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. 2006 Mar 20;203(3):743-53.
doi: 10.1084/jem.20052283. Epub 2006 Mar 6.

VSports注册入口 - Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy

Yasuhito Hamaguchi  1 , Yan Xiu, Kazuhiro Komura, Falk Nimmerjahn, Thomas F Tedder
Affiliations

"VSports注册入口" Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy

Yasuhito Hamaguchi et al. J Exp Med. .

Abstract

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

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VSports - Figures

Figure 1.
Figure 1.
IgG1, IgG2c, and IgG2b CD20 mAb reactivity with B cells in wild-type, FcRγ−/−, FcγRI−/−, FcγRIIB−/−, and FcγRIII−/− mice. CD20 mAb reactivity with enriched spleen B cells as assessed by indirect immunofluorescence staining with flow cytometry analysis. Fluorescence intensities of CD20+ cells stained with CD20 (solid line) or isotype-matched control (dashed line) mAbs shown on a four-decade log scale.
Figure 2.
Figure 2.
Isotype-specific CD20 mAb utilization of FcγRI, FcγRIIB, FcγRIII, and FcRγ during B cell depletion. (A) MB20-1 (IgG1), MB20-11 (IgG2c), or MB20-18 (IgG2b) CD20 mAb depletion of B cells in wild-type, FcγRI−/−, FcγRIIB−/−, and FcγRIII−/− mice. Bone marrow (mature IgM+B220hi), blood (B220+), spleen (mature CD24+CD21+B220+), and peripheral lymph node (B220+) B cell numbers were determined for 7 d after mAb treatment at the indicated doses. Values (±SEM) represent the percentage of B cells present in mAb-treated mice (two or more mice per value) relative to control mAb–treated littermates (250 μg; two or more mice per value). Significant differences between sample means of mice treated with MB20-1 and MB20-11 mAbs (*, P < 0.05; **, P < 0.01) or MB20-1 and MB20-18 mAbs (†, P < 0.05; ††, P < 0.01) are indicated. (B) Comparison of B cell depletion for each mAb isotype in FcRγ−/−, FcγRI−/−, and FcγRIII−/− mice as shown in A. Significant differences between sample means of wild-type mice and each mutant strain are indicated: †, P < 0.05; ††, P < 0.01.
Figure 3.
Figure 3.
FcγRIV mediates B cell depletion by IgG2b (MB20-18) and IgG2c (MB20-11) CD20 mAbs. (A) Blood, spleen, and lymph node B cell depletion in FcγRI−/−/FcγRIII−/− and wild-type mice treated with MB20-18 (100 μg; gray circles/bars), MB20-11 (25 μg; filled circles/bars), or control IgG2a (100 μg; open circles/bars) mAbs. Values (±SEM) indicate mean circulating B cell numbers (per ml) before (time 0) and 1 h or 1, 2, 4, or 7 d after mAb treatment (three or more mice per value). Mean (±SEM) spleen or lymph node B cell numbers were determined 7 d after mAb treatment (three or more mice per group). (B) B cell depletion in wild-type mice treated with IgG2b control mAb (100 μg; open circles/bars) or MB20-18 mAb (100 μg; filled circles/bars) in combination with FcγRIV-blocking 9E9 (200 μg; gray circles/bars) or control (CTL; 200 μg; filled circles/bars) mAb on day 0 as indicated. (C) B cell depletion in mAb-treated wild-type or FcγRI−/− mice. Mice were treated with IgG2a control mAb (2.5 or 25 μg; open circles/bars) or MB20-11 mAb (2.5 or 25 μg; filled circles/bars) in combination with FcγRIV-blocking 9E9 mAb (200 μg; gray circles/bars) or control (CTL; 200 μg; filled circles/bars) mAb on day 0 as indicated. In A–C, significant differences between mean results for control and CD20 mAb–treated mice are indicated (†, P < 0.05; ††, P < 0.01), with numbers indicating the mean relative percentages of B220+ lymphocytes in MB20-11/MB20-18 mAb–treated mice compared with control mAb–treated littermates.
Figure 4.
Figure 4.
FcγRIIB deficiency augments CD20 mAb–induced B cell depletion. Bone marrow (mature IgM+B220hi), blood (B220+), spleen (mature CD24+CD21+B220+), and lymph node (B220+) B cell numbers were determined for wild-type and FcγRIIB−/− mice 7 d after MB20-1, MB20-11, or MB20-18 mAb treatment at the indicated doses. Values (±SEM) represent the percentage of B cells present in mAb-treated mice (two or more mice per value) relative to control mAb–treated littermates (250 μg; two or more mice per value), with significant differences between sample means of wild-type mice and each mutant strain indicated: †, P < 0.05; ††, P < 0.01.
Figure 5.
Figure 5.
FcγRIIB−/− B cells resist CD20 mAb–induced depletion in wild-type mice. (A) Flow cytometry analysis of FcγRIIB expression (thick lines) by B cell subsets from FcRγ−/− mice. Spleen B cell subsets were identified as mature (CD24+CD21+B220+), T1 (CD24hiCD21−B220+), and T2 (CD24hiCD21+B220+). Peritoneal cavity B cell subsets were identified as B-1a (CD5+CD11b+IgMhiB220lo), B-1b (CD5−CD11b+IgMhiB220lo), and B2 (CD5−IgMloB220hi). Solid lines indicate 2.4G2 mAb staining, and dotted lines indicate isotype-matched control mAb reactivity. (B) Flow cytometry analysis of CFSE-labeled B220+ and B220− lymphocytes from wild-type and FcγRIIB−/− mice on day 1 indicating gates used to assess frequencies of adoptively transferred CFSE+ wild-type and FcγRIIB−/− cells. Splenocytes from wild-type (WT) and FcγRIIB−/− (RIIB−/−) mice were labeled with CFSE at different intensities, mixed, and transferred into wild-type littermates 1 d before treatment with MB20-11 or control mAb (25 μg). After 1 d, blood, spleen, and peripheral lymph node lymphocytes were isolated and assessed for B220 expression. Bar graphs indicate the relative ratios of cells from wild-type and FcγRIIB−/− donors within the CFSE-labeled B220+ and B220− lymphocyte populations. Results represent those obtained with three or more mouse pairs, with significant differences between sample means (±SEM) indicated: *, P < 0.05; **, P < 0.01.
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