Tu128 - Discovery of a FcgRIIb agonist antibody for treatment of autoimmune and inflammatory diseases

Abstract Text: Within the family of receptors that bind the Fc portion of IgG (FcgR), FcgRIIb is the only member that functions as an inhibitory receptor. Co-ligation of FcgRIIb with activating receptors induces inhibitory signaling from FcgRIIb that negatively regulates the activation signal. Mice deficient in FcgRIIb have enhanced antibody response, increased IgE induced anaphylactic reactions, hypersensitivity to collagen-induced arthritis, and spontaneous development of lupus-like symptoms. Therapeutic targeting of FcgRIIb has proven challenging due to the 96% sequence identity of the extracellular portions of FcgRIIa, an activating FcgR, and FcgRIIb. Discovering antibodies to FcgRIIb that do not also bind and activate FcgRIIa, which results in an unwanted production of pro-inflammatory cytokines, has been difficult. Furthermore, accelerated clearance has been associated with the use of high affinity antibodies to FcgRIIb. To identify novel FcgRIIb selective antibodies, we employed naïve semi-synthetic libraries. Clone selection was performed by phage/yeast display and validated in scFV-Fc format. Interestingly, we observed that none of our FcgRIIb-selective clones were able to induce SHIP-1 recruitment in a cell-based assay. We then hypothesized that geometry of FcgRIIb binding might play a role in promoting agonism and converted scFVs to full-length antibodies. Converted FcgRIIb clones in the format of antibodies were now capable of initiating downstream signaling from FcgRIIb, highlighting the importance of the geometry in agonizing FcgRIIb. One of the identified FcgRIIb agonist antibodies does not block immune complex binding, has a favorable PK profile, and reduces antigen specific antibody responses in a KLH immunization model.