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BTK is widely involved in B cell activation, proliferation, and survival; it also participates in FcR, cytokines, chemokines and other signaling pathways, and is a key kinase for B cells and immune regulation
.
BTK inhibitors (BTKi) have been on the market with a variety of drugs in the field of tumor treatment
.
Among the first-generation BTK inhibitors, Ibrutinib has achieved sales of more than US$9 billion worldwide
.
Second-generation inhibitors with higher specificity and lower side effects and even siRNA drugs are also under development.
BeiGene's zanubrutinib is listed in China and the United States
.
Some BTK inhibitors (Cancers 2021, 13, 1103.
) BTK has received widespread attention in the field of autoimmune diseases, inflammatory diseases, and even new coronary pneumonia in recent years.
This article will briefly review
.
1.
BTK deficiency in experimental mice with rheumatoid arthritis (RA) has a protective effect in some autoimmune arthritis models
.
The protection is largely due to its role in B cells
.
In animal studies, BTKi improves B-cell dependent/B-cell independent myeloid-mediated arthritis
.
In rheumatoid arthritis, the dysregulation of BCR signaling may lead to abnormal B cell activation and loss of tolerance
.
In RA patients with positive anti-citrullinated protein antibody, BTK protein and pBTK in peripheral blood B cells increase, and the expression of pBTK is related to the level of circulating rheumatoid factor
.
In addition, RA synovial tissue cultured with BTKi showed reduced production of pro-inflammatory cytokines
.
In summary, these data suggest that BTKi may be a beneficial treatment option for RA
.
Genentech, Inc.
's fenebrutinib has shown efficacy at high doses, reducing the levels of pro-inflammatory cytokines and autoantibodies (NCT02833350)
.
However, several other BTKi studies have shown only a slight impact on disease severity, including spebrutinib, evobrutinib (NCT02784106, NCT032333230) and tirabrutinib (NCT02626026)
.
2.
Primary Sjogren’s syndrome (pSS) Some patients with primary Sjogren’s syndrome have elevated levels of BTK protein and pBTK in circulating B cell subgroups, which are related to the number of infiltrating T cells in the parotid gland, and return to normal after treatment with abatacep
.
The expression of BTK in transitional and naive B cells is enhanced, has a more active phenotype, and shows a loss of tolerance in primary Sjogren’s syndrome
.
BTK overexpression may be related to the increased risk of lymphoma development in pSS
.
Therefore, Novartis' BTK inhibitor remibrutinib is undergoing a phase II clinical trial of pSS (NCT04035668)
.
3.
Systemic lupus erythematosus (SLE) In SLE patients, the increase in BTK expression in peripheral B cells is related to lupus nephritis and is related to the severity of the disease
.
In a mouse model of lupus nephritis, BTKi leads to remission of the disease
.
BTKi is performed in some clinical trials in systemic lupus erythematosus, such as EMD Serono's MSC2364447C (NCT02537028), Nuocheng Jianhua, ICP-022 (NCT04305197), ACEA Therapeutics, AC0058TA (NCT03878303)
.
Despite showing strong immunomodulatory effects, the phase II clinical trial of fenebrutinib did not reach its primary endpoint
.
More research is needed to determine the efficacy of BTKi in the treatment of SLE
.
BTK and lupus nephritis (Front.
Immunol.
8:1986) 4.
Systemic sclerosis (SSc) Systemic sclerosis (SSc) is a heterogeneous disease with unknown etiology
.
However, since 90% of patients carry autoantibodies, B cells are thought to play a major role in SSc
.
Genetic susceptibility studies have shown that the BCR signaling pathway is related to the pathogenesis of diseases
.
In SSc patients, circulating BAFF levels are elevated
.
Ibrutinib treatment of SSc patient B cells in vitro reduced the production of IL-6, TNFα and SSc-specific autoantibodies after TLR stimulation
.
Although further research is needed, these results suggest that BTKi may be a treatment option for SSc
.
5.
Multiple sclerosis (MS) Compared with other autoimmune diseases and healthy controls, BCR stimulated multiple sclerosis B cells and did not show an increase in BTK protein expression or pBTK levels
.
