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The Binding of Human IgG to Minipig FcγRs - Implications for Preclinical Assessment of Therapeutic Antibodies

Egli, Jerome and Schlothauer, Tilman and Spick, Christian and Seeber, Stefan and Singer, Thomas and Odermatt, Alex and Iglesias, Antonio. (2019) The Binding of Human IgG to Minipig FcγRs - Implications for Preclinical Assessment of Therapeutic Antibodies. Pharmaceutical research, 36 (3). p. 47.

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Official URL: https://edoc.unibas.ch/71487/

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Abstract

The Göttingen minipig is a relevant non-rodent species for regulatory toxicological studies. Yet, its use with therapeutic antibodies has been limited by the unknown binding properties of human immunoglobulins (huIgG) to porcine Fc gamma receptors (poFcγR) influencing safety and efficacy readouts. Therefore, knowing IgG-FcγR interactions in the animal model is a prerequisite for the use of minipigs in preclinical safety and efficacy studies with therapeutic antibodies. Here, we describe the cloning and expression of poFcγRs and their interactions with free and complexed human therapeutic IgG1 by surface plasmon resonance and flow cytometry. We show here that poFcγRIa, poFcγRIIa, and poFcγRIIb bind huIgG1 antibodies with comparable affinities as corresponding huFcγRs. Importantly, poFcγRs bind huIgG immune complexes with high avidity, thus probably allowing human-like effector functions. However, poFcγRIIIa binds poIgG1a but not to huIgG1. The lack of binding of poFcγRIIIa to huIgG1 might cause underestimation of FcγRIIIa-mediated efficacy or toxicity as mediated by porcine natural killer cells. Therefore, the suitability of minipigs in preclinical studies with human therapeutic antibodies has to be assessed case by case. Our results facilitate the use of Göttingen minipigs for assessment of human therapeutic antibodies in preclinical studies.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Springer
ISSN:0724-8741
e-ISSN:1573-904X
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:13 Jan 2020 09:53
Deposited On:13 Jan 2020 09:53

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