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Cd20 pharmacokinetics

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https://www.readbyqxmd.com/read/27892793/physiologically-based-modeling-to-predict-the-clinical-behavior-of-monoclonal-antibodies-directed-against-lymphocyte-antigens
#1
Patrick M Glassman, Joseph P Balthasar
Many clinically approved and investigational monoclonal antibody (mAb)-based therapeutics are directed against proteins located in the systemic circulation, including cytokines, growth factors, lymphocyte proteins, and shed antigens. Interaction between mAb and target may lead to non-linear pharmacokinetics (PK), characterized by rapid, target-mediated elimination. Several groups have reported that determinants of target-mediated elimination could include mAb-target binding, target expression, and target turnover...
November 28, 2016: MAbs
https://www.readbyqxmd.com/read/27783363/influence-of-fcgr3a-158v-f-genotype-and-baseline-cd20-antigen-count-on-target-mediated-elimination-of-rituximab-in-patients-with-chronic-lymphocytic-leukemia-a-study-of-filo-group
#2
Mira Tout, Anne-Laure Gagez, Stéphane Leprêtre, Valérie Gouilleux-Gruart, Nicolas Azzopardi, Alain Delmer, Mélanie Mercier, Loïc Ysebaert, Kamel Laribi, Hugo Gonzalez, Gilles Paintaud, Guillaume Cartron, David Ternant
BACKGROUND AND OBJECTIVES: Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcγRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL. METHODS: Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance...
October 25, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27689933/improved-in-vivo-stability-of-radioiodinated-rituximab-using-an-iodination-linker-for-radioimmunotherapy
#3
Eun Jung Kim, Byoung Soo Kim, Dan Bee Choi, Sung-Gil Chi, Tae Hyun Choi
PURPOSE: Directly radioiodinated [(131)I]-rituximab has been developed as a radioimmunotherapeutic agent in patients with CD20-positive B cell non-Hodgkin's lymphoma. However, there are concerns over its in vivo catabolism and deiodination. A novel radioiodination linker, N-(4-isothiocyanatobenzyl)-2-(3-(tributylstannyl)phenyl) acetamide (IBPA), was synthesized for the preparation of stable radioiodinated proteins. METHODS: The authors evaluated the potential of IBPA as a stable radioiodinated linker for rituximab...
September 30, 2016: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/27617674/synthesis-of-site-specific-radiolabeled-antibodies-for-radioimmunotherapy-via-genetic-code-expansion
#4
Yiming Wu, Hua Zhu, Bo Zhang, Fei Liu, Jingxian Chen, Yufei Wang, Yan Wang, Ziwei Zhang, Ling Wu, Longlong Si, Huan Xu, Tianzhuo Yao, Sulong Xiao, Qing Xia, Lihe Zhang, Zhi Yang, Demin Zhou
Radioimmunotherapy (RIT) delivers radioisotopes to antigen-expressing cells via mono-antibodies for the imaging of lesions or medical therapy. The chelates are typically conjugated to the antibody through cysteine or lysine residues, resulting in heterogeneous chelate to antibody ratios and various conjugation sites. To overcome this heterogeneity, we have developed an approach for site-specific radiolabeling of antibodies by combination of genetic code expansion and click chemistry. As a proof of concept study, model systems including anti-CD20 antibody rituximab, positron-emitting isotope 64Cu, and a newly synthesized bifunctional linker DIBO-DOTA were used...
September 12, 2016: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/27524505/preclinical-evaluation-of-a-diabody-based-177-lu-radioimmunoconjugate-for-cd22-directed-radioimmunotherapy-in-a-non-hodgkin-lymphoma-mouse-model
#5
Tobias Weber, Benedikt Bötticher, Michaela A E Arndt, Walter Mier, Max Sauter, Evelyn Exner, Armin Keller, Susanne Krämer, Karin Leotta, Artjom Wischnjow, Ludger Grosse-Hovest, Dirk Strumberg, Dirk Jäger, Hermann-Josef Gröne, Uwe Haberkorn, Gottfried Brem, Jürgen Krauss
Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma...
