BOT191, Fibroferon®, is the PDGF-ß-receptor targeted signaling domain of interferon gamma.
Interferon gamma (IFN gamma), a cytokine produced by immune cells, exerts both pro- and anti-fibrotic effects. It induces an inflammatory M1 activation state of macrophages, which produced pro-inflammatory factors that can activate myofibroblasts. On the other hand, the cytokine has direct antifibrotic effects when it interacts with myofibroblasts. Increased production of IFN gamma, as secreted by NK cells in fibrosis, causes both induction of apoptosis and cell cycle arrest in fibroblasts.
The N-terminal side of IFN gamma plays an important role in the recognition of the extracellular domain of the IFN gamma receptor, whereas the C-terminus is involved in endocytosis by binding to the membrane proximal region of the cytoplasmic part of the IFN gamma R1 subunit (IFNGR1), next to the JAK2 binding site. Therefore, the N-terminal region of IFN gamma is involved in species-specific recognition and binding, whereas the C-terminal region is involved in binding of internalized IFN gamma to the cytoplasmic receptor domain.
The noncanonical mechanism of IFN gamma signaling has led to the design of a mimetic, truncated C-terminal fragment of IFN gamma, which enables activation of IFN gamma signaling when internalized and bound to the cytoplasmic IFNGR1, but that does not recognize the receptor extracellular domain.
For BOT191 the mimetic, truncated C-terminal fragment of IFN gamma is conjugated to BiOrion’s PDGF-ß-receptor binding bicyclic peptide. This conjugate enables internalization and IFN gamma signaling exclusively in activated myofibroblasts that overexpress PDGF-ß-receptors. On the other hand, the extracellular IFN gamma receptors are not recognized and therefore a pro-inflammatory immune response, on e.g. macrophages, is prevented.
BOT191 inhibits fibrogenesis in acute and chronic CCl4-induced hepatic fibrosis mice models as well as in UUO-induced renal fibrosis mice models. Translational research in ex-vivo human fibrotic tissue from Dupuytren’s Disease patients supports the hypothesis that BOT191 changes the activated myofibroblast phenotype to a quiescent fibroblast in human fibrotic tissues.