Wound healing and repair of injured tissues is an essential biological process which allows directed replacement of dead or damaged cells with connective tissue after injury. The repaired area is addressed as a scar. Hence, scarring represents a survival mechanism that is conserved throughout evolution and appears to be most pronounced in humans.
Fibrosis is a consequence of chronic cycles of tissue injury and repair leading to the accumulation of excessive scar tissue in affected organs and disruption of normal tissue architecture and function. Fibrosis is the final common pathway in virtually all forms of chronic organ failure. The cellular and molecular biology of fibrosis is similar across multiple organs and multiple sources of tissue injury, such as chronic infections, chronic exposure to alcohol and other toxins, steatohepatitis caused by liver fat accumulation in obesity, diabetes, heart failure after myocardial infarction, among others.
Upon scarring, there is migration, proliferation and differentiation of fibroblasts followed by deposition of extracellular matrix, including collagen. PDGF and TGF-β are the main drivers of fibrosis and are attractive targets for fibrosis treatment.
Myofibroblasts are highly responsive to PDGF and TGF-β, the main drivers of fibrosis and express high levels of their receptors of fibrotic cells. The receptor for TGF-β is not myofibroblast-specific, and regulates many other relevant processes in the human body. The over-expression of the receptor for PDGF, on the other hand, is myofibroblast-specific.
PDGF receptor subtypes α are target for PDGF-AA, whereas PDGFR subtypes β are target for PDGF-AB, BB, CC and DD. Although a few other cell-types have very low basal levels of the PDGF-β-receptor, the over-expression of the PDGF-β-receptor on activated myofibroblasts is very specific and allows cell-specific targeting to myofibroblasts, thereby leaving other cells unaffected.
BiOrion’s proprietary technology is based on a bicyclic peptide recognizing the PDGF-BB binding pocket of the homo-dimeric PDGF-β-receptor. BiOrion has identified and selected bicyclic peptides with only a medium affinity for the PDGF-β-receptor. Binding of the bicyclic-peptide conjugate on cells other than myofibroblasts, has shown to be negligible.
Although it was demonstrated that the PDGF-β-receptor is over-expressed in fibrotic tissue from all major organs, at BiOrion we are currently focusing on cardiac fibrosis and hepatic fibrosis. Both diseases have a high medical need and urgency in providing less invasive diagnostic tools in addition to effective disease-specific treatments.
Further, in colorectal cancer, near 25% of the cancers are PDGF-β-receptor positive, which has shown to correlate with a worse prognosis for survival regarding metastatic spreading. This supports the development of a novel diagnostic screening method of patients much earlier in the development of their disease and a potential effective disease-specific treatment.