Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models
Sylvia Herter,Frank Herting,Olaf Mundigl,Inja Waldhauer,Tina Weinzierl,Tanja Fauti,Gunter Muth,Doris Ziegler-Landesberger,Erwin van Puijenbroek,Sabine Lang,Minh Ngoc Duong,Lina Reslan,Christian Gerdes,Thomas Friess,Ute Baer,Helmut Burtscher,K. Michael Weidner,Charles Dumontet,Pablo Umana,Gerhard Niederfellner,Marina Bacac,Christian Klein +21 more
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The first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies was reported in this article.Abstract:
We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigationread more
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Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions
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Michael Hallek,Kirsten Fischer,Günter Fingerle-Rowson,Anna-Maria Fink,Raymonde Busch,Jiří Mayer,Manfred Hensel,Georg Hopfinger,G D Hess,U. Von Grünhagen,Matthias Bergmann,John Catalano,Pier Luigi Zinzani,Federico Caligaris-Cappio,John F. Seymour,Alain Berrebi,Ulrich Jäger,Bruno Cazin,Marek Trneny,Anne Westermann,Clemens M. Wendtner,Barbara Eichhorst,Peter Staib,Andreas Bühler,Dirk Winkler,Thorsten Zenz,S Böttcher,Matthias Ritgen,Myriam Mendila,Michael Kneba,Hartmut Döhner,Stephan Stilgenbauer +31 more
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Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte
Bertrand Coiffier,Catherine Thieblemont,Eric Van Den Neste,Gérard Lepeu,Isabelle Plantier,Sylvie Castaigne,Sophie Lefort,Gerald Marit,Margaret Macro,Catherine Sebban,Karim Belhadj,Dominique Bordessoule,Christophe Fermé,Hervé Tilly +13 more
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Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicity
Ekkehard Mössner,Peter Brünker,Samuel Moser,Ursula Püntener,Carla Schmidt,Sylvia Herter,Roger Grau,Christian Gerdes,Adam Nopora,Erwin van Puijenbroek,Claudia Ferrara,Peter Sondermann,Christiane Jäger,Pamela Strein,Georg Fertig,Thomas Friess,Christine Schüll,Sabine Bauer,Joseph Dal Porto,Christopher Del Nagro,Karim Dabbagh,Martin J. S. Dyer,Sibrand Poppema,Christian Klein,Pablo Umana +24 more
TL;DR: In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival and in nonhuman primates, GA 101 demonstrates superior B cell-depleting activity in lymphoid tissue, including in lymph nodes and spleen.
Journal ArticleDOI
Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose
Claudia Ferrara,Sandra Grau,Christiane Jäger,Peter Sondermann,Peter Brünker,Inja Waldhauer,Michael Hennig,Armin Ruf,Arne C. Rufer,Martine Stihle,Pablo Umana,Jörg Benz +11 more
TL;DR: A detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC is obtained and a unique mechanism by which the immune system can regulate antibody-mediated effector functions is suggested.
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Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas
Jessica L. Teeling,Ruth R. French,Mark S. Cragg,Jeroen van den Brakel,Marielle Pluyter,Haichun Huang,Claude H.T. Chan,Paul W. H. I. Parren,C. Erik Hack,Michael Dechant,Thomas Valerius,Jan G. J. van de Winkel,Martin J. Glennie +12 more
TL;DR: With increasing evidence that mAb therapeutic activity in vivo depends on complement activation, these new CD20 reagents with their slow off-rates and increased potency in CDC hold considerable promise for improved clinical activity.
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