Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

Tada, Minoru; Aoyama, Michihiko; Ishii‐Watabe, Akiko

doi:10.1016/j.xphs.2019.10.046

Cited by 20 publications

(24 citation statements)

References 42 publications

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“…FcgRIa, IIa, and IIIa activation was assessed using Jurkat cells expressing each FcgR via NFAT-driven expression of the luciferase gene. 6,29 The Jurkat/FcgRIa/NFAT-Luc cells, Jurkat/FcgRIIa/NFAT-Luc cells, and Jurkat/FcgRIIIa/NFAT-Luc cells (5 Â 10 4 cells/well) suspended with Opti-MEM I Reduced Serum Media (Thermo Fisher Scientific) were seeded in a 96-well plate with serially diluted agitated sample. After incubation for 5 h at 37 C in 5% CO 2 , the luciferase activities were determined using the ONE-Glo Luciferase Assay System (Promega, Cat #E6110) on an Ensight Multimode Plate Reader (PerkinElmer).…”

Section: Fcgrs Reporter Cell Assaymentioning

confidence: 99%

“…24 Tada et al have described the detailed FcgRs activation properties evoked by agitation-induced antibody aggregates. 6 These observations have led us to hypothesize that the affinity of aggregated antibody-SO complexes for FcgRs could be increased by Fc-multivalent binding. 25,26 Despite there have been several reports indicating that the aggregated protein-SO complexes could exhibit higher immunogenicity, 18,27,28 the FcgRs activation capability of them remains unclear, limiting our understanding of their immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Aggregated Antibody-Silicone Oil Complexes: From Perspectives of Morphology, 3D Image, and Fcγ Receptor Activation

Kiyoshi

Tada

Shibata

et al. 2021

Journal of Pharmaceutical Sciences

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Pre-filled syringes (PFS) have been in widespread use as an administration device for therapeutic antibodies in recent decades. Generally, the inner barrel and syringe of PFS are coated with silicone oil (SO) for lubrication. Multiple studies have focused on the fact that the SO adsorbs denatured antibody molecules, and induces antibody aggregation. Aggregated antibodies are recognized as a potential risk for evoking immunogenic responses in patients. The characteristics of the aggregated antibody-SO complexes, including their concentration, population, shape, three-dimensional (3D) image, and Fcg Receptors (FcgRs) activation have been obscurely acknowledged so far. In the present work, we prepared aggregated antibody-SO complexes by agitation and analyzed using multifaceted techniques such as flow imaging, confocal fluorescence microscopy, and cell-based assays for FcgRs activation. The results emphasized that the SO accelerates the increase in sub-visible particles and antibody aggregation. The confocal fluorescence microscopy analysis revealed the high-resolution 3D images of aggregated antibody-SO complexes. The FcgRs reporter cell assay clarified that the pre-mixed and agitated Ab þ SO have higher FcgRs activation capability compared to the agitated Ab. Overall, this study advances the view that SO has an effect to increase the risk of agitation-induced aggregated antibody particles.

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Section: Fcgrs Reporter Cell Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of Aggregated Antibody-Silicone Oil Complexes: From Perspectives of Morphology, 3D Image, and Fcγ Receptor Activation

Kiyoshi

Tada

Shibata

et al. 2021

Journal of Pharmaceutical Sciences

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“…Fc duplication (or tandem-Fc) or multiplication, whereby multiple Fcs are linked within one IgG1 molecule, has been shown to augment FcγR binding avidity and increase ADCC and ADCP [ 56 , 57 , 58 , 59 ] ( Figure 2 C). A theoretical safety concern for Fc multiplication strategies is the fact that natural antibody oligomerization may result in unwanted immune activation [ 60 ]. However, studies have reported minimal in vitro aggregation and no in vivo adverse events so far [ 57 , 59 ].…”

Section: Fc Engineering To Enhance Fc-effector Functionsmentioning

confidence: 99%

Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies

Horst

Nijhof

Mutis

et al. 2020

Cancers

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Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM).

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“…Indeed, Polumuri et al showed no implication of TLRs, including TLR2 and TLR4, in the activation of HEK293 cells expressing TLRs in response to IVIG aggregates (50). More recently, the use of other reporter cell models showed that antibody aggregates induced FcγRs activation, mainly FcγRIIa and FcγRIIIa; however, they did not activate TLRs (51). Taken together, all these results indicate that the activation of PBMCs in response to aggregated antibodies is multifactorial, through the potential engagement of multiple receptors.…”

Section: Interaction Of Antibody Aggregates With Peripheral Blood Monmentioning

confidence: 99%

“…This strongly suggests that these aggregates would be internalized by either phagocytosis or macropinocytosis; however, no data has yet confirmed this FIGURE 1 | Antibody aggregates act as danger signals for innate immune cells. [1] Aggregates interact with antigen-presenting cells (APCs) via Fcγ receptors (FcγRs) or toll-like receptors (TLRs) (47,(49)(50)(51). [2] Aggregates induce the phosphorylation of intracellular signaling kinases (50,55).…”

Section: The Role Of Antibody Aggregates In the Initiation Of A Specimentioning

confidence: 99%

Immunogenicity of Bioproducts: Cellular Models to Evaluate the Impact of Therapeutic Antibody Aggregates

2020

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Patients treated with bioproducts (BPs) frequently develop anti-drug antibodies (ADAs) with potential neutralizing capacities leading to loss of clinical response or potential hypersensitivity reactions. Many factors can influence BP immunogenicity and could be related to the patient, the treatment, as well as to the product itself. Among these latter factors, it is now well accepted that BP aggregation is associated with an increased potential for immunogenicity, as aggregates seem to be correlated with ADA development. Moreover, the presence of high-affinity ADAs suggests a CD4 T-cell dependent adaptive immune response and therefore a pivotal role for antigenpresenting cells (APCs), such as dendritic cells (DCs). In this review, we address the in vitro methods developed to evaluate how monoclonal antibodies could trigger the immunization process by focusing on the role of aggregated antibodies in the establishment of this response. In particular, we will present the different cell-based assays that have been used to assess the potential of antibodies and their aggregates to modulate cellular mechanisms leading to activation and the biological parameters (cellular activation markers, proliferation and secreted molecules) that can be measured to evaluate the different cell activation stages and their consequences in the propagation of the immune response. Indeed, the use of such strategies could help evaluate the risk of BP immunogenicity and their role in mitigating this risk.

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Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

Cited by 20 publications

References 42 publications

Characterization of Aggregated Antibody-Silicone Oil Complexes: From Perspectives of Morphology, 3D Image, and Fcγ Receptor Activation

Characterization of Aggregated Antibody-Silicone Oil Complexes: From Perspectives of Morphology, 3D Image, and Fcγ Receptor Activation

Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies

Immunogenicity of Bioproducts: Cellular Models to Evaluate the Impact of Therapeutic Antibody Aggregates

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