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Dariush Shanehbandi, Jafar Majidi, Tohid Kazemi, Behzad Baradaran, Leili Aghebati-Maleki
BACKGROUND: CD20-based targeting of B-cells in hematologic malignancies and autoimmune disorders is associated with outstanding clinical outcomes. Isolation and characterization of VH and VL cDNAs encoding the variable regions of the heavy and light chains of monoclonal antibodies (MAb) is necessary to produce next generation MAbs and their derivatives such as and bispecific antibodies (bsAb) and single-chain variable fragments (scFv). OBJECTIVE: This study was aimed at cloning and characterization of the VH and VL cDNAs from a hybridoma cell against the CD20 antigen...
February 24, 2017: Human Antibodies
Othman Al-Sawaf, Kirsten Fischer, Anja Engelke, Natali Pflug, Michael Hallek, Valentin Goede
For decades, treatment of chronic lymphocytic leukemia (CLL) has been based on chemotherapy. This changed when the first CD20 antibody rituximab was introduced. Since 2008, the combination of chemotherapy and CD20 antibodies has become the standard of care for most patients, and a significant fraction of patients had very long-lasting remissions after chemoimmunotherapy. Despite the improvement of response rates and overall survival (OS) by the use of chemoimmunotherapy, most CLL patients will relapse eventually...
2017: Drug Design, Development and Therapy
Wei Wen Chien, Charlène Niogret, Romain Jugé, Loïc Lionnard, Aurélie Cornut-Thibaut, Jérôme Kucharczak, Ariel Savina, Gilles Salles, Abdel Aouacheria
GA101, also known as obinutuzumab or Gazyva (Gazyvaro), is a glycoengineered type II humanized antibody that targets the CD20 antigen expressed at the surface of B-cells. This novel anti-CD20 antibody is currently assessed in clinical trials with promising results as a single agent or as part of therapeutic combinations for the treatment of B-cell malignancies. Detailed understanding of the mechanisms of GA101-induced cell death is needed to get insight into possible resistance mechanisms occurring in patients...
January 18, 2017: Leukemia Research
Kensei Tobinai, Christian Klein, Naoko Oya, Günter Fingerle-Rowson
Obinutuzumab (GA101) is a novel, type II, glycoengineered, humanized anti-CD20 monoclonal antibody that has been developed to address the need for new therapeutics with improved efficacy in patients with lymphocytic leukemia and lymphoma of B-cell origin. Obinutuzumab has a distinct mode of action relative to type I anti-CD20 antibodies, such as rituximab, working primarily by inducing direct cell death and antibody-dependent cell-mediated cytotoxicity. Obinutuzumab is under investigation in a wide-ranging program of clinical trials in patients with B-cell malignancies...
February 2017: Advances in Therapy
Capucine L Grandjean, Fabricio Montalvao, Susanna Celli, David Michonneau, Beatrice Breart, Zacarias Garcia, Mario Perro, Olivier Freytag, Christian A Gerdes, Philippe Bousso
Anti-CD20 monoclonal antibodies (mAbs) represent an effective treatment for a number of B cell malignancies and autoimmune disorders. Glycoengineering of anti-CD20mAb may contribute to increased anti-tumor efficacy through enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP) as reported by in vitro studies. However, where and how glycoengineered Ab may potentiate therapeutic responses in vivo is yet to be elucidated. Here, we have performed mouse liver transplants to demonstrate that the liver is sufficient to mediate systemic B cells depletion after anti-CD20 treatment...
October 4, 2016: Scientific Reports
Tomoko Yasuhiro, Wako Sawada, Christian Klein, Ryohei Kozaki, Shingo Hotta, Toshio Yoshizawa
The activated B-cell diffuse large B-cell-like lymphoma (ABC-DLBCL) correlates with poor prognosis. The B-cell receptor signaling pathway is known to be dysregulated in NHL/CLL and given BTK is a downstream mediator of BCR signaling, BTK constitutes an interesting and obvious therapeutic target. Given the high potency and selectivity of the BTK inhibitor, ONO/GS-4059, it was hypothesized that, the anti-tumor activity of ONO/GS-4059 could be further enhanced by combining it with the anti-CD20 Abs, rituximab (RTX) or obinutuzumab (GA101)...
March 2017: Leukemia & Lymphoma
Laura M Rogers, Sarah L Mott, Brian J Smith, Brian K Link, Deniz Sahin, George J Weiner
Purpose: Anti-CD20 mAb therapies, including rituximab and obinutuzumab (GA101), are common treatments for follicular lymphoma. In an effort to better understand the role of complement in mAb action, we recently performed germline SNP profiling on 142 follicular lymphoma patients and found rs3766404 genotype correlated with patient response to rituximab. To assess the role of three SNP-associated complement-regulatory proteins (CFH, CFHR1, and CFHR3) in clinical response to anti-CD20 mAb, we studied two cohorts of patients treated with anti-CD20 mAb...
February 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Laurie H Sehn, Neil Chua, Jiri Mayer, Gregg Dueck, Marek Trněný, Kamal Bouabdallah, Nathan Fowler, Vincent Delwail, Oliver Press, Gilles Salles, John Gribben, Anne Lennard, Pieternella J Lugtenburg, Natalie Dimier, Elisabeth Wassner-Fritsch, Günter Fingerle-Rowson, Bruce D Cheson
BACKGROUND: Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population. METHODS: In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America...
