Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies.
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.
Bornstein
Gadi Gazit
GG
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. gadi.gazit-bornstein@astrazeneca.com
Quéva
Christophe
C
Tabrizi
Mohammad
M
van Abbema
Anne
A
Chavez
Carlos
C
Wang
Ping
P
Foord
Orit
O
Ahluwalia
Kiran
K
Laing
Naomi
N
Raja
Sandhya
S
Wen
Shenghua
S
Green
Larry L
LL
Yang
Xiaodong
X
Webster
Carl
C
Stewart
Ross
R
Blakey
David
D
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*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D010455:Peptides; D000069283:Rituximab