Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man

Hendriks, Rudi W.; Bredius, Robbert G. M.; Pike-Overzet, Karin; Staal, Frank J. T.

doi:10.1517/14728222.2011.585971

Cited by 52 publications

(49 citation statements)

References 151 publications

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“…2 BTK comprises 5 structural domains, including pleckstrin homology, TEC homology, Src homology 2 and Src homology 3, and kinase domains 3 ; full BTK kinase activation is dependent on recruitment to the plasma membrane via the pleckstrin homology domain following phosphatidylinositol (3,4,5) triphosphate binding. 4 In humans, BTK mutations result in arrested B-cell development leading to severe agammaglobulinemia.…”

Section: Introductionmentioning

confidence: 99%

“…4 In humans, BTK mutations result in arrested B-cell development leading to severe agammaglobulinemia. 5 This, along with the observations of the central role of BTK in signaling from the B-cell receptor, has indicated that BTK is a functional therapeutic target and has led to the development of small-molecule BTK inhibitors for the treatment of B-cell malignancies and autoimmune conditions. 6 An interesting feature of the adenosine triphosphate-binding pocket of BTK is the presence of a cysteine residue at 481; only 9 other kinases retain cysteine at comparable sites.…”

Section: Introductionmentioning

confidence: 99%

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A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

Walter

Rule

Dyer

et al. 2016

Blood

241

188

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Key Points• We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.• ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/ refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a doselimiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. (Blood. 2016;127(4):411-419)

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

Walter

Rule

Dyer

et al. 2016

Blood

241

188

View full text Add to dashboard Cite

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“…A pathogenic role for BTK in rheumatic diseases is further emerging from mouse studies demonstrating that smallmolecule BTK inhibitors prevent or ameliorate lupus nephritis and experimental arthritis (25)(26)(27)(28)(29)(30)(31). However, BTK inhibitors are likely to have effects beyond BCR signaling, because BTK functions downstream of many receptors, including chemokine and TLRs, and is also expressed in myeloid cells (32). Apart from direct effects on BTK-expressing cells, BTK inhibition was associated with diminished activation of both helper and cytotoxic T cells (25), raising the question how these T cells are indirectly activated in a BTK-dependent manner.…”

mentioning

confidence: 99%

Enhanced Expression of Bruton’s Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis

Corneth

Bruijn

Rip

et al. 2016

The Journal of Immunology

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Upon BCR stimulation, naive B cells increase protein levels of the key downstream signaling molecule Bruton’s tyrosine kinase (BTK). Transgenic CD19-hBtk mice with B cell–specific BTK overexpression show spontaneous germinal center formation, anti-nuclear autoantibodies, and systemic autoimmunity resembling lupus and Sjögren syndrome. However, it remains unknown how T cells are engaged in this pathology. In this study, we found that CD19-hBtk B cells were high in IL-6 and IL-10 and disrupted T cell homeostasis in vivo. CD19-hBtk B cells promoted IFN-γ production by T cells and expression of the immune-checkpoint protein ICOS on T cells and induced follicular Th cell differentiation. Crosses with CD40L-deficient mice revealed that increased IL-6 production and autoimmune pathology in CD19-hBtk mice was dependent on B–T cell interaction, whereas IL-10 production and IgM autoantibody formation were CD40L independent. Surprisingly, in Btk-overexpressing mice, naive B cells manifested increased CD86 expression, which was dependent on CD40L, suggesting that T cells interact with B cells in a very early stage of immune pathology. These findings indicate that increased BTK-mediated signaling in B cells involves a positive-feedback loop that establishes T cell–propagated autoimmune pathology, making BTK an attractive therapeutic target in autoimmune disease.

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“…[11][12][13] The defects in murine Btk-deficient B cells range from reduced responsiveness to BCR and Toll-like receptor (TLR) stimulation to decreased signaling of chemokine receptors. 14 Several lines of evidence indicate that Btk expression levels may present the rate-limiting step in BCR signaling and that tight regulation of Btk expression and kinase activity is essential for normal B-cell development and activation. Firstly, expression of subphysiologic levels of transgenic Btk only partially corrects the phenotype of Btk-deficient B cells, 15 whereas physiologic levels fully rescue this phenotype.…”

mentioning

confidence: 99%

Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice

Kil

Bruijn

Nimwegen

et al. 2012

Blood

185

165

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On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-κB activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.

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Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man

Abstract: Work from various laboratories demonstrates the feasibility of using gene-corrected HSCs to complement the immune defects of Btk-deficiency in mice. We propose that it is timely to start clinical programs to develop stem cell based therapy for XLA, using gene-corrected autologous HSC.

Cited by 52 publications

References 151 publications

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

Enhanced Expression of Bruton’s Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis

Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice

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