title: Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20(+) rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): potential targeted therapy in patients with poor risk CD20(+) BL and pre-B-ALL.
abstract: Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs. 25·1 ± 2·0%, (P = 0·001), Raji4RH 19·7 ± 2·2% vs. 7·9 ± 1·5% (P = 0·001) and U-698-M 47·3 ± 4·9% vs. 23·2 ± 0·5% (P = 0·001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73·8 ± 8·1% vs. 56·81 ± 4·6% (P = 0·001), Raji-4RH 40·0 ± 1·6% vs. 0·5 ± 1·1% (P = 0·001) and U-698-M 70·0 ± 1·6% vs. 45·5 ± 0·1% (P = 0·001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (P = 0·05), Raji4RH (P = 0·02) and U698-M (P = 0·03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Aradhana
authors.initials: A
authors.lastname: Awasthi
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Ayello
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Carmella
authors.initials: C
authors.lastname: Van de Ven
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Elmacken
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Sabulski
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Barth
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, NY, USA.
authors.forename: Humayun
authors.initials: H
authors.lastname: Islam
authors.affiliation: Roche Pharmaceutical Research & Early Development, Roche Innovation Centre, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY, USA.|Department of Pathology, New York Medical College, Valhalla, NY, USA.|Department of Medicine, New York Medical College, Valhalla, NY, USA.|Department of Microbiology & Immunology, New York Medical College, Valhalla, NY, USA.|Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000188:drug therapy*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D000069283:Rituximab / Q000494:pharmacology*; D016019:Survival Analysis; D014183:Transplantation, Heterologous
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D052118:Lysosomal-Associated Membrane Protein 1; D000069283:Rituximab; D007371:Interferon-gamma; D020169:Caspases; C543332:obinutuzumab
keywords: obinutuzumab; pre-B-ALL; rituximab; rituximab-resistant BL; rituximab-sensitive BL