Ibrutinib

Brand Name: Imbruvica

Ibrutinib is used to treat chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenström's macroglobulinemia.1

How Does Ibrutinib Work?

B cell receptor on the surface of the cell.

B cell receptor (BCR) is a protein complex found on the surface of B cell, a type of immune cell. This protein complex consists of an antigen receptor domain outside the cell connected to an activation motif inside the cell.2

Self-antigens floating around inactive B cell receptor.

B cells are constantly exposed to various antigens, which are fragments of proteins. In healthy conditions, these antigens are predominantly self-antigens derived from our own cells. Generally, the antigen receptor of BCR do not bind to self-antigens.3

Foreign antigens bound to B cell receptor, which is activated.

Pathogens like bacteria, and many types of cancer, produce antigens that are unlike ones found normally in our body. BCR recognizes and binds to these foreign antigens, which results in the activation of B cells to mobilize an immune response against these threats.4

Activated BCR activates BTK.

Mechanistically, activated BCR leads to the conversion of a protein called BTK from its inactive to active form.5

Tyrosine kinase uses ATP to attach a phosphate tag on other proteins in a process called phosphorylation. This results in the transmission of growth signals.

BTK is a type of protein called tyrosine kinase, which transmits cellular growth signals through a process called phosphorylation.5 In this process, tyrosine kinase attaches a phosphate tag, derived from a molecule called ATP, to another protein.

Active BTK phosphorylates other proteins to transmit growth signals.

Likewise, BCR-activated BTK proceeds to phosphorylate other proteins to transmit growth signals, which results in the proliferation of B cells.5 Of note, because the activation of BTK requires the binding of foreign antigens to BCR, growth signals transmitted by BTK is controllable; when foreign antigens are no longer present, BCR and BTK returns to their inactive state.

Normal receptors bind foreign antigens. Malignant receptors bind self-antigens.

However, in some types of cancer that develop from B cells, malignant BCR that recognizes self-antigen is expressed.6,7

BTK is constitutively active in cancer cells with malignant BCR.

Because self-antigens are ubiquitous, malignant BCR is constitutively active. As a result BTK in these cancer cells are constitutively active as well.8

Uncontrolled phosphorylation by BTK leads to transmission of oncogenic growth signal.

Uncontrolled phosphorylation by BTK leads to an oncogenic growth signal that drives the growth of these cancer cells.8

Ibrutinib blocks the ATP-binding site of BTK and stops growth signal transmission.

Ibrutinib is a type of drug called kinase inhibitors. It blocks the kinase domain of BTK from accessing the ATP required for phosphorylation.9 This turns off the growth signal, and as a result, cancer growth is halted.

References

1. IMBRUVICA - Label. U.S. Food and Drug Administration (2023).

2. Hombach, J., Tsubata, T., Leclercq, L., Stappert, H. & Reth, M. Molecular components of the B-cell antigen receptor complex of the IgM class. Nature 343, 760-762 (1990).

3. Hartley, S. B. et al. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353, 765-769 (1991).

4. Kwak, K., Akkaya, M. & Pierce, S. K. B cell signaling in context. Nature Immunology 20, 963-969 (2019).

5. Qiu, Y. & Kung, H. Signaling network of the Btk family kinases. Oncogene 19, 5651-5661 (2000).

6. Dühren-von Minden, M. et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 489, 309-312 (2012).

7. Young, R. M., Wu, T., Schmitz, R. & Staudt, L. M. Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. Proceedings of the National Academy of Sciences of the United States of America 112, 13447-13454 (2015).

8. Burger, J. A. & Wiestner, A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nature Reviews Cancer 18, 148-167 (2018).

9. Pan, Z. et al. Discovery of Selective Irreversible Inhibitors for Bruton's Tyrosine Kinase. ChemMedChem 2, 58-61 (2007).