title: Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies.
abstract: Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to rituximab, in the Ramos lymphoma cell line. Also, mAb 1.5.3 mediated both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) similar to rituximab in human B-lymphoma lines. Interestingly, mAb 1.5.3 demonstrated superior ADCC compared to rituiximab when FcgammaRIIIa F/F allotype donors were profiled and superior cytolytic activity across multiple human B-lymphoma and chronic B-cell leukemia lines in an in vitro whole blood assay. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Ramos, Daudi, and Namalwa tumour xenograft models. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to rituximab in a primate pharmacodynamic (PD) model. These findings underscore the potential of mAb 1.5.3 to exhibit improved clinical activity in the treatment of B-cell malignancies compared to rituximab.
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. gadi.gazit-bornstein@astrazeneca.com
authors.forename: Gadi Gazit
authors.initials: GG
authors.lastname: Bornstein
authors.forename: Christophe
authors.initials: C
authors.lastname: Quéva
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tabrizi
authors.forename: Anne
authors.initials: A
authors.lastname: van Abbema
authors.forename: Carlos
authors.initials: C
authors.lastname: Chavez
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Orit
authors.initials: O
authors.lastname: Foord
authors.forename: Kiran
authors.initials: K
authors.lastname: Ahluwalia
authors.forename: Naomi
authors.initials: N
authors.lastname: Laing
authors.forename: Sandhya
authors.initials: S
authors.lastname: Raja
authors.forename: Shenghua
authors.initials: S
authors.lastname: Wen
authors.forename: Larry L
authors.initials: LL
authors.lastname: Green
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.forename: Carl
authors.initials: C
authors.lastname: Webster
authors.forename: Ross
authors.initials: R
authors.lastname: Stewart
authors.forename: David
authors.initials: D
authors.lastname: Blakey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D018951:Antigens, CD20 / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018604:Epitope Mapping; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D010455:Peptides; D000069283:Rituximab