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 Blood, 15 August 2008, Vol. 112, No. 4, pp. 1205-1213.
Prepublished online as a Blood First Edition Paper on May 21, 2008; DOI 10.1182/blood-2008-01-135160.

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IMMUNOBIOLOGY

Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage Fc{gamma}RI, Fc{gamma}RIII, and Fc{gamma}RIV

Veronique Minard-Colin1,*, Yan Xiu1,*, Jonathan C. Poe1, Mayuka Horikawa1, Cynthia M. Magro2, Yasuhito Hamaguchi1, Karen M. Haas1, and Thomas F. Tedder1

1 Department of Immunology, Duke University Medical Center, Durham, NC; and 2 Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York, NY

Despite the demonstrated clinical efficacy of CD20 monoclonal antibody (mAb) for lymphoma therapy, the in vivo mechanisms of tumor depletion remain controversial and variable. To identify the molecular mechanisms responsible for lymphoma killing by CD20 mAb in a homologous system amenable to mechanistic studies and genetic manipulation, a mouse lymphoma model was developed using primary tumor cells from a C57BL/6 Eµ-cMyc transgenic mouse and mouse antimouse CD20 mAbs. CD20 mAb treatment of syngeneic mice with adoptively transferred lymphomas prevented tumor development or significantly prolonged mouse survival depending on tumor volume, mAb dose, and treatment timing. Cooperative Fc{gamma}RIV, Fc{gamma}RIII, and Fc{gamma}RI interactions mediated optimal lymphoma depletion by CD20 mAb in vivo, whereas clodronate-mediated depletion of macrophages eliminated the therapeutic benefit of CD20 mAb. Although CD20 mAbs activated complement in vitro and in vivo, normal and malignant B-cell depletion was induced through C1q- and C3-independent mechanisms. Thus, the ability of CD20 mAbs to deplete malignant B cells in vivo required Fc{gamma}R-dependent use of the innate mononuclear cell immune system. These findings allow for mechanism-based predictions of the biologic outcome of CD20 mAb therapy and treatment optimization.


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