The phase II clinical trial of Merck's evobrutinib showed good clinical results at the highest dose, and clinical recruitment for phase 3 relapsing multiple sclerosis (RMS) is now underway (NCT04338022, NCT04338061)
.
Sanofi's tolebrutinib trials for relapsing and progressive multiple sclerosis are currently underway (NCT04410978, NCT04410991 and NCT04458051)
.
Since BTKi is a small molecule inhibitor, they may be more suitable for entering the central nervous system and reaching pathogenic B cells than therapeutic antibodies such as rituximab
.
6.
Pemphigus Pemphigus and pemphigoid are autoimmune diseases characterized by blistering and erosion of the skin or mucous membranes, and are related to IgG autoantibodies against the structural proteins of epithelial cells
.
Treatment includes high-dose glucocorticoids and rituximab, which can relieve 80% of patients
.
Principia Biopharma (a Sanofi Company) PRN1008, currently has phase II (NCT02704429) and phase III (NCT03762265) clinical trials
.
7.
Immune Thrombocytopenic Purpura Immune Thrombocytopenic Purpura (ITP) is an autoimmune disease characterized by autoantibodies that target platelets
.
BTKi has been shown to be effective in a mouse model.
Currently PRN1008 of Principia Biopharma (a Sanofi Company) is undergoing phase I/II clinical trials (NCT03395210), and the first results showed clinical activity
.
Type 8.
1 diabetes (T1D) In non-obese diabetic (NOD) mice, BTK deficiency reduces the number of autoreactive BCR, thereby reducing pathogenic autoantibodies
.
However, autoreactive B cells can still escape selection, and their phenotype can be restored by providing an insulin-specific BCR
.
In another study, treatment of NOD mice with SYK inhibitors delayed the onset and progression of anti-insulin responses
.
These data indicate that targeting BCR signaling pathways, especially BTK, may be beneficial for diabetics
.
9.
Granulomatous polyangiitis In granulomatous disease of patients with polyangiitis (GPA), BTK levels in peripheral B cells of patients with active disease are elevated, but patients with remission do not increase, indicating that it is related to disease activity Related
.
Compared with the healthy control group, as the ratio of pBTK and pPLCγ2 stimulation increased, the newly emerged transitional and initial B cells were more sensitive to BCR stimulation
.
Targeting BCR signals by BTKi may be a new treatment option for GPA
.
10.
Psoriasis Psoriasis is an autoinflammatory disease of the skin characterized by epidermal hyperplasia and hypokeratosis
.
Therefore, the cytokines produced by TLR-activated myeloid cells are essential for the differentiation of IL-17 and IL-22-produced T cells
.
Studies have found that BTKi can reduce TLR7-driven psoriasis-like inflammation in mice, probably by acting on innate immune cells
.
The editor concludes that BTK plays a key role in the development of B cells and participates in multiple signaling pathways such as TLR, cytokines, and chemokines
.
Therefore, BTK is an important drug development target for diseases involving or mediated by B cells, and breakthroughs have been made in B cell malignancies
.
Now more efforts have begun to expand to autoimmune diseases, and even inflammatory diseases such as new coronary pneumonia, which have shown good clinical effects in many diseases
.
References 1.
Rip, J.
, Van Der Ploeg, EK, Hendriks, RW, and Corneth, OBJ (2018).
The role of bruton's tyrosine kinase in immune cell signaling and systemic autoimmunity.
Crit.
Rev.
Immunol.
38, 17 –62.
doi: 10.
1615/CritRevImmunol.
20180251842.
Cohen, S.
, Tuckwell, K.
, Katsumoto, TR, Zhao, R.
, Galanter, J.
, Lee, C.
, et al.
(2020).
Fenebrutinib versus Placebo or Adalimumab in rheumatoid arthritis: a randomized, double-blind, phase II Trial (ANDES Study).
Arthritis Rheumatol.
72, 1435–1446.
doi: 10.
1002/art.
412753.
Philipp von Hundelshausen et al, Bleeding by Bruton Tyrosine Kinase- Inhibitors: Dependency on Drug Type and Disease, Cancers 2021, 13, 11034.
Satterthwaite AB (2018) Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus.
Front.
Immunol.
8:1986.
