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Investigational New Drugs

, Volume 28, Issue 5, pp 561–574 | Cite as

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
  • David Blakey
PRECLINICAL STUDIES

Summary

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 FcγRIIIa 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.

Keywords

CD20 Antibody ADCC CDC Apoptosis Lymphoma 

Notes

Acknowledgments

This study was supported by research funding from AstraZeneca PLC to GGB, CQ, MT, AV, CC, PW, NL, SR, SW, OF, KA, LLG, XY, CW, RS, and DB.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Gadi Gazit Bornstein
    • 1
  • Christophe Quéva
    • 1
  • Mohammad Tabrizi
    • 2
  • Anne van Abbema
    • 2
  • Carlos Chavez
    • 2
  • Ping Wang
    • 2
  • Orit Foord
    • 2
  • Kiran Ahluwalia
    • 2
  • Naomi Laing
    • 1
  • Sandhya Raja
    • 1
  • Shenghua Wen
    • 1
  • Larry L. Green
    • 2
  • Xiaodong Yang
    • 2
  • Carl Webster
    • 3
  • Ross Stewart
    • 3
  • David Blakey
    • 4
  1. 1.AstraZeneca R&D BostonWalthamUSA
  2. 2.Amgen Fremont Inc.FremontUSA
  3. 3.MedImmune Ltd.CambridgeUK
  4. 4.AstraZenecaCheshireUK

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