Advances in the assessment and control of the effector functions of therapeutic antibodies

Jiang, Xu‐Rong; Song, An; Bergelson, Svetlana; Arroll, Thomas; Parekh, Bhavin S.; May, Kimberly; Chung, Shan; Strouse, Robert J.; Mire‐Sluis, Anthony R.; Schenerman, Mark A.

doi:10.1038/nrd3365

Cited by 281 publications

(237 citation statements)

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“…The importance of antibodies in the adaptive immune response during vaccination is well recognized, and the use of antibodies as therapeutics against infectious disease is building credibility as well (6,28,29). It is only recently, however, that passive immunization for EBOV-with macaque polyclonal IgG and with mouse mAbshas been demonstrated (20,21).…”

Section: Discussionmentioning

confidence: 99%

“…Although the majority of the 20 or more mAb products approved by the FDA are for noninfectious disease indications (6), passive immunization with antibodies has been an effective method to prevent a variety of viral, bacterial, fungal, and parasitic diseases that cause disease in humans and animals (7,8). However, the use of antibody therapy for EBOV has been fraught with conflicting data as to the utility of this class of intervention.…”

mentioning

confidence: 99%

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Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques

Olinger

Pettitt

Kim

et al. 2012

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

351

344

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Filovirus infections can cause a severe and often fatal disease in humans and nonhuman primates, including great apes. Here, three anti-Ebola virus mouse/human chimeric mAbs (c13C6, h-13F6, and c6D8) were produced in Chinese hamster ovary and in whole plant (Nicotiana benthamiana) cells. In pilot experiments testing a mixture of the three mAbs (MB-003), we found that MB-003 produced in both manufacturing systems protected rhesus macaques from lethal challenge when administered 1 h postinfection. In a pivotal followup experiment, we found significant protection (P < 0.05) when MB-003 treatment began 24 or 48 h postinfection (four of six survived vs. zero of two controls). In all experiments, surviving animals that received MB-003 experienced little to no viremia and had few, if any, of the clinical symptoms observed in the controls. The results represent successful postexposure in vivo efficacy by a mAb mixture and suggest that this immunoprotectant should be further pursued as a postexposure and potential therapeutic for Ebola virus exposure.passive immunization | therapy

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques

Olinger

Pettitt

Kim

et al. 2012

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

351

344

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“…Interactions of IgGs with effector cells through fragment crystallizable γ (Fcγ) receptors are often considered a mode of action of therapeutic antibodies 2, 3, 4. Fcγ receptors are cell surface receptors that can be found on innate immune effector cells such as natural killer cells and macrophages.…”

mentioning

confidence: 99%

Rapid screening of IgG quality attributes – effects on Fc receptor binding

Geuijen¹,

Oppers-Tiemissen

Egging

et al. 2017

FEBS Open Bio

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The interactions of therapeutic antibodies with fragment crystallizable γ (Fcγ) receptors and neonatal Fc receptors (FcRn) are measured in vitro as indicators of antibody functional performance. Antibodies are anchored to immune cells through the Fc tail, and these interactions are important for the efficacy and safety of therapeutic antibodies. High‐throughput binding studies on each of the human Fcγ receptor classes (FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb) as well as FcRn have been developed and performed with human IgG after stress‐induced modifications to identify potential impact in vivo. Interestingly, we found that asparagine deamidation (D‐N) reduced the binding of IgG to the low‐affinity Fcγ receptors (FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb), while FcγRI and FcRn binding was not impacted. Deglycosylation completely inhibited binding to all Fcγ receptors, but showed no impact on binding to FcRn. On the other hand, afucosylation only impacted binding to FcγRIIIa and FcγRIIIb. Methionine oxidation at levels below 7%, multiple freeze/thaw cycles and short‐term thermal/shake stress did not influence binding to any of the Fc receptors. The presence of high molecular weight species, or aggregates, disturbed measurements in these binding assays; up to 5% of aggregates in IgG samples changed the binding and kinetics to each of the Fc receptors. Overall, the screening assays described in this manuscript prove that rapid and multiplexed binding assays may be a valuable tool for lead optimization, process development, in‐process controls, and biosimilarity assessment of IgGs during development and manufacturing of therapeutic IgGs.

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“…This process is known as cytotoxicity and is mediated through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) and ultimately results in cell lysis, which is the basic protective response against pathogenic agents [5,[39][40][41].…”

Section: The Fc Fragment In Physiologymentioning

confidence: 99%