Copyright statement welcomes personal comments and sharing
.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and see "Reposted from: Aogu" in a prominent position
.
.
BTK inhibitors (BTKi) have been on the market with a variety of drugs in the field of tumor treatment
.
Among the first-generation BTK inhibitors, Ibrutinib has achieved sales of more than US$9 billion worldwide
.
Second-generation inhibitors with higher specificity and lower side effects and even siRNA drugs are also under development.
BeiGene's zanubrutinib is listed in China and the United States
.
Some BTK inhibitors (Cancers 2021, 13, 1103.
) BTK has received widespread attention in the field of autoimmune diseases, inflammatory diseases, and even new coronary pneumonia in recent years.
This article will briefly review
.
1.
BTK deficiency in experimental mice with rheumatoid arthritis (RA) has a protective effect in some autoimmune arthritis models
.
The protection is largely due to its role in B cells
.
In animal studies, BTKi improves B-cell dependent/B-cell independent myeloid-mediated arthritis
.
In rheumatoid arthritis, the dysregulation of BCR signaling may lead to abnormal B cell activation and loss of tolerance
.
In RA patients with positive anti-citrullinated protein antibody, BTK protein and pBTK in peripheral blood B cells increase, and the expression of pBTK is related to the level of circulating rheumatoid factor
.
In addition, RA synovial tissue cultured with BTKi showed reduced production of pro-inflammatory cytokines
.
In summary, these data suggest that BTKi may be a beneficial treatment option for RA
.
Genentech, Inc.
's fenebrutinib has shown efficacy at high doses, reducing the levels of pro-inflammatory cytokines and autoantibodies (NCT02833350)
.
However, several other BTKi studies have shown only a slight impact on disease severity, including spebrutinib, evobrutinib (NCT02784106, NCT032333230) and tirabrutinib (NCT02626026)
.
2.
Primary Sjogren’s syndrome (pSS) Some patients with primary Sjogren’s syndrome have elevated levels of BTK protein and pBTK in circulating B cell subgroups, which are related to the number of infiltrating T cells in the parotid gland, and return to normal after treatment with abatacep
.
The expression of BTK in transitional and naive B cells is enhanced, has a more active phenotype, and shows a loss of tolerance in primary Sjogren’s syndrome
.
BTK overexpression may be related to the increased risk of lymphoma development in pSS
.
Therefore, Novartis' BTK inhibitor remibrutinib is undergoing a phase II clinical trial of pSS (NCT04035668)
.
3.
Systemic lupus erythematosus (SLE) In SLE patients, the increase in BTK expression in peripheral B cells is related to lupus nephritis and is related to the severity of the disease
.
In a mouse model of lupus nephritis, BTKi leads to remission of the disease
.
BTKi is performed in some clinical trials in systemic lupus erythematosus, such as EMD Serono's MSC2364447C (NCT02537028), Nuocheng Jianhua, ICP-022 (NCT04305197), ACEA Therapeutics, AC0058TA (NCT03878303)
.
Despite showing strong immunomodulatory effects, the phase II clinical trial of fenebrutinib did not reach its primary endpoint
.
More research is needed to determine the efficacy of BTKi in the treatment of SLE
.
BTK and lupus nephritis (Front.
Immunol.
8:1986) 4.
Systemic sclerosis (SSc) Systemic sclerosis (SSc) is a heterogeneous disease with unknown etiology
.
However, since 90% of patients carry autoantibodies, B cells are thought to play a major role in SSc
.
Genetic susceptibility studies have shown that the BCR signaling pathway is related to the pathogenesis of diseases
.
In SSc patients, circulating BAFF levels are elevated
.
Ibrutinib treatment of SSc patient B cells in vitro reduced the production of IL-6, TNFα and SSc-specific autoantibodies after TLR stimulation
.
Although further research is needed, these results suggest that BTKi may be a treatment option for SSc
.
5.
Multiple sclerosis (MS) Compared with other autoimmune diseases and healthy controls, BCR stimulated multiple sclerosis B cells and did not show an increase in BTK protein expression or pBTK levels
.
The phase II clinical trial of Merck's evobrutinib showed good clinical results at the highest dose, and clinical recruitment for phase 3 relapsing multiple sclerosis (RMS) is now underway (NCT04338022, NCT04338061)
.
