The Binding of Human IgG to Minipig Fc?Rs - Implications for Preclinical Assessment of Therapeutic Antibodies.

ABSTRACT: PURPOSE: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 (poFc?R) influencing safety and efficacy readouts. Therefore, knowing IgG-Fc?R interactions in the animal model is a prerequisite for the use of minipigs in preclinical safety and efficacy studies with therapeutic antibodies. METHODS:Here, we describe the cloning and expression of poFc?Rs and their interactions with free and complexed human therapeutic IgG1 by surface plasmon resonance and flow cytometry. RESULTS:We show here that poFc?RIa, poFc?RIIa, and poFc?RIIb bind huIgG1 antibodies with comparable affinities as corresponding huFc?Rs. Importantly, poFc?Rs bind huIgG immune complexes with high avidity, thus probably allowing human-like effector functions. However, poFc?RIIIa binds poIgG1a but not to huIgG1. CONCLUSIONS:The lack of binding of poFc?RIIIa to huIgG1 might cause underestimation of Fc?RIIIa-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.

SUBMITTER: Egli J 

PROVIDER: S-EPMC6373530 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature