Idelalisib

Brand Name: Zydelig

Idelalisib is used to treat chronic lymphocytic leukemia1

How Does Idelalisib 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 recruits a protein called PI3Kδ to the surface of the cell and activates it.

Mechanistically, activated BCR recruits a protein called PI3Kδ to the surface of the cell and activates it.5

PI3Kδ converts PIP2 to PIP3.

PI3Kδ is an enzyme that converts a molecule found on the surface of the cell called PIP2 to PIP3, which serves as a signaling conduit to transmit growth signals within the cell.6 This conversion requires a molecule called ATP.

Without foreign antigens, PIP3 is absent on the surface of the cell and growth signal is not transmitted.

In the absence of foreign antigens, BCR and PI3Kδ, remains inactive. In this condition, PIP2 predominates on the surface of the cell and growth signal is not transmitted.6

In the presence of foreign antigens, PI3K convers PIP2 to PIP3 and growth signal is transmitted.

In the presence of foreign antigens, BCR-activated PI3Kδ converts PIP2 to PIP3. Growth signals transmitted via PIP3 results in the proliferation of B cells in reponse to foreign antigens.7 Of note, because this process requires the binding of foreign antigens to BCR, growth signals transmitted through this process is controllable; when foreign antigens are no longer present, BCR and PI3Kδ returns to their inactive state, PIP3 is no longer produced, and B cell proliferation ceases.

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

PI3Kδ is constitutively active in cancer cells with malignant BCR.

Because self-antigens are ubiquitous, malignant BCR is constitutively active. As a result PI3Kδ in these cancer cells are constitutively active as well.8

Uncontrolled production of PIP3 leads to transmission of oncogenic growth signal.

An uncontrolled production of PIP3 by PI3Kδ leads to an oncogenic growth signal that drives the growth of these cancer cells.8

Idelalisib blocks PI3Kδ from accessing ATP and growth signal is turned off.

Idelalisib is a PI3Kδ inhibitor drug. It blocks the PI3Kδ from accessing ATP required for PIP3 production.9 This turns off the growth signal, and as a result, cancer growth is halted.

References

1. ZYDELIG - Label. U.S. Food and Drug Administration (2022).

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. Srinivasan, L. et al. PI3 Kinase Signals BCR-Dependent Mature B Cell Survival. Cell 139, 573-586 (2009).

6. Okkenhaug, K. & Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nature Reviews Immunology 3, 317-330 (2003).

7. Gold, M. R. & Aebersold, R. Both phosphatidylinositol 3-kinase and phosphatidylinositol 4-kinase products are increased by antigen receptor signaling in B cells. The Journal of Immunology 152, 42-50 (1994).

8. Xu, W., Berning, P. & Lenz, G. Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma. Blood 138, 1110-1119 (2021).

9. Lannutti, B. J. et al. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 117, 591-594 (2011).