Sanofi's tolebrutinib trials for relapsing and progressive multiple sclerosis are currently underway (NCT04410978, NCT04410991 and NCT04458051)
.
Since BTKi is a small molecule inhibitor, they may be more suitable for entering the central nervous system and reaching pathogenic B cells than therapeutic antibodies such as rituximab
.
6.
Pemphigus Pemphigus and pemphigoid are autoimmune diseases characterized by blistering and erosion of the skin or mucous membranes, and are related to IgG autoantibodies against the structural proteins of epithelial cells
.
Treatment includes high-dose glucocorticoids and rituximab, which can relieve 80% of patients
.
Principia Biopharma (a Sanofi Company) PRN1008, currently has phase II (NCT02704429) and phase III (NCT03762265) clinical trials
.
7.
Immune Thrombocytopenic Purpura Immune Thrombocytopenic Purpura (ITP) is an autoimmune disease characterized by autoantibodies that target platelets
.
BTKi has been shown to be effective in a mouse model.
Currently PRN1008 of Principia Biopharma (a Sanofi Company) is undergoing phase I/II clinical trials (NCT03395210), and the first results showed clinical activity
.
Type 8.
1 diabetes (T1D) In non-obese diabetic (NOD) mice, BTK deficiency reduces the number of autoreactive BCR, thereby reducing pathogenic autoantibodies
.
However, autoreactive B cells can still escape selection, and their phenotype can be restored by providing an insulin-specific BCR
.
In another study, treatment of NOD mice with SYK inhibitors delayed the onset and progression of anti-insulin responses
.
These data indicate that targeting BCR signaling pathways, especially BTK, may be beneficial for diabetics
.
9.
Granulomatous polyangiitis In granulomatous disease of patients with polyangiitis (GPA), BTK levels in peripheral B cells of patients with active disease are elevated, but patients with remission do not increase, indicating that it is related to disease activity Related
.
Compared with the healthy control group, as the ratio of pBTK and pPLCγ2 stimulation increased, the newly emerged transitional and initial B cells were more sensitive to BCR stimulation
.
Targeting BCR signals by BTKi may be a new treatment option for GPA
.
10.
Psoriasis Psoriasis is an autoinflammatory disease of the skin characterized by epidermal hyperplasia and hypokeratosis
.
Therefore, the cytokines produced by TLR-activated myeloid cells are essential for the differentiation of IL-17 and IL-22-produced T cells
.
Studies have found that BTKi can reduce TLR7-driven psoriasis-like inflammation in mice, probably by acting on innate immune cells
.
The editor concludes that BTK plays a key role in the development of B cells and participates in multiple signaling pathways such as TLR, cytokines, and chemokines
.
Therefore, BTK is an important drug development target for diseases involving or mediated by B cells, and breakthroughs have been made in B cell malignancies
.
Now more efforts have begun to expand to autoimmune diseases, and even inflammatory diseases such as new coronary pneumonia, which have shown good clinical effects in many diseases
.
References 1.
Rip, J.
, Van Der Ploeg, EK, Hendriks, RW, and Corneth, OBJ (2018).
The role of bruton's tyrosine kinase in immune cell signaling and systemic autoimmunity.
Crit.
Rev.
Immunol.
38, 17 –62.
doi: 10.
1615/CritRevImmunol.
20180251842.
Cohen, S.
, Tuckwell, K.
, Katsumoto, TR, Zhao, R.
, Galanter, J.
, Lee, C.
, et al.
(2020).
Fenebrutinib versus Placebo or Adalimumab in rheumatoid arthritis: a randomized, double-blind, phase II Trial (ANDES Study).
Arthritis Rheumatol.
72, 1435–1446.
doi: 10.
1002/art.
412753.
Philipp von Hundelshausen et al, Bleeding by Bruton Tyrosine Kinase- Inhibitors: Dependency on Drug Type and Disease, Cancers 2021, 13, 11034.
Satterthwaite AB (2018) Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus.
Front.
Immunol.
8:1986.
Copyright statement welcomes personal comments and sharing
.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and see "Reposted from: Aogu" in a prominent position
.
