Rituximab-Dependent Cytotoxicity by Natural Killer Cells

Dall'ozzo, Sebastien; Tartas, Sophie; Paintaud, Gilles; Cartron, Guillaume; Colombat, Philippe; Bardos, P.; Watier, Hervé; Thibault, Gilles

doi:10.1158/0008-5472.can-03-2862

Cited by 380 publications

(95 citation statements)

References 50 publications

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“…Notably, affinities of the best variants for F158 Fc␥RIIIa are significantly better than that of WT for the V158 isoform, inferred from the AlphaScreen data. This result suggests that the variants may enable the clinical efficacy of Abs for the less-responsive patient population to achieve that currently possible for high responders (8)(9)(10). Together the results indicate that the Fc variants will be broadly applicable to the entire patient population and that clinical improvement will potentially be greatest for the less-responsive patients who need it most.…”

Section: Discussionmentioning

confidence: 81%

“…First, xenograft studies in Fc␥R knockout mice indicate that activation receptors are necessary and inhibitory receptors detrimental to the efficacy of rituximab and trastuzumab (7). Second, a number of studies have documented a correlation between the clinical efficacy of Abs in humans and their allotype of high-affinity (V158) or low-affinity (F158) polymorphic forms of Fc␥RIIIa (8)(9)(10). Finally, it has been shown via mutagenesis (11)(12)(13)(14) and glycoform engineering (15) that the affinity of interaction between Fc and certain Fc␥Rs correlates with cytotoxicity in cell-based assays.…”

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confidence: 99%

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Engineered antibody Fc variants with enhanced effector function

Lazar

Dang²,

Karki³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

713

583

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Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fc␥ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fc␥ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.antibody-dependent cell-mediated cytotoxicity ͉ Fc␥R ͉ protein engineering ͉ cancer

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

Engineered antibody Fc variants with enhanced effector function

Lazar

Dang²,

Karki³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

713

583

View full text Add to dashboard Cite

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“…The 158FF variant of the Fc fragment of IgG receptor IIIa gene ( FCGR3A ), a relatively common low-affinity variant found in 44% of patients with systemic lupus erythematosus and 26% of healthy control individuals 221 , causes decreased antibody-dependent cellular cytotoxicity leading to inefficient rituximab-mediated B cell killing 222 . Patients with systemic lupus erythematosus who are homozygous for the low-affinity F allele require 10-fold higher serum rituximab levels to achieve the same level of B cell depletion as patients with the high-affinity 158VV genotype 223 .…”

Section: Managementmentioning

confidence: 99%

Pemphigus

Kasperkiewicz

Ellebrecht

Takahashi

et al. 2017

Nat Rev Dis Primers

433

429

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Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell–cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.

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“…1). FCGR3A, which encodes the FcgRIIIa protein, displays a nucleotide polymorphism at position 559 that results in an amino acid change at position 158 of FcgRIIIa, which affects its affinity for human IgG1 (47,48). Thus, human IgG1 binds more strongly to NK cells homozygous for FCGR3A-158V than to NK cells homozygous for FCGR3A-158F (48).…”

Section: Host-related Originsmentioning

confidence: 99%

“…In an in vitro study, it was shown that FcgRIIIa-158V homozygous NK cells and FcgRIIIa-158F homozygous NK cells had the same ability to induce ADCC at a high rituximab concentration, but the rituximab concentration required for lysis of 50% of cells was four times lower for the homozygous FcgRIIIa-158V NK cells (48).…”

Section: How To Increase Rituximab Response: From Biological Origins mentioning

confidence: 99%

Interindividual Variability of Response to Rituximab: From Biological Origins to Individualized Therapies

Cartron

Trappe

Solal‐Céligny

et al. 2011

Clinical Cancer Research

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Rituximab has markedly changed the treatment of B-cell malignancies. Despite its widespread use, however, its precise mode of action and the impact of host-and tumor-related factors on rituximabactivated biological pathways were only recently clarified. Biological mechanisms resulting in complete resistance to rituximab may exist at both the cellular and subcellular level; however, their frequency and their impact on clinical response are unclear. The identification of Fcg receptor polymorphisms that can influence anti-CD20 antibody activity has resulted in the development of third-generation anti-CD20 antibodies. However, it is also now appreciated that pharmacokinetic variability is a major factor affecting clinical response to anti-CD20 antibodies. The concept of antigenic mass, which takes into account the total tumor load and the expression levels of the target antigen CD20, is able to explain the correlation between rituximab plasma concentrations and treatment responses. Thus, it can be hypothesized that dosing regimens that take this information into account will help to improve response rates.

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Rituximab-Dependent Cytotoxicity by Natural Killer Cells

Cited by 380 publications

References 50 publications

Engineered antibody Fc variants with enhanced effector function

Engineered antibody Fc variants with enhanced effector function

Pemphigus

Interindividual Variability of Response to Rituximab: From Biological Origins to Individualized Therapies

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