Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies

  • Invest New Drugs. 2010 Oct;28(5):561-74. doi: 10.1007/s10637-009-9291-z.
Gadi Gazit Bornstein  1 ,  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 ,  David Blakey
Affiliations
  • 1. AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. [email protected]
PMID: 19626278 DOI: 10.1007/s10637-009-9291-z
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.

Products