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LAG-3 inhibitor (BI 754111)

BI 754111: a lymphocyte-activation gene 3 targeting monoclonal antibody

BI 754111* is a humanised lymphocyte-activation gene 3 (LAG-3) targeting monoclonal antibody (mAb) that inhibits the interaction between LAG-3 and its ligand major histocompatibility complex (MHC) class II.1 This reduces immune cell exhaustion, allowing T cells to continue to destroy tumour cells.2

Clinical trials (monotherapy and combination therapy): BI 754111 is currently being investigated as a monotherapy in patients with solid tumours.3 Trials of BI 754111 in combination with the programmed death-1 (PD-1)-targeting mAb BI 754091* as well as in combination with both BI 754091 and BI 907828* (a murine double minute 2 [MDM2]-p53 antagonist) are also ongoing.3‒7

Role of LAG-3

MHC class II molecules on the surface of tumours present antigens that are recognised by T-cell receptors, initiating a signalling pathway that promotes an adaptive immune response to the tumour.8

LAG-3 is an immune checkpoint receptor located on the surface of T cells in the tumour microenvironment,8  which binds to the MHC class II molecules in the presence of antigens. The binding causes a signalling cascade that contributes to immune cell exhaustion, a state in which T cells can no longer proliferate in response to antigen presentation, and lack cytotoxic activity.2,8,9 Immune cell exhaustion is thought to be a tumour cell escape mechanism, allowing them to avoid immune detection and destruction.2

Exhausted T cells expressing LAG-3 are known to be present at tumour sites.8,10 Preclinical studies suggest that LAG-3 inhibition allows T cells to regain their cytotoxic function and inhibit tumour growth.11

About BI 754111

Mechanism of action

BI 754111 is a humanised LAG-3-targeting mAb that inhibits the interaction between LAG-3 and its ligand, MHC class II.1 LAG-3 inhibition may be able to reduce the effects of T-cell exhaustion and restore the immune response to the tumour cell.2,4,12

Combination therapy

Preclinical studies have demonstrated that sustained expression of LAG-3 and PD-1 on tumour-invading CD4 and CD8 T cells dampens the immune response to tumour cells.2 Combined targeting of PD-1 and LAG-3 may, therefore, have a synergistic effect, reactivating the T-cell response in the tumour microenvironment.1,2

 

Mechanism of action: dual PD-1 and LAG-3 immune checkpoint inhibition1

LAG-3 inhibitor mechanism of action

APC, antigen-presenting cell; LAG-3, lymphocyte activation gene-3, PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; TCR, T cell receptor

Clinical development

BI 754111 is currently being investigated in combination with the PD-1 inhibitor BI 754091 in patients with solid tumours,3─5 non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinomas (HNSCC).6  BI 754111 is also being investigated in combination with both BI 754091 and BI 907828 in patients with solid tumours.7

 

Solid tumours

Clinical trials of a PD-1 inhibitor in combination with a LAG-3 inhibitor in patients with solid tumours

NSCLC and HNSCC

Clinical trials of a PD-1 inhibitor in combination with a LAG-3 inhibitor in patients with NSCLC or HNSCC

DC, disease control; DLT, dose-limiting toxicity; DoR, duration of response; LAG-3, lymphocyte-activation gene 3; MTD, maximum tolerated dose; OR, objective response; PD-1, programmed cell death protein-1; PFS, progression-free survival; PK, pharmacokinetics; PK/PD, pharmacokinetics/pharmacodynamics; 89Zr, isotope of zirconium.

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References

1

Zettl M, et al. Annual Meeting of the American Association for Cancer Research 2018; Abstract 4547.

2

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

3

ClinicalTrials.gov. NCT03156114. https://clinicaltrials.gov/ct2/show/NCT03156114 (Accessed: November 2019).

4

ClinicalTrials.gov. NCT03433898. https://clinicaltrials.gov/ct2/show/NCT03433898 (Accessed: November 2019).

5

ClinicalTrials.gov. NCT03697304. https://clinicaltrials.gov/ct2/show/NCT03697304 (Accessed: November 2019).

6

ClinicalTrials.gov. NCT03780725. https://clinicaltrials.gov/ct2/show/NCT03780725 (Accessed: November 2019).

7

ClinicalTrials.gov. NCT03964233. https://clinicaltrials.gov/ct2/show/NCT03964233 (Accessed: November 2019)

8

Turnis ME, et al. Eur J Immunol 2015;45(7):1892–905.

9

Maçon-Lemaître L, Triebel F. Immunology 2005;115(2):170–8.

10

Huang CT, et al. Immunity 2004;21(4):503–13.

11

Camisaschi C, et al. J Immunol 2010;184(11):6545–51.

12

Grosso JF, et al. J Clin Invest 2007;117(11):3383–92.

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

© 2019 Boehringer Ingelheim International GmbH. All rights reserved.

Page last updated: November 2019