Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During an ongoing immune response, immune complexes, composed of Ag, complement factors, and Igs, are formed that can interact with complement receptors (CRs) and IgG Fc receptors (Fc gamma R). The role of CR1/2 and Fc gamma R in the regulation of the immune response was investigated using OVA that was chemically conjugated to whole IgG of the rat anti-mouse CR1/2 mAb 7G6. FACS analysis using the murine B cell lymphoma IIA1.6 confirmed that the 7G6-OVA conjugate recognized CR1/2. Incubating IIA1.6 cells with 7G6-OVA triggered tyrosine phosphorylation and Ag presentation to OVA-specific T cells in vitro. Immunizing mice with 7G6-OVA at a minimal dose of 1 microgram i.p. per mouse markedly enhanced the anti-OVA Ig response, which was primarily of the IgG1 isotype subclass. The 7G6-OVA did not enhance the anti-OVA response in CR1/2-deficient mice. OVA coupled to an isotype control Ab induced a considerably lower anti-OVA response compared with that induced by OVA alone, suggesting inhibition by interaction between the Fc part of the Ab and the inhibitory Fc gamma RIIb on B cells. This findings was supported by the observation that IIA1.6 cells which were incubated with 7G6-OVA lost the ability to present Ag upon transfection with Fc gamma RIIb. In sum, 7G6-conjugated OVA, resembling a natural immune complex, induces an enhanced anti-OVA immune response that involves at least CR1/2-mediated stimulation and that may be partially suppressed by Fc gamma RIIb.
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PMID:Modulation of the humoral immune response by antibody-mediated antigen targeting to complement receptors and Fc receptors. 1009 61

The fragment crystallizable (Fc) region of the immunoglobulin G, low affinity III A receptor (FCGR3a, also known as CD16) belongs to the Fc gamma receptor family (FCGR), which plays an important role in immunoinflammatory processes. It is a low affinity, transmembrane receptor that is mainly expressed in monocytes, natural killer cells, and macrophages. It has been implicated in various inflammatory conditions, and recently a polymorphism (rs396991) in this gene has been shown to influence response to rituximab (anti-CD20) therapy in various disorders. We evaluated two molecular methods to genotype this polymorphism. Archived, formalin-fixed, paraffin-embedded samples from 26 biopsies of diffuse large B-cell lymphoma were retrieved and DNA was extracted. The samples were tested for the FCGR3a polymorphism using real-time polymerase chain reaction (PCR) followed by melt curve analysis or by a standard TaqMan allelic discrimination assay using the ABI 7500 FAST real-time PCR instrument. With the TaqMan allelic discrimination assay, we found that 16 cases were the wild type genotype, homozygous phenylalanine (F/F), for the FCGR3a receptor, whereas two cases had the homozygous valine (V/V) polymorphism and eight cases were heterozygous with a V/F genotype. Results with the real-time PCR followed by melt curve analysis were similar for 25 cases; however, four samples did not have sufficient DNA for the melt curve analysis method, and the result from one sample was discordant. The new TaqMan assay offers several advantages over previously published assays, such as faster turnaround time and ease of interpretation. These performance characteristics make it highly suitable for use in a clinical laboratory.
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PMID:Detection of the FCGR3a polymorphism using a real-time polymerase chain reaction assay. 2368 Apr 10

The influence of Fc gamma receptor IIIA (FCGR3A) 158V/F polymorphisms on the response to rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; R-CHOP) therapy in diffuse large B-cell lymphoma (DLBCL) is uncertain. Thus, a retrospective study and a meta-analysis were performed to examine the possible correlation between FCGR3A 158V/F polymorphism and the response rate of R-CHOP regimen in patients with newly diagnosed DLBCL. The genotypes of FCGR3A 158V/F in 164 newly diagnosed DLBCL patients treated with R-CHOP were determined in this retrospective study. Additionally, a meta-analysis of current and previously published studies was conducted. Overall response rate (complete and partial response, ORR) and complete response rate (CR) were evaluated. The results of our retrospective study showed lack of correlation between FCGR3A 158V/F polymorphism and ORR (p=0.78) or CR (p=0.76) with R-CHOP therapy. A meta-analysis of 731 cases also showed lack of significant association of ORR and CR in all genetic models with FCGR3A 158V/F polymorphism. In survival analysis, the homozygous F genotype correlated with a shorter progression-free survival than that of non-F/F genotype (p=0.05), this was significant for the non-GC subset of DLBCL (p=0.04), but no association was found between overall survival and FCGR3A 158V/F polymorphism. Further analysis with nonsuperiority test (p<0.0001) suggested that FCGR3A 158V/F polymorphism was not associated with better ORR or CR in newly diagnosed DLBCL patient treated with R-CHOP. No clear relationship was found between FCGR3A 158V/F polymorphism and response to frontline R-CHOP therapy in patients with DLBCL.
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PMID:FCGR3A 158V/F polymorphism and response to frontline R-CHOP therapy in diffuse large B-cell lymphoma. 2505 Aug 83

Rituximab is a chimeric mouse/human monoclonal antibody (mAb) therapy with binding specificity to CD20. It was the first therapeutic antibody approved for oncology patients and was the top-selling oncology drug for nearly a decade with sales reaching $8.58 billion in 2016. Since its initial approval in 1997, it has improved outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. Despite widespread use, most mechanistic data have been gathered from in vitro studies while the roles of the various response mechanisms in humans are still largely undetermined. Polymorphisms in Fc gamma receptor and complement protein genes have been implicated as potential predictors of differential response to rituximab, but have not yet shown sufficient influence to impact clinical decisions. Unlike most targeted therapies developed today, no known biomarkers to indicate target engagement/tumor response have been identified, aside from reduced tumor burden. The lack of companion biomarkers beyond CD20 itself has made it difficult to predict which patients will respond to any given anti-CD20 antibody. In the past decade, two new anti-CD20 antibodies have been approved: ofatumumab, which binds a distinct epitope of CD20, and obinutuzumab, a mAb derived from rituximab with modifications to the Fc portion and to its glycosylation. Both are fully humanized and have biological activity that is distinct from that of rituximab. In addition to these new anti-CD20 antibodies, another imminent change in targeted lymphoma treatment is the multitude of biosimilars that are becoming available as rituximab's patent expires. While the widespread use of rituximab itself will likely continue, its biosimilars will increase global access to the therapy. This review discusses current research into mechanisms and potential biomarkers of rituximab response, as well as its biosimilars and the newer CD20 binding mAb therapies. Increased ability to assess the effectiveness of rituximab in an individual patient, along with the availability of alternative anti-CD20 antibodies will likely lead to dramatic changes in how we use CD20 antibodies going forward.
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PMID:Past, Present, and Future of Rituximab-The World's First Oncology Monoclonal Antibody Therapy. 2991 19


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