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

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 (Fc gamma R)-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 Fc gamma RI, Fc gamma RIII, Fc gamma RIV, or FcR common.. chain, or inhibitory Fc gamma RIIB. IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity Fc gamma RIII. IgG2b CD20 mAbs interacted preferentially with intermediate affinity Fc gamma RIV. The potency of IgG2a/c CD20 mAbs resulted from Fc gamma RIV interactions, with potential contributions from high-affinity Fc gamma RI. Regardless, Fc gamma RIV could mediate IgG2a/b/c CD20 mAb-induced depletion in the absence of Fc gamma RI and Fc gamma RIII. In contrast, inhibitory Fc gamma RIIB deficiency significantly increased CD20 mAb induced B cell depletion by enhancing monocyte function. Although Fc gamma R-dependent pathways regulated B cell depletion from lymphoid tissues, both Fc gamma R-dependent and -independent pathways contributed to mature bone marrow and circulating B cell clearance by CD20 mAbs. Thus, isotype-specific mAb interactions with distinct Fc gamma Rs contribute significantly to the effectiveness of CD20 mAbs in vivo, which may have important clinical implications for CD20 and other mAb-based therapies.