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

Fc-engineering is commonly used to improve the therapeutic potency of antibody (Ab) treatments. Because FcƳRIIb is the only inhibitory FcƳR that contains an immunoreceptor tyrosinebased inhibition motif (ITIM), Fc-engineered Abs with enhanced binding affinity to FcƳRIIb might provide immune suppression in clinical contexts. GYM329 is an anti-latent myostatin Fc-engineered Ab with increased affinity to FcƳRIIb which is expected to improve muscle strength in patients with muscular disorders. Cross-linking of FcƳRIIb 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 FcƳRIIb 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 FcƳRIIb (×5) induced neither ITIM phosphorylation nor B cell apoptosis. As for GYM329, FcƳRIIb 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 FcƳRIIb (×4), induced ITIM phosphorylation and B cell apoptosis. The result of the present study demonstrated that Fc-engineered Abs with similar binding affinity to FcƳRIIb had different effects. Thus, it is important to also investigate FcƳR-mediated immune functions other than binding to fully understand the biological effects of Fc-engineered Abs. [ABSTRACT FROM AUTHOR]