Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases

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 T_H17/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 (ClinicalTrials.gov Identifier: NCT02243787).     

Localization of the human neonatal Fc receptor (FcRn) in human nasal epithelium

The airway epithelium is a central player in the defense against pathogens including efficient mucociliary clearance and secretion of immunoglobulins, mainly polymeric IgA, but also IgG. Pulmonary administration of therapeutic antibodies on one hand, and intranasal immunization on the other, are powerful tools to treat airway infections. In either case, the airway epithelium is the primary site of antibody transfer. In various epithelia, bi-polar transcytosis of IgG and IgG immune complexes is mediated by the human neonatal Fc receptor, FcRn, but FcRn expression in the nasal epithelium had not been demonstrated, so far. We prepared affinity-purified antibodies against FcRn α-chain and confirmed their specificity by Western blotting and immunofluorescence microscopy. These antibodies were used to study the localization of FcRn α-chain in fixed nasal tissue. We here demonstrate for the first time that ciliated epithelial cells, basal cells, gland cells, and endothelial cells in the underlying connective tissue express the receptor. A predominant basolateral steady state distribution of the receptor was observed in ciliated epithelial as well as in gland cells. Co-localization of FcRn α-chain with IgG or with early sorting endosomes (EEA1-positive) but not with late endosomes/lysosomes (LAMP-2-positive) in ciliated cells was observed. This is indicative for the presence of the receptor in the recycling/transcytotic pathway but not in compartments involved in lysosomal degradation supporting the role of FcRn in IgG transcytosis in the nasal epithelium.     

Melanoma central nervous system metastases: An update to approaches,challenges, and opportunities

In February 2018, the Melanoma Research Foundation and the Moffitt Cancer Center hosted the Second Summit on Melanoma Central Nervous System (CNS) Metastases in Tampa, Florida. In this white paper, we outline the current status of basic science, translational, and clinical research into melanoma brain metastasis development and therapeutic management. We further outline the important challenges that remain for the field and the critical barriers that need to be overcome for continued progress to be made in this clinically difficult area.     

Plant invasion alters trait composition and diversity across habitats

Increased globalization has accelerated the movement of species around the world. Many of these nonnative species have the potential to profoundly alter ecosystems. The mechanisms underpinning this impact are often poorly understood, and traits are often overlooked when trying to understand and predict the impacts of species invasions on communities. We conducted an observational field experiment in Canada's first National Urban Park, where we collected trait data for seven different functional traits (height, stem width, specific leaf area, leaf percent nitrogen, and leaf percent carbon) across an abundance gradient of the invasive Vincetoxicum rossicum in open meadow and understory habitats. We assessed invasion impacts on communities, and associated mechanisms, by examining three complementary functional trait measures: community‐weighted mean, range of trait values, and species’ distances to the invader in trait space. We found that V. rossicum invasion significantly altered the functional structure of herbaceous plant communities. In both habitats V. rossicum changed the community‐weighted means, causing invaded communities to become increasingly similar in their functional structure. In addition, V. rossicum also reduced the trait ranges for a majority of traits indicating that species are being deterministically excluded in invaded communities. Further, we observed different trends in the meadow and understory habitats: In the understory, resident species that were more similar to V. rossicum in multivariate trait space were excluded more, however this was not the case in the meadow habitat. This suggests that V. rossicum alters communities uniquely in each habitat, in part by creating a filter in which only certain resident species are able to persist. This filtering process causes a nonrandom reduction in species' abundances, which in turn would be expected to alter how the invaded ecosystems function. Using trait‐based frameworks leads to better understanding and prediction of invasion impacts. This novel framework can also be used in restoration practices to understand how invasion impacts communities and to reassemble communities after invasive species management.