Glycoform-resolved pharmacokinetic studies in a rat model employing glycoengineered variants of a therapeutic monoclonal antibody

Falck, David; Thomann, Marco; Lechmann, Martin; Koeleman, Carolien A. M.; Malik, Sebastian; Jany, Cordula; Wuhrer, Manfred; Reusch, Dietmar

doi:10.1080/19420862.2020.1865596

Cited by 27 publications

(39 citation statements)

References 38 publications

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“…So far, a plethora of mAbs has been tested in the clinic, and huge inter-antibody variability in the PK profiles have been observed. Molecular size, 2 , 3 glycosylation, 4 immunogenicity, 5 TMDD, 6 and FcRn binding have all been shown to impact the PK of protein therapeutics. 7 , 8 However, the majority of therapeutic and investigational mAbs have similar molecular weights and glycosylation patterns, and even in the absence of TMDD and immunogenicity, mAbs with similar FcRn binding kinetics have still exhibited disparate plasma PK profiles.…”

Section: Introductionmentioning

confidence: 99%

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Liu

Verma

Kettenberger

et al. 2021

mAbs

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Section: Introductionmentioning

confidence: 99%

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Liu

Verma

Kettenberger

et al. 2021

mAbs

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“…Literature regarding IgG‐Man5 remains controversial. For example, the pharmacokinetic study by Falck et al (2021) determined pharmacokinetic effects of modified glycoengineered IgG1 derived from CHO cells. To generate large amounts of the desired IgG1 glycoforms, chemo‐enzymatic modification and/or glycosidase treatment were applied.…”

Section: N‐glycosylation Patterns Of Therapeutic Antibodiesmentioning

confidence: 99%

Strategies to control therapeutic antibody glycosylation during bioprocessing: Synthesis and separation

Edwards

Livanos

Krueger

et al. 2022

Biotech & Bioengineering

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Glycosylation can be a critical quality attribute in biologic manufacturing. In particular, it has implications on the half-life, immunogenicity, and pharmacokinetics of therapeutic monoclonal antibodies (mAbs), and must be closely monitored throughout drug development and manufacturing. To address this, advances have been made primarily in upstream processing, including mammalian cell line engineering, to yield more predictably glycosylated mAbs and the addition of media supplements during fermentation to manipulate the metabolic pathways involved in glycosylation. A more robust approach would be a conjoined upstream-downstream processing strategy. This could include implementing novel downstream technologies, such as the use of Fc γ-based affinity ligands for the separation of mAb glycovariants. This review highlights the importance of controlling therapeutic antibody glycosylation patterns, the challenges faced in terms of glycosylation during mAb biosimilar development, current efforts both upstream and downstream to control glycosylation and their limitations, and the need for research in the downstream space to establish holistic and consistent manufacturing processes for the production of antibody therapies.

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“…Modeling approaches incorporating the impact of glycosylation on mAb PK are less explored. This is in part due to inconsistent observations of the effect of high mannose (Kanda et al, 2007;Yu et al, 2012), hybrid type glycans (Kanda et al, 2007;Falck et al, 2021), and galactosylation (Wright et al, 2000;Falck et al, 2021) on clearance. As glycoengineering of TPs gain more popularity, it can be expected that glycosylation will be an important covariate in PK models.…”

Section: 𝑆𝐶mentioning

confidence: 99%

Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics

Liu¹,

Shah²

2022

Drug Metab Dispos

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Therapeutic proteins (TPs) have ranked among the most important and fastest-growing classes of drugs in the clinic, yet the development of successful TPs is often limited by unsatisfactory efficacy.Understanding pharmacokinetic (PK) characteristics of TPs is key to achieving sufficient and prolonged exposure at the site-of-action, which is a prerequisite for eliciting desired pharmacological effects. PK modeling represents a powerful tool to investigate factors governing in vivo disposition of TPs. In this mini-review, we discuss many state-of-the-art models that recapitulate critical processes in each of the absorption, distribution, metabolism/catabolism, and excretion (ADME) pathways of TPs, which can be integrated into the physiologically-based pharmacokinetic (PBPK) framework. Additionally, we provide our perspectives on current opportunities and challenges for evolving the PK models to accelerate the discovery and development of safe and efficacious TPs. Significance statementThis minireview provides an overview of mechanistic PK models developed to characterize ADME properties of therapeutic proteins (TPs), which can be used to support model-informed discovery and development of TPs. As the next-generation of TPs with diverse physicochemical properties and mechanism-of-action are being developed rapidly, there is an urgent need to better understand the determinants for the ADME of TPs and evolve existing platform PK models to facilitate successful bench-to-bedside translation of these promising drug molecules.

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Glycoform-resolved pharmacokinetic studies in a rat model employing glycoengineered variants of a therapeutic monoclonal antibody

Cited by 27 publications

References 38 publications

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Strategies to control therapeutic antibody glycosylation during bioprocessing: Synthesis and separation

Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics

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