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Antibody isotype-specific engagement of Fc receptors regulates B lymphocyte depletion during CD20 immunotherapy

¹ Department of Immunology, Duke University Medical Center, Durham, NC 27710
² Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021

CORRESPONDENCE Thomas F. Tedder: thomas.tedder{at}duke.edu

CD20 monoclonal antibody (mAb) immunotherapy is effective for lymphoma and autoimmune disease. In a mouse model of immunotherapy using mouse anti–mouse CD20 mAbs, the innate monocyte network depletes B cells through immunoglobulin (Ig)G Fc receptor (FcR)-dependent pathways with a hierarchy of IgG2a/c>IgG1/IgG2b>IgG3. To understand the molecular basis for these CD20 mAb subclass differences, B cell depletion was assessed in mice deficient or blocked for stimulatory FcRI, FcRIII, FcRIV, or FcR common chain, or inhibitory FcRIIB. IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity FcRIII. IgG2b CD20 mAbs interacted preferentially with intermediate affinity FcRIV. The potency of IgG2a/c CD20 mAbs resulted from FcRIV interactions, with potential contributions from high-affinity FcRI. Regardless, FcRIV could mediate IgG2a/b/c CD20 mAb–induced depletion in the absence of FcRI and FcRIII. In contrast, inhibitory FcRIIB deficiency significantly increased CD20 mAb–induced B cell depletion by enhancing monocyte function. Although FcR-dependent pathways regulated B cell depletion from lymphoid tissues, both FcR-dependent and -independent pathways contributed to mature bone marrow and circulating B cell clearance by CD20 mAbs. Thus, isotype-specific mAb interactions with distinct FcRs contribute significantly to the effectiveness of CD20 mAbs in vivo, which may have important clinical implications for CD20 and other mAb-based therapies.

Abbreviations used: Ab, antibody; ADCC, Ab-dependent cellular cytotoxicity; FcR, Fc receptor for IgG; FcR, Fc receptor common chain.

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