clinical development

There are three clinical trials currently investigating BI 754091 in solid tumour, as a monotherapy1 and in combination with BI 891065 and BI 754111, mAbs that target immune-response pathways.

BI 891065 is a novel second mitochondria-derived activator of caspases (SMAC) mimetic, which sensitises tumours to cell death by extrinsic death ligands and blocks pro-survival signalling.6 BI 754111 is an anti-lymphocyte activation gene-3 (LAG3) mAb, which ensures appropriate T cell homeostasis.7 Preclinical data have shown tumour regression in mouse tumour models treated with SMAC mimetics and a PD-1 inhibitor,8 and other preclinical studies have shown a synergistic effect between the PD-1 and LAG3 pathways.7,9,10

Solid tumours

BI 754091 is currently being investigated as monotherapy and combination therapy in solid tumours.1-3

BI 754091 solid tumour trials

AE, adverse event; CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; OR, objective response; PFS, progression-free survival; PK/PD, pharmacokinetics; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors.

 

§Patients with multiple myeloma and NSCLC.

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References

1

ClinicalTrials.gov. NCT02952248.  https://clinicaltrials.gov/ct2/show/NCT02952248. Accessed: July 2017.

2

ClinicalTrials.gov. NCT03166631.  https://clinicaltrials.gov/ct2/show/NCT03166631. Accessed: July 2017.

3

ClinicalTrials.gov. NCT03156114.  https://clinicaltrials.gov/ct2/show/NCT03156114. Accessed: July 2017.

4

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

5

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

6

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

7

Woo SR, et al. Cancer Res 2012;72(4):917-27.

8

Impagnatiello MA, et al. Poster presented at AACR Annual Meeting 2017;Abstract 2330.

9

Huang RY, et al. Oncotarget 2015;6(29):27359-77.

10

Andrews LP, et al. Immunol Rev 2017;276(1):80-96.

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