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Critical Reviews™ in Immunology
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ISSN Print: 1040-8401
ISSN Online: 2162-6472

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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2014009761
pages 199-214

Complement in Antibody-Based Tumor Therapy

Stefanie Derer
Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany
Frank J. Beurskens
Genmab, 3584 CM Utrecht, The Netherlands
Thies Rosner
Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany
Matthias Peipp
Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany
Thomas Valerius
Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany

ABSTRACT

Monoclonal antibodies constitute a major treatment option for many tumor patients. Due to their specific recognition sites in their constant Fc regions, antibodies are able to trigger antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). While the contribution of ADCC to clinical efficacy has been strengthened by observations that patients with favorable F receptor polymorphisms display better response rates to therapeutic antibodies, the contribution of CDC to their clinical efficacy remains controversial. In the background of high expression of complement-regulatory proteins on tumor cells as well as of the fact that some therapeutic antibodies lack the capacity to trigger efficient CDC, strategies have been implemented to improve either the capacity of antibodies to initiate the complement cascade or to interfere with tumor cells' resistance mechanisms. Although both strategies have demonstrated therapeutic benefit in vitro and in murine models, CDC-enhanced antibodies−to the best of our knowledge−have not been clinically tested, and evidence for the potential of CDC-optimizing approaches has yet to be generated in humans. Hence, the potency of complement activation and its impact on the clinical efficacy of therapeutic antibodies still remains to be elucidated in clinical trials encompassing novel complement-enhancing molecules.


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