October 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27494885/bromodomain-inhibitor-otx015-mk-8628-combined-with-targeted-agents-shows-strong-in-vivo-antitumor-activity-in-lymphoma
#6
Eugenio Gaudio, Chiara Tarantelli, Maurilio Ponzoni, Elodie Odore, Keyvan Rezai, Elena Bernasconi, Luciano Cascione, Andrea Rinaldi, Anastasios Stathis, Eugenia Riveiro, Esteban Cvitkovic, Emanuele Zucca, Francesco Bertoni
The bromodomain inhibitor OTX015 (MK-8628) has shown anti-lymphoma activity as a single agent in both the preclinical and clinical settings, as well as in vitro synergism with several anticancer agents. Here, we report in vivo data for OTX015 in combination with the histone deacetylase inhibitor vorinostat, the Bruton's tyrosine kinase inhibitor ibrutinib, the anti-CD20 monoclonal antibody rituximab, and the mTOR inhibitor everolimus in a diffuse large B cell lymphoma model. The antitumor effect of OTX015-containing combinations in SU-DHL-2 xenografts in mice was much stronger than the activity of the corresponding single agents with almost complete tumor eradication for all four combinations...
August 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27389174/associations-of-ofatumumab-exposure-and-treatment-outcomes-in-patients-with-untreated-cll-receiving-chemoimmunotherapy
#7
Roxanne C Jewell, Thomas J Kipps, Jan Dürig, Laimonas Griskevicius, Stephan Stilgenbauer, Lukáš Smolej, Jiří Mayer, Georg Hess, Francisco J Hernandez-Ilizaliturri, Swaminathan Padmanabhan-Iyer, Lei Fang, Nancy Goldstein, Michele Gorczyca, Ira Gupta, Steen Lisby, William G Wierda
: Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients...
February 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27329361/population-pharmacokinetics-of-reditux%C3%A2-a-biosimilar-rituximab-in-diffuse-large-b-cell-lymphoma
#8
Vikram Gota, Ashwin Karanam, Sanhita Rath, Akanksha Yadav, Prashant Tembhare, P Subramanian, Manju Sengar, Reena Nair, Hari Menon
PURPOSE: Rituximab (MabThera™, Roche) is a chimeric IgG1 monoclonal antibody targeting the CD20 surface antigen on normal and neoplastic B cells. It revolutionized the treatment of non-Hodgkin's lymphoma with superior progression-free and overall survival. However, its prohibitively high cost makes it inaccessible to majority of patients in developing countries. Reditux™ (Dr. Reddy's Laboratories, India), a biosimilar, was introduced in India in 2007 at nearly half the price of the innovator...
August 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27265023/inflammation-causes-resistance-to-anti-cd20-mediated-b-cell-depletion
#9
Lindsay H Laws, Clare E Parker, Ganesh Cherala, Yoshinobu Koguchi, Ari Waisman, Mark K Slifka, Martin H Oberbarnscheidt, Jagdeep S Obhrai, Melissa Y Yeung, Leonardo V Riella
B cells play a central role in antibody-mediated rejection and certain auto-immune diseases. However, B-cell-targeted therapy such as anti-CD20 B cell-depleting antibody(aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B-cell reconstitution leading to aCD20 depletion-resistance could account for these discrepancies. Using a transplantation model, we found that antigen-independent inflammation, likely through TLR signals, was sufficient to mitigate B cell depletion...
June 6, 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/27199517/phase-i-study-of-chimeric-anti-cd20-monoclonal-antibody-in-chinese-patients-with-cd20-positive-non-hodgkin-s-lymphoma
#10
Lin Gui, Xiaohong Han, Xiaohui He, Yuanyuan Song, Jiarui Yao, Jianliang Yang, Peng Liu, Yan Qin, Shuxiang Zhang, Weijing Zhang, Wenlin Gai, Liangzhi Xie, Yuankai Shi
OBJECTIVE: This study was designed to determine the safety, pharmacokinetics and biologic effects of a human-mouse chimeric anti-CD20 monoclonal antibody (SCT400) in Chinese patients with CD20-positive B-cell non-Hodgkin's lymphoma (CD20(+) B-cell NHL). SCT400 has an identical amino acid sequence as rituximab, with the exception of one amino acid in the CH1 domain of the heavy chain, which is common in Asians. METHODS: Fifteen patients with CD20(+) B-cell NHL received dose-escalating SCT400 infusions (250 mg/m(2): n=3; 375 mg/m(2): n=9; 500 mg/m(2): n=3) once weekly for 4 consecutive weeks with a 24-week follow-up period...
