Effect of anti‐CD20 monoclonal antibody, Rituxan, on cynomolgus monkey and human B cells in a whole blood matrix

Vugmeyster, Yulia; Howell, Kathy; Bakshl, Anahid; Flores, C.; Canova-Davis, Eleanor

doi:10.1002/cyto.a.10030

Cited by 41 publications

(34 citation statements)

References 25 publications

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“…2B). Consistent with the reports of Vugmetster et al (22,34) that target B cells were sufficiently depleted from human whole blood just after 1-hour treatment with rituximab at 10 Ag/mL, the added anti-CD20s effectively depleted B cells and showed the saturable efficacy at antibody concentrations over 1 Ag/mL regardless of the incubation time. The greatly enhanced ex vivo ADCC of nonfucosylated anti-CD20 was clearly observed even after 4 hours of incubation.…”

Section: Resultssupporting

confidence: 88%

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Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa

Iida

Misaka

Inoue

et al. 2006

Clinical Cancer Research

195

148

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Purpose: Recent studies have revealed that fucosylated therapeutic IgG1s need high concentrations to compensate for FcgRIIIa-competitive inhibition of antibody-dependent cellular cytotoxicity (ADCC) by endogenous human plasma IgG. Here, we investigated whether ADCC of nonfucosylated therapeutic IgG1 is also influenced by plasma IgG in the same way as fucosylated IgG1s. Experimental Design: Ex vivo ADCC upon CD20 + human B cells was induced by incubation of human whole blood with nonfucosylated and/or fucosylated anti-CD20 IgG1s rituximab, and quantified by measuring the remaining CD19 + human B cells using flow cytometry. Results: Nonfucosylated anti-CD20 showed markedly higher (over 100-fold based on EC 50 ) ex vivo B-cell depletion activity than its fucosylated counterpart in the presence of plasma IgG. The efficacy of fucosylated anti-CD20 was greatly diminished in plasma, resulting in the need for a high concentration (over 1.0 Ag/mL) to achieve saturated efficacy. In contrast, nonfucosylated anti-CD20 reached saturated ADCC at lower concentrations (0.01-0.1 Ag/mL) with much higher efficacy than fucosylated anti-CD20 in all nine donors through improved FcgRIIIa binding. Noteworthy, the high efficacy of nonfucosylated anti-CD20 was inhibited by addition of fucosylated anti-CD20. Thus, the efficacy of a 1:9 mixture (10 Ag/mL) of nonfucosylated and fucosylated anti-CD20s was inferior to that of a 1,000-fold dilution (0.01 Ag/mL) of nonfucosylated anti-CD20 alone. Conclusions: Our data showed that nonfucosylated IgG1, not including fucosylated counterparts, can evade the inhibitory effect of plasma IgG on ADCC through its high FcgRIIIa binding. Hence, nonfucosylated IgG1exhibits strong therapeutic potential through dramatically enhanced ADCC at low doses in humans in vivo.

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Section: Resultssupporting

confidence: 88%

“…A FACSCalibur was used for acquisition and analysis of all samples. The B-cell depletion activity of anti-CD20 IgG1 was determined by the following gating strategy as reported previously (22,34). The lymphocyte population was gated on the forward and side scatter dot plot.…”

Section: Methodsmentioning

confidence: 99%

Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa

Iida

Misaka

Inoue

et al. 2006

Clinical Cancer Research

195

148

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“…Several control antibodies were used in this study, including MSL109 as a negative control, rituximab (Rituxan; Genentech/Biogen Idec), an anti-CD20 antibody that depletes B cells in vitro and in vivo (36,37), and alemtuzumab (Campath1H; Berlex/ILEX Oncology Inc/Genzyme), an anti-CD52 antibody that depletes various lymphocytes in vivo (38) as positive controls. Samples were tested for depletion of T, NK, B, and memory B cells as measured by a decrease in absolute cell counts by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

Hsi

Steinle

Balasa

et al. 2008

Clinical Cancer Research

509

537

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Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models. Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.Results: CS1mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like Tcells, and CD8+ Tcells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice. Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1with HuLuc63 for the treatment of multiple myeloma.

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“…Rituximab induces B cell death primarily through complement-dependent lysis and antibody-dependent cellular toxicity effector mechanisms and to a lesser degree via cellular apoptosis (106). Administration of rituximab results in rapid and sustained depletion of circulating and tissue B cells in humans and monkeys (106)(107)(108)(109). The strong evidence for biodistribution of rituximab in critical organs such as lymph nodes and bone marrow was recently determined via evaluation of tissue B cell depletion under steady-state antibody serum concentrations (110).…”

Section: Biodistribution Of Marketed Antibodiesmentioning

confidence: 99%

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

267

185

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Abstract. The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

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Effect of anti‐CD20 monoclonal antibody, Rituxan, on cynomolgus monkey and human B cells in a whole blood matrix

Cited by 41 publications

References 25 publications

Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa

Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

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