Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy

Mimura, Yusuke; Katoh, Toshihiko; Saldova, Radka; O’Flaherty, Róisín; Izumi, Takeki; Mimura‐Kimura, Yuka; Utsunomiya, Toshiaki; Mizukami, Yoichi; Yamamoto, Kenji; Matsumoto, Tsuneo; Rudd, Pauline M.

doi:10.1007/s13238-017-0433-3

Cited by 177 publications

(129 citation statements)

References 135 publications

(174 reference statements)

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“…Currently, only a limited number of engineered glycans can be produced on monoclonal Abs (Dekkers et al, 2016). However, efforts to produce Abs with any one of the ~36 naturally occurring Ab glycan substructures are underway and will allow the dissection of the role of specific structures in modulating functional activity (Mimura et al, 2018). In addition, engineered Fc-point mutations that selectively enhance binding to different FcRs may also provide a means to enhance specific functions in the development of future mAbs.…”

Section: Discussionmentioning

confidence: 99%

A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus

Gunn

Karim

et al. 2018

Cell Host & Microbe

212

210

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The recent Ebola virus (EBOV) epidemic highlighted the need for effective vaccines and therapeutics to limit and prevent outbreaks. Host antibodies against EBOV are critical for controlling disease, and recombinant monoclonal antibodies (mAbs) can protect from infection. However, antibodies mediate an array of antiviral functions including neutralization as well as engagement of Fc-domain receptors on immune cells, resulting in phagocytosis or NK cell-mediated killing of infected cells. Thus, to understand the antibody features mediating EBOV protection, we examined specific Fc features associated with protection using a library of EBOV-specific mAbs. Neutralization was strongly associated with therapeutic protection against EBOV. However, several neutralizing mAbs failed to protect, while several non-neutralizing or weakly neutralizing mAbs could protect. Antibody-mediated effector functions, including phagocytosis and NK cell activation, were associated with protection, particularly for antibodies with moderate neutralizing activity. This framework identifies functional correlates that can inform therapeutic and vaccine design strategies against EBOV and other pathogens.

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Section: Discussionmentioning

confidence: 99%

A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus

Gunn

Karim

et al. 2018

Cell Host & Microbe

212

210

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“…Chlamydomonas reinhardtii has been suggested as a potential biofactory for the production of protein‐based pharmaceuticals (Barrera and Mayfield, ; Mathieu‐Rivet et al , ; Rasala and Mayfield, ; Hempel and Maier, ). A substantial portion of the protein‐based pharmaceuticals, such as monoclonal antibodies and erythropoietin, are glycosylated proteins (Walsh, ; Mathieu‐Rivet et al , ), and it is well established that the N ‐glycosylation of the protein represents a critical quality attribute influencing the half‐life of the protein, its biological activity, as well as its safety and immunogenicity (Lingg et al , ; Buettner et al , ; Mimura et al , ). Indeed, glyco‐epitopes that are absent in mammalian cells could be immunogenic when proteins carrying such decorations are injected into humans (van Beers and Bardor, ).…”

Section: Discussionmentioning

confidence: 99%

Multiple xylosyltransferases heterogeneously xylosylate proteinN‐linked glycans inChlamydomonas reinhardtii

et al. 2020

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Summary Nowadays, little information is available regarding the N‐glycosylation pathway in the green microalga Chlamydomonas reinhardtii. Recent investigation demonstrated that C. reinhardtii synthesizes linear oligomannosides. Maturation of these oligomannosides results in N‐glycans that are partially methylated and carry one or two xylose residues. One xylose residue was demonstrated to be a core β(1,2)‐xylose. Recently, N‐glycoproteomic analysis performed on glycoproteins secreted by C. reinhardtii demonstrated that the xylosyltransferase A (XTA) was responsible for the addition of the core β(1,2)‐xylose. Furthermore, another xylosyltransferase candidate named XTB was suggested to be involved in the xylosylation in C. reinhardtii. In the present study, we focus especially on the characterization of the structures of the xylosylated N‐glycans from C. reinhardtii taking advantage of insertional mutants of XTA and XTB, and of the XTA/XTB double‐mutant. The combination of mass spectrometry approaches allowed us to identify the major N‐glycan structures bearing one or two xylose residues. They confirm that XTA is responsible for the addition of the core β(1,2)‐xylose, whereas XTB is involved in the addition of the xylose residue onto the linear branch of the N‐glycan as well as in the partial addition of the core β(1,2)‐xylose suggesting that this transferase exhibits a low substrate specificity. Analysis of the double‐mutant suggests that an additional xylosyltransferase is involved in the xylosylation process in C. reinhardtii. Additional putative candidates have been identified in the C. reinhardtii genome. Altogether, these results pave the way for a better understanding of the C. reinhardtii N‐glycosylation pathway.

