Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BTK inhibitors and anti-CD20 monoclonal antibodies for treatment-naive elderly patients with CLL.

ABSTRACT: Older patients account for the majority of patients with chronic lymphocytic leukemia (CLL), and so strategies for managing CLL in this population is of upmost importance. Inhibition of Bruton's tyrosine kinase (BTK) has been a successful therapeutic strategy in CLL, and the first-generation BTK inhibitor ibrutinib has been shown to be superior to standard chemoimmunotherapy in multiple studies specifically targeting older patients. A second-generation BTK inhibitor, acalabrutinib, has also been studied in CLL, and has recently been granted breakthrough designation by the United States Food and Drug Administration. One ongoing question is whether the addition of anti-CD20 monoclonal antibodies improve response or response durability with BTK inhibitors. In this review, we will discuss clinical trials of ibrutinib and acalabrutinib in older patients with CLL, and the possible contributions of anti-CD20 antibodies to these therapies.

SUBMITTER: Rogers A

PROVIDER: S-EPMC7092382 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

BTK inhibitors and anti-CD20 monoclonal antibodies for treatment-naïve elderly patients with CLL.

Rogers Andrew A Woyach Jennifer A JA

Therapeutic advances in hematology 20200323

Older patients account for the majority of patients with chronic lymphocytic leukemia (CLL), and so strategies for managing CLL in this population is of upmost importance. Inhibition of Bruton's tyrosine kinase (BTK) has been a successful therapeutic strategy in CLL, and the first-generation BTK inhibitor ibrutinib has been shown to be superior to standard chemoimmunotherapy in multiple studies specifically targeting older patients. A second-generation BTK inhibitor, acalabrutinib, has also been ...[more]

PMID: 32231778

Similar Datasets

Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment.

Project description:The clinical success of anti-CD20 monoclonal antibody (mAb)-mediated B cell depletion therapy has contributed to the understanding of B cells as major players in several autoimmune diseases. The first therapeutic anti-CD20 mAb, rituximab, is a murine-human chimera to which many patients develop antibodies and/or experience infusion-related reactions. A second generation of anti-CD20 mAbs has been designed to be more effective, better tolerated, and of lower immunogenicity. These include the humanized versions: ocrelizumab, obinutuzumab, and veltuzumab, and the fully human, ofatumumab. We conducted a literature search of relevant randomized clinical trials in the PubMed database and ongoing trials in Clinicaltrials.gov. Most of these trials have evaluated intravenous ocrelizumab or subcutaneous ofatumumab in rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus. Understanding how newer anti-CD20 mAbs compare with rituximab in terms of efficacy, safety, convenience, and cost is important for guiding future management of anti-CD20 mAb therapy in autoimmune diseases.

| S-EPMC5688039 | biostudies-literature

Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies.

Project description:Clinical trials with SRC family kinases (SFKs) inhibitors used alone or in a combination with anti-CD20 monoclonal antibodies (mAbs) are currently underway in the treatment of B-cell tumors. However, molecular interactions between these therapeutics have not been studied so far. A transcriptional profiling of tumor cells incubated with SFKs inhibitors revealed strong downregulation of MS4A1 gene encoding CD20 antigen. In a panel of primary and established B-cell tumors we observed that SFKs inhibitors strongly affect CD20 expression at the transcriptional level, leading to inhibition of anti-CD20 mAbs binding and increased resistance of tumor cells to complement-dependent cytotoxicity. Activation of the AKT signaling pathway significantly protected cells from dasatinib-triggered CD20 downregulation. Additionally, SFKs inhibitors suppressed antibody-dependent cell-mediated cytotoxicity by direct inhibition of natural killer cells. Abrogation of antitumor activity of rituximab was also observed in vivo in a mouse model. Noteworthy, the effects of SFKs inhibitors on NK cell function are largely reversible. The results of our studies indicate that development of optimal combinations of novel treatment modalities with anti-CD20 mAbs should be preceded by detailed preclinical evaluation of their effects on target cells.

| S-EPMC4622538 | biostudies-literature

Anti-CD20 monoclonal antibodies: reviewing a revolution.

Project description:Since the inception of rituximab in the 1990s, anti-CD20 monoclonal antibodies have revolutionised the treatment of B cell hematological malignancies and have become a cornerstone of modern gold-standard practice. Additionally, the potent efficacy of these agents in depleting the B cell compartment has been used in the management of a broad array of autoimmune diseases. Multiple iterations of these agents have been investigated and are routinely used in clinical practice. In this review, we will discuss the physiology of CD20 and its attractiveness as a therapeutic target, as well as the pharmacology, pre-clinical and clinical data for the major anti-CD20 monoclonal antibodies: rituximab, obinutuzumab and ofatumumab.

| S-EPMC6343614 | biostudies-literature

Anti-CD20 monoclonal antibodies: historical and future perspectives.

