About Potential of BTK Inhibitors

B Cell Receptor (BCR) signaling pathway overview

BCR is a transmembrane protein complex that controls B cell maturation, survival, apoptosis, and the production of plasma cell antibodies starting from the expression form of pro-BCR and pre-BCR.

BCR signaling is connected by a network of kinases and phosphatases, and its pathways can be divided into two types: chronically activated BCR and tetanic BCR. Chronically activated BCR is an antigen-dependent process, mainly using NF-kB and MAPK/ERK pathways. Tetanic BCR is antigen-independent and maintains the survival of B cells through PI3K/AKT pathways.

BTK, a non-receptor intracellular kinase, belongs to the TEC family of tyrosine kinases and is an important part of the BCR signaling pathway. BTK protein consists of 659 amino acids and 5 domains (PH, TH, SH3, SH2, kinase domain), among which Y223 of the SH3 domain and Y551 of the kinase domain are two key tyrosine phosphorylation sites.

types of BTK inhibitors and their binding sites
Covalent BTK inhibitors can irreversibly bind to C481 residues in the kinase domain. Non-covalent BTK inhibitors do not bind to C481 but inhibit BTK by binding with reversible non-covalent bonds, such as Fenebrutinib forming hydrogen bonds with K430, M477, and D539 residues.

It has been shown that BTK can transmit and enhance various cellular surface molecular signals that communicate with TME. In addition, BTK is related to a variety of infections, including COVID-19, myocardial infarction, Alzheimer’s disease, and arteriosclerosis.

Advances in next-generation BTKi

First-generation BTKi
structure of Ibrutinib
Developed by Johnson & Johnson and AbbVie’s Pharmacyclics LLC, Ibrutinib is a first-generation covalent irreversible BTK inhibitor that inhibits B cell proliferation by irreverently binding to C481 and blocking the BCR signaling pathway. In addition, Ibrutinib can bind to other kinases, including ITK, TEC, EGFR, ErbB2, ErbB4, BMX, JAK3, and HER2. Off-target inhibition of these kinases causes a variety of adverse events, usually leading to the discontinuation of Ibrutinib.

Second-generation BTKi
Second-generation BTK inhibitors are covalent to C481 as well. But covalent inhibitor therapy often brings relapse or disease progression, which is usually related to acquired resistance, mainly in MCL and CLL/SLL patients. The most common resistance is caused by a Cys-481 residue mutation, which disrupts the binding of the covalent inhibitor to Cys-481 and weakens the inhibitory effect.

Currently approved Acalabrutinib, Zanubrutinib, Ocrelabrutinib, and Tirabrutinib are all new-generation covalent BTK inhibitors that show higher selectivity and fewer off-target effects than Ibrutinib, thus significantly limiting the occurrence of adverse events.

Third-generation BTKi
Third-generation non-covalent inhibitors do not depend on binding with Cys-481, have better inhibition on Cys-481 mutant BTK, and also show better safety. For instance, Fenebrutinib does not inhibit EGFR or ITK, therefore, it can greatly reduce diarrhea and rash caused by EGFR inhibition and retain the NK cell-mediated ADCC.

Non-covalent inhibitors such as Pirtobrutinib, Nemtabrutinib, and Fenebrutinib (GDC-0853) have better safety and efficacy than covalent inhibitors.

Applications of BTK inhibitors in broad disease areas

Tumor
At present, BTK is mainly applied in the field of B-cell lymphoma (BCL), including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM).

Autoimmunity
B cells have different roles in autoimmunity, including cytokine and autoantibody production and interaction with T cells. Autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS) involve B-cell dysfunction. There is ample evidence that BTK is an important driver of B-cell T-cell interaction, promoting autoimmunity.

The first evidence of a protective effect of BTK inhibition on autoimmunity came from animal studies, which observed that inhibition of BTK reduced the disease symptoms, while overexpression of transgenic BTK induced systemic autoimmunity in mice.

But high-potency BTKi (such as Ibrutinib and Acalabrutinib) has limited selectivity, resulting in off-target activity and serious side effects. This may be acceptable in cancer treatment given the severity of the disease and the limited time window for treatment. However, it limits the use of BTKi in the chronic treatment of autoimmune diseases.

In view of the role of BTK in autoimmunity, some BTKi with higher selectivity and lower off-target related adverse reactions are being tested for the treatment of autoimmune diseases. Roche’s non-covalent Fenebrutinib has begun to seek applications in the field of autoimmunity, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS).

COVID – 19
The effect of BTKi on BCL and COVID-19 patients is also under clinical study. Research has shown that an 81-year-old WM and COVID-19 patient needs non-invasive ventilation in ICU once Ibrutinib is discontinued, and the respiratory symptoms have improved significantly after the resumption.

In addition, Acalabrutinib, Zanubrutinib, and Spebrutinib have been shown to reduce cytokine storm-mediated lung damage by inhibiting the BTK-dependent NF-κB pathway, normalizing T lymphocytes, and even acting as COVID-19 ligand with antiviral effects.

When the novel coronavirus enters the respiratory tract and causes infection, alveolar macrophages may engulf viral particles or cell debris. The virus’ single-stranded RNA (ssRNA) binds to TLR7/8 and then activates BTK and MYD88. Further activation of the NF-kB pathway leads to the production of a series of pro-inflammatory cytokines and chemokines, known as cytokine storms. Among them, IL-8 can recruit more neutrophils in the advanced stages of COVID-19 infection. BTKi inhibits this process, thereby preventing cytokine production.

Future directions of BTKi development

The efficacy of BTKi in anti-tumor has been verified, and a variety of combined therapies are also being explored, such as the combination with CD20 antibody, which is well tolerated and produces a long-lasting response by enhancing NK cell-induced ADCC. In addition, the combination of BTKi with CD19 CAR-T cells, BiAbs, or checkpoint blocking deserves further exploration.

With respect to COVID-19, BTKi appears to inhibit cytokine storms by inhibiting monocyte/macrophage activation induced by COVID-19 and improving the survival rate for patients with CLL, which demonstrates the promising application of BTKi in diseases related to macrophage activation.

BTKi has been proven to suppress immune responses to novel antigens, suggesting that patient-appropriate vaccination should be used in patients with CLL based on disease status and previous treatment. The effects of BTKi on the immune system and potential combined therapies should be further investigated to provide clinicians with the best practice guidance for managing adverse events such as infections.

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