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CYTRIX Report Summary

Project ID: 339147
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Final Report Summary - CYTRIX (Engineering Cytokines for Super-Affinity Binding to Matrix in Regenerative Medicine)

The overall objective of the project was to identify a peptide domain would bind to extracellular matrix (ECM) proteins in a high affinity and promiscuous manner. This would then allow protein therapeutics to be covalently conjugated or recombinantly fused to such a peptide such that the high affinity for ECM proteins is conferred to the therapeutic. Thus, the therapeutic, when applied to or injected within a tissue site, would remain bound within that tissue site, to enable a prolonged mode of action at lowered dose compared to the wild type therapeutic. An affinity peptide was found within the heparin-binding domain of the cytokine PlGF-2, namely PlGF-2123-144. We have fused this domain to growth factors including PDGF-BB, VEGF-A, FGF18, and CXCL12, all of which are implicated in tissue repair applications, for example in skin repair in chronic wounds and in cartilage repair in osteoarthritis. We have demonstrated that fusion of these growth factors with the PlGF-2123-144 domain yields 1-10 nM dissociation constants with a number of ECM proteins, and we have shown that fusion leads to prolonged retention in sites of tissue administration. We have evaluated the PlGF-2123-144 peptide fusions with the growth factors VEGF-A and PDGF-BB in skin wound healing, and the results demonstrated a strong benefit in wound healing for the fusion proteins that display super-affinity for extracellular matrix compared to the wild-type growth factors. These factors have been used in combination and individually; the most effective treatment was with the growth factors in combination. We have evaluated the PlGF-2123-144 peptide fusion with FGF-18, a growth factor implicated in cartilage repair. Several models for cartilage repair were evaluated and compared, and one model was selected for pilot and efficacy studies with the engineered FGF-18. These pilot studies demonstrated good efficacy as judged by retention of morphology in injured knees, determined by blinded scoring of histological sections. Based on this, a larger study in mice has been initiated based on produced engineered FGF-18, and multiple engineered variations of FGF-18 fusion protein were studied. Our work was based on binding of cytokines to ECM molecules such as fibrinogen, fibronectin, vitronectin, osteopontin and tenascin C. We have further explored interactions with other ECM proteins, such as laminin family members and von Willebrand factor. We have identified high affinity growth factor binding domains in all five laminin alpha chains. Further, we have identified a high affinity growth factor binding domain within von Willeband factor.

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