April 2016: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
https://www.readbyqxmd.com/read/27140410/anti-cd20-monoclonal-antibodies-in-chronic-lymphocytic-leukemia-from-uncertainties-to-promises
#11
Cristina Bagacean, Mihnea Zdrenghea, Adrian Tempescul, Victor Cristea, Yves Renaudineau
Over the last two decades, anti-CD20 monoclonal antibody (mAb) therapy has improved patient outcome in B-cell malignancies, and confirmed CD20 as an important target in chronic lymphocytic leukemia (CLL). Until recently, the gold standard was based on the utilization of rituximab combined with chemotherapy (fludarabine and cyclophosphamide), but patients often relapse. Next, with our better understanding of mAb engineering, anti-CD20 mAb therapy has evolved with the development of new mAb permitting significant clinical responses by improving pharmacokinetics, safety, activity and immunogenicity...
May 2016: Immunotherapy
https://www.readbyqxmd.com/read/27117452/obinutuzumab-for-the-treatment-of-indolent-lymphoma
#12
Jennifer Edelmann, John G Gribben
Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody designed for strong induction of direct cell death and antibody-dependent cell-mediated cytotoxicity. The Phase III GADOLIN trial tested the clinical efficacy of obinutuzumab plus bendamustine followed by obinutuzumab monotherapy in rituximab-refractory indolent non-Hodgkin lymphoma versus treatment with bendamustine alone. It demonstrated significantly longer progression-free survival for the obinutuzumab-containing regimen in this difficult to treat patient group...
August 2016: Future Oncology
https://www.readbyqxmd.com/read/27112532/safety-tolerability-pharmacokinetic-and-pharmacodynamic-properties-of-sbi-087-a-cd20-directed-b-cell-depleting-agent-phase-1-dose-escalating-studies-in-patients-with-either-mild-rheumatoid-arthritis-or-systemic-lupus
#13
Stanley Cohen, Megan Clowse, Patricia Pardo, Indranil Bhattacharya, Sandeep Menon, Ian Gourley, Annette Diehl
PURPOSE: SBI-087 is a Small Modular Immunopharmaceutical Protein™(SMIP™) drug that binds to CD20 and has been reported to deplete B cells in murine/primate studies. The safety, tolerability and pharmacokinetic/pharmacodynamic properties of SBI-087 were evaluated in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODS: Single-dose SBI-087 was evaluated in 2 Phase I, open-label, escalating-dose studies in patients with RA or SLE...
June 2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/27069950/preclinical-safety-pharmacokinetics-pharmacodynamics-and-biodistribution-studies-with-ad35k-protein-a-novel-rituximab-cotherapeutic
#14
Maximilian Richter, Roma Yumul, Kamola Saydaminova, Hongjie Wang, Michael Gough, Audrey Baldessari, Roberto Cattaneo, Frank Lee, Chung-Huei Katherine Wang, Haishan Jang, Anne Astier, Ajay Gopal, Darrick Carter, André Lieber
Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/26967902/treating-chronic-lymphocytic-leukemia-with-obinutuzumab-safety-and-efficacy-considerations
#15
G Reda, N Orofino, R Cassin, M Sciumè, B Fattizzo, A Cortelezzi
INTRODUCTION: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody (MoAb) with a higher affinity for CD20 epitope. It was approved by the United States Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). AREAS COVERED: This article evaluates the safety of obinutuzumab in CLL patients, also addressing pharmacokinetics/pharmacodynamics (PK/PD), clinical use and efficacy...
