I am a Healthcare Professional outside the US and UK

I am a Healthcare Professional outside the US and UK

Click here for international medical scientific information about Oncology for Healthcare Professionals.

I am not a Healthcare Professional and I am outside the US and the UK

I am not a Healthcare Professional and I am outside the US and the UK

Click here for general international information for patients, caregivers and the general public.

Country-specific medical scientific information

Country-specific medical scientific information

Country-specific medical scientific information for Healthcare Professionals.

This site uses cookies to improve your browsing experience. By using this site, you agree to their use. Cookie Information

InOncology.com

LAG-3 inhibitor

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 BI 754111 is currently being investigated in combination with the programmed death-1 (PD-1)-targeting mAb BI 754091* in Phase I trials in solid tumours.3,4

The role of LAG-3

LAG-3 is an immune checkpoint receptor located on the surface of T cells in the tumour microenvironment.5

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.5

In the presence of antigens, LAG-3 binds to the MHC Class II molecule on the tumour cell, starting a signalling cascade that reduces T-cell activation and proliferation.5

Preclinical studies suggest that the expression of LAG-3 on T cells and binding to its ligand MHC II within the tumour microenvironment contributes to immune cell exhaustion, a state in which T cells can no longer proliferate in response to antigen presentation, and lack cytotoxic activity.2,5,6 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.5,7 Preclinical studies suggest that LAG-3 inhibition allows T cells to regain their cytotoxic function and inhibit tumour growth.8

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 II.1 LAG-3 inhibition may be able to reduce the effects of T-cell exhaustion, such as impaired immune cell proliferation and cytokine production, and restore the immune response to the tumour cell.2,4,9

Preclinical studies have demonstrated that the sustained co-expression of LAG-3 and PD-1 on tumour-invading CD4 and CD8 T cells dampens the immune response to tumour cells.2 Rationally designed synergistic combination therapies, such as the dual blockade of PD-1 and LAG-3, should enhance anti-tumour activity compared with immune checkpoint inhibitor monotherapy.1,2

LAG-3 inhibitor mechanism of action

Clinical development

BI 754111 is currently being investigated in combination with the PD-1 inhibitor BI 754091 in two Phase I studies in solid tumours.3,4

Solid tumours

image

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.

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: August 2018).

4

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

5

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

6

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

7

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

8

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

9

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

Did you find this information useful?

*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