Abstract
Safety and efficacy of therapeutic antibodies are often dependent on their interaction with Fc receptors for IgG (FcγRs). The Göttingen minipig represents a valuable species for biomedical research but its use in preclinical studies with therapeutic antibodies is hampered by the lack of knowledge about the porcine FcγRs. Genome analysis and sequencing now enabled the localization of the previously described FcγRIIIa in the orthologous location to human FCGR3A. In addition, we identified nearby the gene coding for the hitherto undescribed putative porcine FcγRIIa. The 1′241 bp long FCGR2A cDNA translates to a 274aa transmembrane protein containing an extracellular region with high similarity to human and cattle FcγRIIa. Like in cattle, the intracellular part does not contain an immunoreceptor tyrosine-based activation motif (ITAM) as in human FcγRIIa. Flow cytometry of the whole blood and single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) of Göttingen minipigs revealed the expression profile of all porcine FcγRs which is compared to human and mouse. The new FcγRIIa is mainly expressed on platelets making the minipig a good model to study IgG-mediated platelet activation and aggregation. In contrast to humans, minipig blood monocytes were found to express inhibitory FcγRIIb that could lead to the underestimation of FcγR-mediated effects of monocytes observed in minipig studies with therapeutic antibodies.
Highlights
Therapeutic antibodies of the IgG isotype represent an important group of new medical entities and interactions of Fc gamma receptors (FcγRs) with the Fc part of IgG antibodies are crucial in the antibody-based immunotherapy
The low-affinity FCGR locus on chromosome 4 in the minipig genome draft based on Sus scrofa 10.2 was successfully supplemented with contigs from the Göttingen and the Wuzishan minipig and completed by PCR, cloning, and sequencing (Fig. 1, Online Resource 3)
Exon sequences were detected with high similarity to the porcine FCGR2B extracellular domain (ECD) and to porcine FCGR3A transmembrane/cytoplasmic (TM/C) region
Summary
Therapeutic antibodies of the IgG (immunoglobulin G) isotype represent an important group of new medical entities and interactions of Fc gamma receptors (FcγRs) with the Fc part of IgG antibodies are crucial in the antibody-based immunotherapy. Most mammals were shown to have three functionally distinct classes of FcγRs with different affinities and properties. Its expression and function are conserved in most mammalian species, including pigs (Akula et al 2014; van der Poel et al 2011). Low-affinity receptors efficiently bind immune complexes and are divided into inhibitory and activating FcγRs. The structure and function of FcγRIIb (CD32b), the inhibitory low-affinity receptor, is highly conserved in humans, pigs, mice, and other mammalian species (Akula et al 2014). FcγRIIIa (CD16a) is an activating low-affinity FcγR that requires the association with FcR γ-chain (Fc receptor common gamma chain) for signaling (Kim et al 2003). Different affinities to IgG were observed for the human FcγRIIIa V158F polymorphism within the extracellular domain (ECD). FcγRIIa (CD32a) is another activating low-affinity receptor present in humans, non-human primates (NHPs), cattle, and rat and named as Immunogenetics (2019) 71:123–136
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