Antibody-drug conjugates and small-molecule-drug conjugates have been proposed as alternatives to conventional anticancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues. Here, we describe a novel small-molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload. A potent anticancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering IL2 to the tumor neovasculature), all treated mice in the combination group could be rendered tumor free, in a process that favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small-molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX. These findings may be of clinical significance, because carbonic anhydrase IX is overexpressed in the majority of clear cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of IL2 helps potentiate the action of targeted cytotoxics, leading to cancer eradication in models that cannot be cured by conventional chemotherapy. .

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IL22-F8 is a promising biopharmaceutical drug candidate for the treatment of ulcerative colitis.

Background and Aims. Fibronectin containing the extra domain A (ED-A+ Fn) was proven to serve as a valuable biomarker for cardiac remodeling. The study was aimed at establishing an ELISA to determine ED-A+ Fn in serum of heart failure patients. Methods. ED-A+ Fn was quantified in serum samples from 114 heart failure patients due to ischemic (ICM, n = 44) and dilated (DCM, n = 39) cardiomyopathy as well as hypertensive heart disease (HHD, n = 31) compared to healthy controls (n = 12). Results. In comparison to healthy volunteers, heart failure patients showed significantly increased levels of ED-A+ Fn (p < 0.001). In particular in ICM patients there were significant associations between ED-A+ Fn serum levels and clinical parameters, for example, increased levels with rising NYHA class (p = 0.013), a negative correlation with left ventricular ejection fraction (p = 0.026, r: −0.353), a positive correlation with left atrial diameter (p = 0.008, r: 0.431), and a strong positive correlation with systolic pulmonary artery pressure (p = 0.002, r: 0.485). In multivariate analysis, ED-A+ Fn was identified as an independent predictor of an ischemic heart failure etiology. Conclusions. The current study could clearly show that ED-A+ Fn is a promising biomarker in cardiovascular diseases, especially in heart failure patients due to an ICM. We presented a valid ELISA method, which could be applied for further studies investigating the value of ED-A+ Fn.