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Molecular Cancer Therapeutics
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Large Molecule Therapeutics

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 A. Gerdes, Thomas Friess, Ute Baer, Helmut Burtscher, Michael Weidner, Charles Dumontet, Pablo Umana, Gerhard Niederfellner, Marina Bacac and Christian Klein
Sylvia Herter
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Frank Herting
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Olaf Mundigl
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Inja Waldhauer
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Tina Weinzierl
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Tanja Fauti
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Gunter Muth
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Doris Ziegler-Landesberger
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Erwin Van Puijenbroek
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Sabine Lang
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Minh Ngoc Duong
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Lina Reslan
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Christian A. Gerdes
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Thomas Friess
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Ute Baer
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Helmut Burtscher
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Michael Weidner
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Charles Dumontet
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Pablo Umana
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Gerhard Niederfellner
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Marina Bacac
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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Christian Klein
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland; 2Discovery Oncology and 3Large Molecule Research, Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany; and 4Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Medicale (INSERM) UMR 1052/CNRS 5286, Lyon, France
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DOI: 10.1158/1535-7163.MCT-12-1182 Published October 2013
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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 investigation. Mol Cancer Ther; 12(10); 2031–42. ©2013 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received December 10, 2012.
  • Revision received May 23, 2013.
  • Accepted June 25, 2013.
  • ©2013 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 12 (10)
October 2013
Volume 12, Issue 10
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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 A. Gerdes, Thomas Friess, Ute Baer, Helmut Burtscher, Michael Weidner, Charles Dumontet, Pablo Umana, Gerhard Niederfellner, Marina Bacac and Christian Klein
Mol Cancer Ther October 1 2013 (12) (10) 2031-2042; DOI: 10.1158/1535-7163.MCT-12-1182

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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 A. Gerdes, Thomas Friess, Ute Baer, Helmut Burtscher, Michael Weidner, Charles Dumontet, Pablo Umana, Gerhard Niederfellner, Marina Bacac and Christian Klein
Mol Cancer Ther October 1 2013 (12) (10) 2031-2042; DOI: 10.1158/1535-7163.MCT-12-1182
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Molecular Cancer Therapeutics
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