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Investigational new drugs · Oct 2010
Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies.
- Gadi Gazit Bornstein, Christophe Quéva, Mohammad Tabrizi, Anne van Abbema, Carlos Chavez, Ping Wang, Orit Foord, Kiran Ahluwalia, Naomi Laing, Sandhya Raja, Shenghua Wen, Larry L Green, Xiaodong Yang, Carl Webster, Ross Stewart, and David Blakey.
- AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. gadi.gazit-bornstein@astrazeneca.com
- Invest New Drugs. 2010 Oct 1; 28 (5): 561-74.
AbstractDespite 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.
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