Taking immunogenicity assessment of therapeutic proteins to the next level

Büttel, Isabel; Chamberlain, Paul; Chowers, Yehuda; Ehmann, Falk; Greinacher, Andreas; Jefferis, Royston; Kramer, Daniel; Kropshofer, Harald; Lloyd, Peter; Lubiniecki, Anthony S.; Krause, Richard M.; Mire‐Sluis, Anthony R.; Platts-Mills, Thomas A.E.; Ragheb, Jack A.; Reipert, Birgit M.; Schellekens, Huub; Seitz, Rainer; Stas, Philippe; Subramanyam, Meena; Thorpe, Robin; Trouvin, Jean‐Hugues; Weise, Martina; Windisch, Jörg M.; Schneider, Christian K.

doi:10.1016/j.biologicals.2011.01.006

Cited by 126 publications

(82 citation statements)

References 35 publications

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“…In fact, mAbs have been compared to the ideal of a magic bullet proposed by Paul Ehrlich because of their high target specificity. 9 Presently, intravenous (IV) infusion is the most commonly used route of administration for mAb drug products. However, an alternative route, subcutaneous administration, is being increasingly used for patients with chronic diseases because frequent dosing may be needed over their lifetimes.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Tomar

Kumar

Singh

et al. 2016

mAbs

160

145

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Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored.

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Section: Introductionmentioning

confidence: 99%

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Tomar

Kumar

Singh

et al. 2016

mAbs

160

145

View full text Add to dashboard Cite

show abstract

“…While generally deleterious to protein function, aggregation is particularly problematic to the biopharmaceutical industry as aggregates have been linked to immunogenic reactions in patients (Büttel et al, 2011) and to shortened therapeutic half‐life (Dobson et al, 2016). In addition, the presence of aggregates during development can lead to a decreased yield and an increase in time to market, due to the need to optimize manufacturing conditions/formulation (Cromwell, Hilario, & Jacobson, 2006; Zurdo et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Using extensional flow to reveal diverse aggregation landscapes for three IgG1 molecules

Willis

Kumar

Dobson

et al. 2018

Biotech & Bioengineering

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Monoclonal antibodies (mAbs) currently dominate the biopharmaceutical sector due to their potency and efficacy against a range of disease targets. These proteinaceous therapeutics are, however, susceptible to unfolding, mis‐folding, and aggregation by environmental perturbations. Aggregation thus poses an enormous challenge to biopharmaceutical development, production, formulation, and storage. Hydrodynamic forces have also been linked to aggregation, but the ability of different flow fields (e.g., shear and extensional flow) to trigger aggregation has remained unclear. To address this question, we previously developed a device that allows the degree of extensional flow to be controlled. Using this device we demonstrated that mAbs are particularly sensitive to the force exerted as a result of this flow‐field. Here, to investigate the utility of this device to bio‐process/biopharmaceutical development, we quantify the effects of the flow field and protein concentration on the aggregation of three mAbs. We show that the response surface of mAbs is distinct from that of bovine serum albumin (BSA) and also that mAbs of similar sequence display diverse sensitivity to hydrodynamic flow. Finally, we show that flow‐induced aggregation of each mAb is ameliorated by different buffers, opening up the possibility of using the device as a formulation tool. Perturbation of the native state by extensional flow may thus allow identification of aggregation‐resistant mAb candidates, their bio‐process parameters and formulation to be optimized earlier in the drug‐discovery pipeline using sub‐milligram quantities of material.

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“…Nevertheless, although animal models may have a low predictive value for the human situation, the results of immunogenicity studies may have important utility (Büttel et al, 2011). In particular, immunogenicity data from animal studies can be useful for interpreting drug pharmacokinetics (PK) and pharmacodynamics (PD), and can help to elucidate the mechanisms underlying antibody responses against therapeutic proteins (Sauerborn et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Mierlo

Cnubben

Wouters

et al. 2013

Journal of Immunotoxicology

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Immunogenicity is a major issue of concern for monoclonal antibodies used in human diseases and is by default mainly determined in non-human primates (NHP), as target molecules are considered most similar in NHP compared to human. In this manuscript the predictive value of immunogenicity testing in minipigs for human safety is evaluated, as the immune system of the pig is functionally similar to that in other mammalian species. Adalimumab and infliximab (both monoclonal antibodies blocking TNFa) were used as model substances. Female Gö ttingen minipigs (4/group) were treated every other week with low (0.1 mg/kg), mid (1.0 mg/kg), or high dose (5 mg/kg) adalimumab or 5 mg/kg infliximab subcutaneous (SC) over a period of 8 weeks. After first and last dosing, pharmacokinetic analysis was performed. Anti-drug antibodies (ADAs) were measured on several time points. Furthermore, hematology, clinical chemistry, body weight, clinical signs, and histopathology of several organs were evaluated. No signs of toxicity of the treatments were observed in the limited organs and tissues collected. Eleven out of 12 minipigs treated with adalimumab elicited a detectable ADA response. Induction of ADA was correlated with decreased plasma levels of adalimumab. Infliximab clearance was comparable after first and last dose. Therefore, the presence of ADA directed to infliximab was considered highly unlikely. It was concluded that the minipig and NHP showed comparable suitability for immunogenicity prediction in humans. More studies with other biopharmaceutical products are needed to strengthen the status of the minipig as an alternative model for immunotoxicity testing including immunogenicity.

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Taking immunogenicity assessment of therapeutic proteins to the next level

Cited by 126 publications

References 35 publications

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Using extensional flow to reveal diverse aggregation landscapes for three IgG1 molecules

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

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