Rituximab mediates loss of CD19 on B cells in the absence of cell death

Jones, Jonathan D. G.; Hamilton, Byron B.; Rigby, William F.C.

doi:10.1002/art.34560

Cited by 46 publications

(53 citation statements)

References 23 publications

(42 reference statements)

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“…Both hRFB4, a humanized anti-CD22 mAb that binds to a different epitope than epratuzumab, and hA19 also mediate trogocytosis of multiple B-cell proteins, as shown here. In the present study, we confirmed the ex vivo reduction of CD19 on B cells in PBMCs by rituximab, 41 which also mediated trogocytosis of CD21, CD79b, and CD22. Except for CD22, each antigen was reduced more by rituximab than epratuzumab, likely due to the ;10-fold higher expression of CD20 compared with CD22, wherein the latter is also more rapidly internalized upon antibody ligation, 8,9 and internalization is expected to compete with trogocytosis.…”

Section: Discussionsupporting

confidence: 76%

Trogocytosis of multiple B-cell surface markers by CD22 targeting with epratuzumab

Rossi

Goldenberg

Michel

et al. 2013

Blood

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Section: Discussionsupporting

confidence: 76%

Trogocytosis of multiple B-cell surface markers by CD22 targeting with epratuzumab

Rossi

Goldenberg

Michel

et al. 2013

Blood

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“…Many of our findings of trogocytosis and effector function exhaustion with respect to CD20 mAbs in CLL have been replicated and extended, in some cases to other mAb-antigen pairs, in the clinic and in the laboratory Jones et al, 2012;Masuda et al, 2013;Rossi et al, 2013;Baig et al, 2014). Therefore, the implications of these studies with respect to use of CD20 mAbs may also pertain to other mAbs currently used to treat cancer.…”

Section: Possible Generalization To Othermentioning

confidence: 83%

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Taylor

Lindorfer

2014

Mol Pharmacol

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Since approval of rituximab for treatment of B cell non-Hodgkin lymphoma, development of monoclonal antibodies (mAbs) for cancer treatment and elucidation of their cytotoxic mechanisms have been subject to intense investigations. Compelling evidence indicates that rituximab and another CD20 mAb, ofatumumab, must use the body's cellular and humoral immune effector functions to kill malignant cells. Other U.S. Food and Drug Administration-approved mAbs, including obinutuzumab, cetuximab, and trastuzumab, require, in part, these effector mechanisms to eliminate tumor cells. Although gram quantities of mAbs can be administered to patients, our investigations of CD20 mAb-based therapies for chronic lymphocytic leukemia (CLL), including correlative measurements in clinical trials and studies with primary cells and cell lines, indicate that effector mechanisms necessary for mAb activity can be saturated or exhausted if tumor burdens are high, thus substantially compromising the efficacy of high-dose mAb therapy. Under these conditions, another reaction (trogocytosis) predominates in which bound CD20 mAb and CD20 are removed from targeted cells by effector cells that express Fcg receptors, thereby allowing malignant cells to escape unharmed and continue to promote disease pathology. To address this problem, we propose that a low-dose strategy, based on administering 30-50 mg of CD20 mAb three times per week, may be far more effective for CLL than standard dosing because it will minimize effector function saturation and reduce trogocytosis. This approach may have general applicability to other mAbs that use immune effector functions, and could be formulated into a subcutaneous treatment strategy that would be more accessible and possibly more efficacious for patients.

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“…We read with great interest the article by Jones et al in which they reported that measurement of CD19ϩ cells as a marker of rituximab (RTX)-induced B cell depletion might be flawed (1). The authors noted that the addition of RTX to healthy donor peripheral blood mononuclear cells (PBMCs) in vitro resulted in a loss of CD19 expression on B cells in the absence of cell death.…”

Section: To the Editormentioning

confidence: 99%

CD19 Is a Useful B Cell Marker After Treatment With Rituximab: Comment on the Article by Jones et al

Kamburova

Koenen

Joosten

et al. 2013

Arthritis & Rheumatism

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on a model in which pregnant non-SLE mice actively immunized to generate anti-NMDA receptor antibodies (similar to anti-DNA) have more male pups due to toxic effects specific to female mice. Wang and colleagues predict that women with SLE, having similar autoantibodies, will also deliver too few girls.Vinet et al examined administrative records to identify the sex of babies of several pregnancies of women who had a hospital discharge diagnosis code of SLE. We (in the PROMISSE study [ , all of whom were tested for anti-DNA, and a subset of whom were evaluated for anti-NMDA receptors. Vinet et al did not examine autoantibodies.The methods used and the results found in the studies by the PROMISSE group, by Vinet et al, and by Wang et al are clearly discordant (Table 1). In the anti-NMDA receptorpositive mice studied by Wang and colleagues, the male-tofemale ratio was 2.23. In the PROMISSE study, male-tofemale ratios were 0.87 for all SLE patients, 0.91 for SLE patients with anti-NMDA receptors, and 0.67 for SLE patients with anti-DNA. Vinet et al found a male-to-female ratio of 1.26 but did not comment on specific documentation of ACR criteria or autoantibody status during pregnancy. Although a limited sample size was used (which could lead to a Type II error), the PROMISSE study provides stronger evidence to refute Wang and colleagues' prediction regarding the consequences of female susceptibility to anti-NMDA receptors than Vinet's more indirect study does to support it.

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Rituximab mediates loss of CD19 on B cells in the absence of cell death

Cited by 46 publications

References 23 publications

Trogocytosis of multiple B-cell surface markers by CD22 targeting with epratuzumab

Trogocytosis of multiple B-cell surface markers by CD22 targeting with epratuzumab

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

CD19 Is a Useful B Cell Marker After Treatment With Rituximab: Comment on the Article by Jones et al

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