A key task in developing the field of personalized cancer therapy is the identification of novel molecular targets that enable treatment of cancers not susceptible to other means of specific therapy. The collagen receptor uPARAP/Endo180 is overexpressed by malignant cells in several non-epithelial cancers, notably including sarcomas, glioblastomas and subsets of acute myeloid leukemia. In contrast, in healthy adult individuals, expression is restricted to minor subsets of mesenchymal cells. Functionally, uPARAP/Endo180 is a rapidly recycling endocytic receptor that delivers its cargo directly into the endosomal-lysosomal system, thus opening a potential route of entry into receptor-positive cells. This combination of specific expression and endocytic function appears well suited for targeting of uPARAP/Endo180-positive cancers by antibody-drug conjugate (ADC) mediated drug delivery. Therefore, we utilized a specific monoclonal antibody against uPARAP/Endo180, raised through immunization of a uPARAP/Endo180 knock-out mouse, which reacts with both the human and the murine receptor, to construct a uPARAP-directed ADC. This antibody was coupled to the highly toxic dolastatin derivative, monomethyl auristatin E, via a cathepsin-labile valine-citrulline linker. With this ADC, we show strong and receptor-dependent cytotoxicity in vitro in uPARAP/Endo180-positive cancer cell lines of sarcoma, glioblastoma and leukemic origin. Furthermore, we demonstrate the potency of the ADC in vivo in a xenograft mouse model with human uPARAP/Endo180-positive leukemic cells, obtaining a complete cure of all tested mice following intravenous ADC treatment with no sign of adverse effects. Our study identifies uPARAP/Endo180 as a promising target for novel therapy against several highly malignant cancer types.

No abstract

Fast, extensive and simultaneous cartilage and bone degeneration developed shortly after haemarthrosis, as shown by the detailed mapping of the early pathogenesis of HA. The almost immediate loss of cartilage and the pathological bone turnover suggest a direct influence of blood on these processes and are unlikely to be attributed simply to an indirect effect of inflammation.

Insects are suggested as a sustainable protein source of high nutritional quality, but the effects of insect ingestion on processes in the gastrointestinal tract and gut microbiota (GM) remain to be established. We examined the effects of partial substitution of meat with insect protein (Alphitobius diaperinus) in a four-week dietary intervention in a healthy rat model (n = 30). GM composition was characterized using’ 16S rRNA gene amplicon profiling while the metabolomes of stomach, small intestine, and colon content, feces and blood were investigated by 1H-NMR spectroscopy. Metabolomics analyses revealed a larger escape of protein residues into the colon and a different microbial metabolization pattern of aromatic amino acids when partly substituting pork with insect. Both for rats fed a pork diet and rats fed a diet with partial replacement of pork with insect, the GM was dominated by Lactobacillus, Clostridium cluster XI and Akkermansia. However, Bray-Curtis dissimilarity metrics were different when insects were included in the diet. Introduction of insects in a common Western omnivore diet alters the gut microbiome diversity with consequences for endogenous metabolism. This finding highlights the importance of assessing gastrointestinal tract effects when evaluating new protein sources as meat replacements.

Replacement therapy with coagulation factor VIII (FVIII) concurrent with bleeds (on-demand) in haemophilia A (HA) patients has been hypothesized to increase the risk for antidrug antibodies (inhibitors). A danger signal environment, characterized by tissue damage and inflammation at the site of a bleed, is thought to contribute to the anti-FVIII response. The nature of this inflammatory reaction is, however, not fully known, and new insights will be valuable for both managing inhibitors and understanding arthropathy development. To characterize the inflammatory response, locally and systemically, during the first 24 hours following a joint bleed in the HA rat. HA rats received a needle-induced knee joint bleed ( = 83) or a sham procedure ( = 41). Blood samples were collected at selected time points from 0 to 24 hours post injury/sham. Synovial fluid, intra-articular knee tissue and popliteal lymph nodes were collected at 24 hours. Cytokine/chemokine concentrations and gene expression were measured. Gene expression analysis revealed a rapid inflammatory response in the injured knees, accompanied by significantly increased levels of specific gene products in the synovial fluid; IL-1β, TNFα, KC/GRO, IL-6, Eotaxin, MCP-1, MCP-3, MIP-1α, MIP-2, RANTES, A2M and AGP. Plasma analysis demonstrated significantly increased systemic levels of KC/GRO and IL-6 in injured rats already after 5 to 6 hours. A rapid proinflammatory response, locally and systemically, characteristic of innate immunity, was demonstrated. Results reveal a more comprehensive inflammatory picture than previously shown, with resemblance to human haemophilic arthropathy, and with unique correlation between gene expression level, synovial concentration and plasma concentration in individual rats.