Details

Autor(en) / Beteiligte

• Iwata, Yoshika
• Katada, Hitoshi
• Okuda, Momoko
• Doi, Yoshiaki
• Ching, Tim Jang
• Harada, Asako
• Takeiri, Akira
• Honda, Masaki
• Mishima, Masayuki

Titel

Preclinical in vitro evaluation of immune suppression induced by GYM329, Fc-engineered sweeping antibody

Ist Teil von

• The Journal of Toxicological Sciences, 2023, Vol.48(7), pp.399-409

Ort / Verlag

Japan: The Japanese Society of Toxicology

Erscheinungsjahr

2023

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Fc-engineering is commonly used to improve the therapeutic potency of antibody (Ab) treatments. Because FcγRIIb is the only inhibitory FcγR that contains an immunoreceptor tyrosine-based inhibition motif (ITIM), Fc-engineered Abs with enhanced binding affinity to FcγRIIb might provide immune suppression in clinical contexts. GYM329 is an anti-latent myostatin Fc-engineered Ab with increased affinity to FcγRIIb which is expected to improve muscle strength in patients with muscular disorders. Cross-linking of FcγRIIb by immune complex (IC) results in phosphorylation of ITIM to inhibit immune activation and apoptosis in B cells. We examined whether the IC of Fc-engineered Abs with enhanced binding affinity to FcγRIIb causes phosphorylation of ITIM or B cell apoptosis using GYM329 and its Fc variant Abs in human and cynomolgus-monkey (cyno) immune cells in vitro. IC of GYM329 with enhanced binding affinity to human FcγRIIb (×5) induced neither ITIM phosphorylation nor B cell apoptosis. As for GYM329, FcγRIIb should work as an endocytic receptor of small IC to sweep latent myostatin, so it is preferable that GYM329 induces neither ITIM phosphorylation nor B cell apoptosis to prevent immune suppression. In contrast, IC of myo-HuCy2b, the Ab with enhanced binding affinity to human FcγRIIb (×4), induced ITIM phosphorylation and B cell apoptosis. The result of the present study demonstrated that Fc-engineered Abs with similar binding affinity to FcγRIIb had different effects. Thus, it is important to also investigate FcγR-mediated immune functions other than binding to fully understand the biological effects of Fc-engineered Abs.