Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis ( Identifier: NCT02243787).

Background: IL-17A is a proinflammatory cytokine involved in various inflammatory diseases.Results: Potent IL-17A inhibitors were generated by fusing human Fyn SH3 domain derivatives (Fynomers) to the Fc part of an antibody.Conclusion: The linker length between the Fc part and the binding domain influences significantly the potency of Fc fusion proteins.Significance: Fynomers represent a promising class of therapeutic proteins.

Background The lymphatic vascular system regulates tissue fluid homeostasis and plays important roles in immune surveillance, inflammation and cancer metastasis. However, the molecular mechanisms involved in the regulation of lymphangiogenesis remain incompletely characterized. Objective: We aimed to identify new pathways involved in the promotion of skin lymphangiogenesis. Methods We used a mouse embryonic stem cell-derived embryoid body vascular differentiation assay to investigate the effects of a selection of pharmacological agents with the potential to inhibit blood and/or lymphatic vessel formation. We also used a subcutaneous Matrigel assay to study candidate lymphangiogenesis factors as well as skin-specific transgenic mice. Results We found that compounds inhibiting the epidermal growth factor (EGF) receptor (EGFR) led to an impaired formation of lymphatic vessel-like structures. In vitro studies with human dermal lymphatic endothelial cells (LECs), that were found to express EGFR, revealed that EGF promotes lymphatic vessel formation. This effect was inhibited by an EGFR-blocking antibody and by low molecular weight inhibitors of either the EGFR or its associated tyrosine kinase. Incorporation of EGF into a mouse matrigel plug assay showed that EGF promotes enlargement of lymphatic vessels in the skin in vivo. Moreover, transgenic mice with skin-specific overexpression of amphiregulin, another agonistic ligand of the EGFR, displayed an enhanced size and density of lymphatic vessels in the skin. Conclusion These findings reveal that EGFR activation is involved in lymphatic remodeling and suggest that specific EGFR antagonists might be used to inhibit pathological lymphangiogenesis.