June 2016: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/26773870/the-role-of-fc-receptors-in-the-uptake-and-transport-of-therapeutic-antibodies-in-the-retinal-pigment-epithelium
#16
Michaela Dithmer, Kirsten Hattermann, Prasti Pomarius, Shereen Hassan Aboul Naga, Tim Meyer, Rolf Mentlein, Johann Roider, Alexa Klettner
In the ophthalmological clinic, intravitreally applied antibodies or Fc-containing fusion proteins are frequently used, but the biology and pharmacokinetics of these therapeutics in the retina are not well understood. We have previously shown intracellular uptake of Fc-containing molecules in RPE cells. In this study, we investigated the involvement of Fc-receptors, both Fcγ-receptors and the neonatal Fc-receptor (FcRn) in the uptake and intracellular trafficking of the VEGF-antagonists bevacizumab, aflibercept and the anti-CD20 antibody rituximab in three different model systems, primary porcine RPE cells, ARPE-19 cells and porcine RPE/choroid explants...
April 2016: Experimental Eye Research
https://www.readbyqxmd.com/read/26659915/rationale-for-optimal-obinutuzumab-ga101-dosing-regimen-in-b-cell-non-hodgkin-lymphoma
#17
Guillaume Cartron, Florence Hourcade-Potelleret, Franck Morschhauser, Gilles Salles, Michael Wenger, Anna Truppel-Hartmann, David J Carlile
Obinutuzumab (GA101) is a type II, glycoengineered anti-CD20 monoclonal antibody for the treatment of hematologic malignancies. Obinutuzumab has mechanisms of action that are distinct from those of rituximab, potentially translating into improved clinical efficacy. We present the pharmacokinetic and clinical data from the phase I/II GAUGUIN and phase I GAUDI studies that were used to identify the obinutuzumab dose and regimen undergoing phase III assessment. In phase I (GAUGUIN and GAUDI), non-Hodgkin lymphoma patients received up to a maximum 9 fixed doses (obinutuzumab 50-2000 mg)...
February 2016: Haematologica
https://www.readbyqxmd.com/read/26648084/pharmacokinetics-and-safety-of-single-doses-of-tabalumab-in-subjects-with-rheumatoid-arthritis-or-systemic-lupus-erythematosus
#18
Jennifer Witcher, Roy Fleischmann, Vishala L Chindalore, Ryan J Hansen, Leijun Hu, David Radtke, James Voelker, Elisa Gomez, Juliet McColm
AIMS: Two phase 1 studies evaluated the pharmacokinetics (PK), safety and biological activity of tabalumab, a human monoclonal antibody against B-cell activating factor (BAFF), administered intravenously (i.v.) or subcutaneously (s.c.) in subjects with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODS: In study A, subjects with RA (n = 23) or SLE (n = 6) received a single i.v. dose of tabalumab (RA 0.01, 0.04, 0.125, 0.5, 2.0, and 8.0 mg kg(-1) and SLE 0...
May 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/26508306/synergistic-anti-tumor-therapy-by-a-comb-like-multifunctional-antibody-nanoarray-with-exceptionally-potent-activity
#19
Huafei Li, Yun Sun, Di Chen, He Zhao, Mengxin Zhao, Xiandi Zhu, Changhong Ke, Ge Zhang, Cheng Jiang, Li Zhang, Fulei Zhang, Huafeng Wei, Wei Li
Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb...
2015: Scientific Reports
https://www.readbyqxmd.com/read/26382733/safety-pharmacokinetics-and-pharmacodynamics-of-epratuzumab-in-japanese-patients-with-moderate-to-severe-systemic-lupus-erythematosus-results-from-a-phase-1-2-randomized-study
#20
RANDOMIZED CONTROLLED TRIAL
Tomomi Tsuru, Yoshiya Tanaka, Mitsumasa Kishimoto, Kazuyoshi Saito, Seiji Yoshizawa, Yoshinari Takasaki, Tomoya Miyamura, Hiroaki Niiro, Shinji Morimoto, Junichi Yamamoto, Rocio Lledo-Garcia, Jing Shao, Shuichiro Tatematsu, Osamu Togo, Takao Koike
OBJECTIVES: This 12-week, randomized, double-blind, placebo-controlled, multicenter phase 1/2 study (NCT01449071) assessed the safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus despite standard of care. METHODS: Twenty patients were randomized 1:1:1:1:1 to placebo or one of four epratuzumab dose regimens (100 mg every other week [Q2W], 400 mg Q2W, 600 mg every week [QW], or 1200 mg Q2W) administered during an initial 4-week dosing period...
2016: Modern Rheumatology
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