August 2016: Lancet Oncology
Frank Herting, Sylvia Herter, Thomas Friess, Gunther Muth, Marina Bacac, Jitka Sulcova, Pablo Umana, Markus Dangl, Christian Klein
OBJECTIVES: To investigate whether the glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101) combined with the selective MDM2 antagonist idasanutlin (RG7388) offers superior efficacy to monotherapy in treating B-lymphoid malignancies in preclinical models. METHODS: The combined effect of obinutuzumab or rituximab plus idasanutlin on direct cell death/apoptosis induction and antibody-dependent cellular cytotoxicity (ADCC) was evaluated using p53 wild-type Z-138 and DoHH-2 lymphoma cells...
November 2016: European Journal of Haematology
Keith Dawson, Mollie Moran, Kathleen Guindon, Hui Wan
BACKGROUND: In patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, treatment with the glycoengineered, type II anti-CD20 monoclonal antibody obinutuzumab (Gazyva®) (GA101) plus chlorambucil (Leukeran®) was associated with superior outcomes to rituximab (Rituxan®) plus chlorambucil, with a similar safety profile. However, a higher occurrence of infusion-related reactions (IRRs) was reported with obinutuzumab. These reactions typically require additional management...
April 2016: Clinical Journal of Oncology Nursing
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
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
Ricardo García-Muñoz, Ascensión López-Díaz-de-Cerio, Jesus Feliu, Angel Panizo, Pilar Giraldo, Mercedes Rodríguez-Calvillo, Carlos Grande, Esther Pena, Mayte Olave, Carlos Panizo, Susana Inogés
Follicular lymphoma (FL) is a disease of paradoxes-incurable but with a long natural history. We hypothesized that a combination of lymphokine-activated killer (LAK) cells and monoclonal antibodies might provide a robust synergistic treatment and tested this hypothesis in a phase II clinical trial (NCT01329354). In this trial, in addition to R-CHOP, we alternated the administration of only rituximab with rituximab and autologous LAK cells that were expanded ex vivo. Our objective was to determine the in vitro capability of LAK cells generated from FL patients to produce cytotoxicity against tumor cell lines and to determine rituximab- and obinutuzumab-induced cytotoxicity via antibody-dependent cellular cytotoxicity (ADCC) activity...
April 2016: Immunologic Research
L Ysebaert, E Laprévotte, C Klein, A Quillet-Mary
No abstract text is available yet for this article.
November 13, 2015: Blood Cancer Journal
Aradhana Awasthi, Janet Ayello, Carmella Van de Ven, Mona Elmacken, Anthony Sabulski, Matthew J Barth, Myron S Czuczman, Humayun Islam, Christian Klein, Mitchell S Cairo
Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs...
December 2015: British Journal of Haematology
Laurie H Sehn, Andre Goy, Fritz C Offner, Giovanni Martinelli, M Dolores Caballero, Ole Gadeberg, Tara Baetz, Andrew D Zelenetz, Gianluca Gaidano, Luis E Fayad, Rena Buckstein, Jonathan W Friedberg, Michael Crump, Branimir Jaksic, Pier Luigi Zinzani, Swaminathan Padmanabhan Iyer, Deniz Sahin, Akiko Chai, Günter Fingerle-Rowson, Oliver W Press
PURPOSE: Obinutuzumab (GA101), a novel glycoengineered type II anti-CD20 monoclonal antibody, demonstrated responses in single-arm studies of patients with relapsed/refractory non-Hodgkin lymphoma. This is the first prospective, randomized study comparing safety and efficacy of obinutuzumab with rituximab in relapsed indolent lymphoma. The primary end point of this study was the overall response rate (ORR) in patients with follicular lymphoma after induction and safety in patients with indolent lymphoma...
October 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Elisa Göckeritz, Susan Kerwien, Michael Baumann, Marion Wigger, Verena Vondey, Lars Neumann, Thomas Landwehr, Clemens M Wendtner, Christian Klein, Ningshu Liu, Michael Hallek, Lukas P Frenzel, Günter Krause
Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-α or PI3K-γ, respectively...
November 1, 2015: International Journal of Cancer. Journal International du Cancer
Valentin Goede, Christian Klein, Stephan Stilgenbauer
Obinutuzumab (GA101) is a humanized, monoclonal type II CD20 antibody modified by glycoengineering. The glycoengineered Fc portion enhances the binding affinity to the FcγRIII receptor on immune effector cells, resulting in increased antibody-dependent cellular cytotoxicity and phagocytosis. In addition, the type II antibody binding characteristics of obinutuzumab to CD20 lead to an efficient induction of direct non-apoptotic cell death. Preclinical data demonstrated more efficient B-cell depletion in whole blood and superior antitumor activity in xenograft models of obinutuzumab as compared to the type I CD20 antibody rituximab...
2015: Oncology Research and Treatment
Sonia Cerquozzi, Carolyn Owen
The introduction of targeted therapy against CD20(+) with the monoclonal antibody rituximab has dramatically improved the survival of B-cell non-Hodgkin lymphoma including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. Unfortunately, CLL remains incurable with chemoimmunotherapy, with many patients having refractory or relapsing disease after rituximab-containing therapy. Obinutuzumab (GA101) is a novel humanized Type II anti-CD20 monoclonal antibody that has been investigated and compared to rituximab...
2015: Biologics: Targets & Therapy
Lukáš Smolej
Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL...
2015: Pharmacogenomics and Personalized Medicine
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