title: Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.
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.
authors.affiliation: Corresponding Author: Christian Klein, Roche Pharma Research and Early Development, Roche Glycart AG, Wagistrasse 18, CH-8952 Schlieren, Switzerland. christian.klein.ck1@roche.com.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herter
authors.forename: Frank
authors.initials: F
authors.lastname: Herting
authors.forename: Olaf
authors.initials: O
authors.lastname: Mundigl
authors.forename: Inja
authors.initials: I
authors.lastname: Waldhauer
authors.forename: Tina
authors.initials: T
authors.lastname: Weinzierl
authors.forename: Tanja
authors.initials: T
authors.lastname: Fauti
authors.forename: Gunter
authors.initials: G
authors.lastname: Muth
authors.forename: Doris
authors.initials: D
authors.lastname: Ziegler-Landesberger
authors.forename: Erwin
authors.initials: E
authors.lastname: Van Puijenbroek
authors.forename: Sabine
authors.initials: S
authors.lastname: Lang
authors.forename: Minh Ngoc
authors.initials: MN
authors.lastname: Duong
authors.forename: Lina
authors.initials: L
authors.lastname: Reslan
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gerdes
authors.forename: Thomas
authors.initials: T
authors.lastname: Friess
authors.forename: Ute
authors.initials: U
authors.lastname: Baer
authors.forename: Helmut
authors.initials: H
authors.lastname: Burtscher
authors.forename: Michael
authors.initials: M
authors.lastname: Weidner
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.forename: Gerhard
authors.initials: G
authors.lastname: Niederfellner
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; C527517:ofatumumab; C543332:obinutuzumab