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“…Passive immunization is especially effective in infections, such as those with the rabies virus, which avoids apoptosis of infected neurons while killing protective T cells so that carriers do not mount an immune response themselves [29]. A recent review [30] lists 21 mAbs (and a nanobody, a single-chain type of antibody produced by camelids) that are currently in clinical trials in the United States. In addition, polyclonal antibodies have been approved in the European Union or the US for cytomegalovirus, hepatitis viruses A and C, and postexposure prophylaxis against measles, rabies, rubella, and tetanus [31].…”

Section: Challenges To Developing Mabs Against Infectious Diseasesmentioning

confidence: 99%

Reassessing therapeutic antibodies for neglected and tropical diseases

et al. 2020

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In the past two decades there has been a significant expansion in the number of new therapeutic monoclonal antibodies (mAbs) that are approved by regulators. The discovery of these new medicines has been driven primarily by new approaches in inflammatory diseases and oncology, especially in immuno-oncology. Other recent successes have included new antibodies for use in viral diseases, including HIV. The perception of very high costs associated with mAbs has led to the assumption that they play no role in prophylaxis for diseases of poverty. However, improvements in antibody-expression yields and manufacturing processes indicate this is a cost-effective option for providing protection from many types of infection that should be revisited. Recent technology developments also indicate that several months of protection could be achieved with a single dose. Moreover, new methods in B cell sorting now enable the systematic identification of high-quality antibodies from humanized mice, or patients. This Review discusses the potential for passive immunization against schistosomiasis, fungal infections, dengue, and other neglected diseases.PLOS Neglected Tropical Diseases | https://doi.interactions have proved difficult to block. In addition, there has been great progress in the development of technology. Early generations of antibodies for human use were developed from mAbs developed in mice, antibodies that were then humanized. Recently, the technology used peptide and antibody display on phages, for which part of the 2018 Nobel Prize in Chemistry was awarded to Sir Gregory P. Winter [6]. More recently, new technologies have been developed to clone antibodies from memory B cells [7] or plasma B cells [8, 9], allowing the isolation of individual antibodies from patients with viral infections-approaches that can be applied to any infectious disease.A second reason for the popularity of antibodies in recent years is their success rate in clinical development. Once an antibody reaches testing in humans, it has a success rate of 17% to 25% for approval as a new medicine [10], compared with 5% to 10% for small molecules. This success rate is partly due to the exquisite selectivity of mAbs, enabling them to distinguish between closely related molecular targets. In the case of infectious disease, this selectivity can be absolute, since antibodies can be generated that are specific for the invading pathogen and do not cross-react with host tissues. This lack of cross-reactivity with human tissue can be confirmed by immunohistochemistry on both adult and embryonic tissues prior to the start of clinical trials. This is in stark contrast to small molecules, in which sometimes unexpected onand off-target safety signals are frequently seen in the later stages of clinical development, resulting in expensive late-stage attrition. In addition, antibodies show a relatively narrow range of variation in pharmacokinetic exposure, facilitating early estimation of the human effective dose. This is unlike true xenobiotics, whose metabolism an...

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Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy

Cited by 177 publications

References 135 publications

A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus

A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus

Multiple xylosyltransferases heterogeneously xylosylate proteinN‐linked glycans inChlamydomonas reinhardtii

Reassessing therapeutic antibodies for neglected and tropical diseases

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