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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

Combination clinical trials: BI 754111 is currently being investigated in combination with the programmed death-1 (PD-1)-targeting mAb BI 754091* in Phase I and II trials in patients with solid tumours.3–6

The 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.7

LAG-3 is an immune checkpoint receptor located on the surface of T cells in the tumour microenvironment,7  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.2,7,8 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.7,9 Preclinical studies suggest that LAG-3 inhibition allows T cells to regain their cytotoxic function and inhibit tumour growth.10

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.2,4,11

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

 

Combination PD-L1 and LAG-3 inhibitor: mechanism of action1

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 three Phase I studies involving patients with solid tumours3,4 non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinomas (HNSCC),5  and in one Phase II trial involving patients with solid tumours.6

 

Solid tumours

PD-1 Inhibitor in combination with LAG-3

NSCLC and HNSCC

image

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: September 2019).

4

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

5

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

6

ClinicalTrials.gov. NCT03697304. https://clinicaltrials.gov/ct2/show/NCT03468426 (Accessed: September 2019).

7

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

8

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

9

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

10

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

11

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: September 2019