title: Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101.
abstract: GA101 is a novel glycoengineered Type II CD20 monoclonal antibody. When compared with rituximab, it mediates less complement-dependent cytotoxicity (CDC). As expected for a Type II antibody, GA101 appears not to act through CDC and is more potent than the Type I antibody rituximab in inducing cell death via nonclassical induction of apoptosis cytotoxicity, with more direct cytotoxicity and more antibody-dependent cell-mediated cytotoxicity. We evaluated the antitumor activity of GA101 against the human-transformed follicular lymphoma RL model in vivo in severe combined immunodeficient mice (SCID) mice. GA101 induced stronger inhibition of tumor growth than rituximab. Combination of GA101 with cyclophosphamide in vivo confirmed the superiority of GA101 over rituximab. Neutralizing the complement system with cobra venom factor partially impaired the antitumor activity of rituximab, but had no impact on the efficacy of GA101. In vitro GA101 more potently induced cell death of RL cells than rituximab. The expression of a limited number of genes was found to be induced by both antibodies after exposure in vitro. Among these, early growth response 1 and activation transcription factor 3 were confirmed to be increased at the protein level, suggesting a possible role of these proteins in the apoptotic signalling of anti-CD20 antibodies. These data imply that GA101 is superior to rituximab not only as a single agent, but also in combination with chemotherapy. These data suggest the presence of novel signalization pathways activated after exposure to anti-CD20 antibodies.
authors.affiliation: Charles Dumontet, INSERM U590, Laboratoire de Cytologie Analytique, Faculte de Medecine Rockefeller, Universite Claude Bernard Lyon I, Lyon, France. charles.dumontet@chu-lyon.fr
authors.forename: Stephane
authors.initials: S
authors.lastname: Dalle
authors.forename: Lina
authors.initials: L
authors.lastname: Reslan
authors.forename: Timothee
authors.initials: T
authors.lastname: Besseyre de Horts
authors.forename: Stephanie
authors.initials: S
authors.lastname: Herveau
authors.forename: Frank
authors.initials: F
authors.lastname: Herting
authors.forename: Adriana
authors.initials: A
authors.lastname: Plesa
authors.forename: Thomas
authors.initials: T
authors.lastname: Friess
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived / Q000097:blood / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000097:blood / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008224:Lymphoma, Follicular / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab; D003520:Cyclophosphamide; C543332:obinutuzumab