Project description:Antibodies to CD20 have confirmed the hypothesis that monoclonal reagents can be given in vivo to alleviate human diseases. The targeting of CD20 on normal, malignant and auto-immune B-lymphocytes by rituximab has demonstrated substantial benefits for patients with a variety of B-cell lymphomas, as well as some with autoimmune disorders. There has been a notable increase in the survival rates from B-cell lymphoma in the decade since anti-CD20 therapy was introduced.

| S-EPMC2805725 | biostudies-other

Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies.

Project description:CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar). Radiation therapy effects are due to beta emissions with path lengths of 1-5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%-90% in low-grade and follicular lymphoma and 40%-50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement.

| S-EPMC2779347 | biostudies-other

Obinutuzumab activates Fc?RI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL).

Project description:Treatment with monoclonal antibodies has revolutionized clinical medicine, especially in the fields of cancer and immunology. One of the oldest antibodies, which is widely used for the treatment of lymphomas and autoimmune diseases, is the anti-CD20 antibody rituximab. In recent years, new antibodies against CD20 have been developed including ofatumumab and obinutuzumab. An important mechanism of action of therapeutic monoclonal antibodies is activation of immune cells via Fc receptors (Fc?Rs). However, surprisingly, little is known about triggering of Fc?Rs by different therapeutic antibodies in general and anti-CD20 antibodies in particular. Here we establish a reporter assay to assess whether a particular antibody activates a certain Fc receptor. Using this assay we corroborated previous reports demonstrating obinutuzumab's ability to highly activate Fc?RIIIa (CD16a). Importantly, we discovered that obinutuzumab also activates Fc?RI (CD64) significantly more than rituximab and ofatumumab in response to chronic lymphocytic leukemia (CLL) cells obtained from patients. Mechanistically we show that this is due to the lack of Fc?RIIb-mediated internalization of obinutuzumab following binding to CD20. Moreover, we show that obinutuzumab induces increased phagocytosis by primary macrophages in an Fc?RI-dependent manner. Beyond the discovery of a new mechanism of obinutuzumab activity, the reporter assay can be applied to other therapeutic antibodies and may assist in developing antibodies with improved immunological properties.

| S-EPMC5980409 | biostudies-literature

Second cancer incidence in CLL patients receiving BTK inhibitors.

Project description:Chronic lymphocytic leukemia (CLL) is associated with perturbed immune function and increased risk for second primary malignancies (SPM). Ibrutinib and acalabrutinib (BTKi) are effective therapies for CLL resulting in partial restoration of immune function. The incidence of and risk factors for SPM in CLL patients receiving BTKi are not yet characterized. We retrospectively determined the incidence of SPM in CLL patients treated with ibrutinib or acalabrutinib at our institution between 2009 and 2017, assessed for association between baseline characteristics and SPM incidence, and compared the observed to expected cancer incidence among age, sex, and year matched controls without CLL. After a median of 44 months follow-up, 64/691 patients (9%) were diagnosed with SPM (excluding non-melanoma skin cancer [NMSC]). The 3-year cumulative incidence rate was 16% for NMSC and 7% for other SPM. On multivariable analysis, smoking was associated with increased SPM risk (HR 2.8 [95% CI: 1.6-4.8]) and higher baseline CD8 count was associated with lower SPM risk (HR 0.9 for 2-fold increase [95% CI: 0.8-0.9]). The observed over expected rate of SPM was 2.2 [95% CI: 1.7-2.9]. CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.

| S-EPMC7688551 | biostudies-literature

Impact of anti-CD20 monoclonal antibodies on serologic response to BNT162b2 vaccine in B-cell Non-Hodgkin's lymphomas.

Project description: Not available

| S-EPMC8451738 | biostudies-literature

A novel glycosylated anti-CD20 monoclonal antibody from transgenic cattle.

Project description:The monoclonal antibody (mAb) against CD20 known as Rituxan is widely used to treat autoimmune diseases and lymphomas. However, further application of Rituxan faces challenges of high production cost, which limits its availability in developing countries. Here, we report a new approach for large production of a recombinant anti-CD20 mAb in the milk of transgenic cattle (at a yield of up to ~6.8?mg/mL), with ~80% recovery rate and >99% purity. Crystallography study showed that our recombinant mAb is structurally nearly identical to Rituxan with only minor differences in N-linked glycosylation pattern. Functional study showed that, while our mAb shared similar target-cell binding capacities and complement-dependent cytotoxicity with Rituxan, our product exhibited a higher binding affinity for Fc?RIII? and a greater antibody-dependent cellular cytotoxicity. Accordingly, our recombinant mAb demonstrated a superior efficacy over Rituxan against B-cell lymphomas in severe combined immunodeficiency mice. Taken together, our data supports transgenic cattle as a novel model for cost-competitive, large-scale production of therapeutic antibodies.

| S-EPMC6123398 | biostudies-literature

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children.

Project description:Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell-mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.

| S-EPMC4822672 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data