Investigation of the Immunogenicity of Different Types of Aggregates of a Murine Monoclonal Antibody in Mice

Freitag, Angelika; Shomali, Maliheh; Michalakis, Stylianos; Biel, Martin; Siedler, Michael; Kaymakcalan, Zehra; Carpenter, John F.; Randolph, Theodore W.; Winter, Gerhard; Engert, Julia

doi:10.1007/s11095-014-1472-6

Cited by 61 publications

(51 citation statements)

References 43 publications

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“…[12] The ability of aggregates to induce ADAs depends on size, solubility, conformation, and other modifications. [103] Analytical methods for aggregates must cover a wide analytical size range, which is why no one method is adequate for the full characterization. Methods include size-exclusion chromatography, often coupled to light scattering, nano particle tracking analysis, light obscuration, and micro-flow imaging.…”

Section: Aggregates and Fragmentsmentioning

confidence: 99%

Microheterogeneity of Recombinant Antibodies: Analytics and Functional Impact

Beyer

Schuster

Jungbauer

et al. 2017

Biotechnology Journal

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Antibodies are typical examples of biopharmaceuticals which are composed of numerous, almost infinite numbers of potential molecular entities called variants or isoforms, which constitute the microheterogeneity of these molecules. These variants are generated during biosynthesis by so‐called posttranslational modification, during purification or upon storage. The variants differ in biological properties such as pharmacodynamic properties, for example, Antibody Dependent Cellular Cytotoxicity, complement activation, and pharmacokinetic properties, for example, serum half‐life and safety. Recent progress in analytical technologies such as various modes of liquid chromatography and mass spectrometry has helped to elucidate the structure of a lot of these variants and their biological properties. In this review the most important modifications (glycosylation, terminal modifications, amino acid side chain modifications, glycation, disulfide bond variants and aggregation) are reviewed and an attempt is made to give an overview on the biological properties, for which the reports are often contradictory. Even though there is a deep understanding of cellular and molecular mechanism of antibody modification and their consequences, the clinical proof of the effects observed in vitro and in vivo is still not fully rendered. For some modifications such as core‐fucosylation of the N‐glycan and aggregation the effects are clear and should be monitored, but with others such as C‐terminal lysine clipping the reports are contradictory. As a consequence it seems too early to tell if any modification can be safely ignored.

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Section: Aggregates and Fragmentsmentioning

confidence: 99%

Microheterogeneity of Recombinant Antibodies: Analytics and Functional Impact

Beyer

Schuster

Jungbauer

et al. 2017

Biotechnology Journal

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“…27,28,43 These models have been useful for investigations on the relative impacts of product-related factors on immunogenicity, as well as immune mechanisms involved in the breaking of immune tolerance (for a description of the concept of immune tolerance, see Goodnow et al 44 ). A practical advantage of this approach is that the mice in principle are suitable for testing the immunogenicity of any murine protein.…”

Section: Choice Of Mouse Modelmentioning

confidence: 99%

Mouse Models for Assessing Protein Immunogenicity: Lessons and Challenges

Jiskoot

Kijanka

Randolph

et al. 2016

Journal of Pharmaceutical Sciences

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The success of clinical and commercial therapeutic proteins is rapidly increasing, but their potential immunogenicity is an ongoing concern. Most of the studies that have been conducted over the past few years to examine the importance of various product-related attributes (in particular several types of aggregates and particles) and treatment regimen (such as dose, dosing schedule and route of administration) in the development of unwanted immune responses have utilized one of a variety of mouse models. In this review we discuss the utility and drawbacks of different mouse models that have been used for this purpose. Moreover, we summarize the lessons these models have taught us and some of the challenges they present. Finally, we provide recommendations for future research utilizing mouse models to improve our understanding of critical factors that may contribute to protein immunogenicity.

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“…Among these, aggregation of TPP carries particular concern, as it occurs under some conditions with many TPP and several studies have identified associations between aggregates and increased propensity for immunogenicity [51,[81][82][83][84][85][86]. Compared with non-aggregated forms, higher immunogenicity in mice has been observed for aggregates generated under different stress conditions for various TPPs, such as human interferon alpha2b [87][88][89], human mAbs [90][91][92], human epoetin alfa [83], human Factor VIII [93,94], human interferon beta [95], and murine growth hormone [96]. The detailed mechanisms of aggregate-induced immunogenicity are still unknown, but it has been observed that aggregation enhances antigen uptake, increases the total amount of peptides associated with MHC II molecules, and increases danger signals to maturate dendritic cells and activate T cells [52,86,91,97,98].…”

Section: Factors That Influence Immunogenicitymentioning

confidence: 99%