Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models

• Published in: Molecular cancer therapeutics 2013-10, Vol.12 (10), p.2031-2042
• Main Authors: Herter, Sylvia, Herting, Frank, Mundigl, Olaf, Waldhauer, Inja, Weinzierl, Tina, Fauti, Tanja, Muth, Gunter, Ziegler-Landesberger, Doris, Van Puijenbroek, Erwin, Lang, Sabine, Duong, Minh Ngoc, Reslan, Lina, Gerdes, Christian A, Friess, Thomas, Baer, Ute, Burtscher, Helmut, Weidner, Michael, Dumontet, Charles, Umana, Pablo, Niederfellner, Gerhard, Bacac, Marina, Klein, Christian
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Murine-Derived - administration & dosage; Apoptosis - drug effects; Cell Line, Tumor; Cytotoxicity, Immunologic - drug effects; Humans; Mice; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - pathology; Phagocytosis - drug effects; Phagocytosis - immunology; Rituximab; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-12-1182

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.