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BackgroundIn this study, we describe the generation of a fully human monoclonal antibody (named ‘7NP2’) targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.Methods7NP2 was isolated from a synthetic antibody phage display library and was improved by one round of mutagenesis-based affinity maturation. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin (IL)-12 was generated and the anticancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. Furthermore, the safety of the fully human product (named IL12-7NP2) was evaluated in Cynomolgus monkeys.ResultsBiodistribution analysis in tumor-bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted in vivo, showing a potent antitumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.ConclusionsThe results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.

Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFNγ to neoplastic lesions may be limited by the trapping of IFNγ-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFNγ with reduced affinity to its cognate receptor. The product (named L19-IFNγ KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFNγ KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1.

BackgroundFibroblast Activation Protein (FAP) has been described as the “next billion-dollar nuclear theranostics target”1, since more than 28 different tumor types have successfully been imaged in patients with radiolabeled FAP ligands. 2-3 FAP can be found in the tumor microenvironment (TME) of most malignant solid tumors, while being absent in most healthy tissues. Thus, it is an attractive target for both imaging and therapeutic applications. Monoclonal antibodies targeting TME antigens have been considered for the delivery of bioactive payloads, such as proinflammatory cytokines. Antibody-cytokine fusions (also called immunocytokines) may exploit the tumor-homing properties of the antibody moiety, in order to concentrate the cytokine payload at the site of disease and enhance the therapeutic index.4 Interleukin-12 (IL12) have been extensively studied in oncology. IL12 strongly promotes NK cells, CD4+ and CD8+ T cells to produce interferon-gamma (IFN-g), one of the most relevant mediators of anti-cancer immunity.5MethodsIn this work, we describe the generation of a novel anti-FAP antibody, called 7NP2. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin-12 was generated and the anti-cancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. To prepare for future clinical trials, a fusion protein consisting of human IL12 linked to the 7NP2 antibody was further investigated in a toxicology study in Cynomolgus monkeys.ResultsBiodistribution analysis in tumor bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted in vivo, showing a potent anti-tumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.ConclusionsThe results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.ReferencesCalais J. FAP: The next billion dollar nuclear theranostics target?. Journal of Nuclear Medicine 2020;61(2). doi:10.2967/jnumed.119.241232.Kratochwil C, et al, 68Ga-FAPI PET/CT: Tracer uptake in 28 different kinds of cancer. Journal of Nuclear Medicine 2019;60(6). doi: 10.2967/jnumed.119.227967.Backhaus P, et al.Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA. European Journal of Nuclear Medicine and Molecular Imaging 2022;49(6). doi:10.1007/s00259-021-05653-0.Neri D. Antibody–Cytokine Fusions: Versatile Products for the Modulation of Anticancer Immunity. Cancer Immunology Research 2019. doi: 10.1158/2326-6066.CIR-18-0622.Puca E, et al. The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors. International Journal of Cancer 2019. doi:10.1002/ijc.32603.Ethics ApprovalMouse experiments were performed under a project license (license number 04/2018) granted by the Veterinäramt des Kantons Zürich, Switzerland, in compliance with the Swiss Animal Protection Act (TSchG) and the Swiss Animal Protection Ordinance (TSchV).Procedures on Cynomolgus monkeys (including housing, health monitoring, restrain, dosing, etc) and ethical revision were performed according to the current Italian legislation (Legislative Decree March 4th, 2014 n. 26) enforcing the 2010/63/EU Directive on the protection of animals used for biomedical research.

A strong attention is recently paid to surface properties of building materials as these allows controlling solar gains of the building envelope and overheating of buildings and urban areas. In this regard, deterioration phenomena due to biological aggression can quickly damage solar-reflecting roof surfaces and thus increase sharply solar gains, discomfort, air-conditioning costs and waterproofing degradation. The same deterioration problem has deleterious effect on cultural heritage, ruining its huge historic and artistic value. This work is aimed at providing an overview on the different organisms that affect the surface of most used building materials, to support the design of new building materials with long-lasting surface properties and to find a way to preserve cultural heritage. Artificial ageing is the long-term aim of this investigation, in which what in nature happens after months or years is compressed in a very short time by forcing the growth of microorganisms through a strict control on the different conditioning factors. Both natural and artificial ageing are eventually outlined in the last part of this work to provide a comprehensive idea of what is necessary to study in a complete way biological ageing protocols on building materials. Several characterization techniques are also introduced to analyse the influence of microorganisms on the surface of different building materials.

Solar reflectance (SR) is the key performance parameter of cool roof and cool pavement materials. For its assessment, the measured spectral reflectivity of the sample is weighted by a reference spectrum of solar irradiance. Several standard and non-standard spectra are, however, available, taking into account different climate conditions, angle of incidence of the solar beam, and the contribution of the diffuse radiation content. This study is aimed at investigating the impact of using different solar irradiance spectra as specified by existing standards or suggested by qualified research institutions, and verifying if those spectra can yield equivalent SR values from the viewpoint of assessment of standard performance and comparison of commercial products. Several actual material are considered, either white or coloured ones and with assorted spectral behaviour.

Background Older patients are prone to multimorbidity and polypharmacy, with an inherent risk of adverse events and drug interactions. To the best of our knowledge, available information on the appropriateness of lipid-lowering treatment is extremely limited. Aim The aim of the present study was to quantify and characterize lipid-lowering drug use in a population of complex in-hospital older patients. Methods We analyzed data from 87 units of internal medicine or geriatric medicine in the REPOSI (Registro Politerapie della Società Italiana di Medicina Interna) study, with reference to the 2010 and 2012 patient cohorts. Lipid-lowering drug use was closely correlated with the clinical profiles, including multimorbidity markers and polypharmacy. Results 2171 patients aged >65 years were enrolled (1057 males, 1114 females, mean age 78.6 years). The patients treated with lipid-lowering drugs amounted to 508 subjects (23.4%), with no gender difference. Atorvastatin (39.3%) and simvastatin (34.0%) were the most widely used statin drugs. Likelihood of treatment was associated with polypharmacy (≥5 drugs) and with higher Cumulative Illness Rating Scale (CIRS) score. At logistic regression analysis, the presence of coronary heart disease, peripheral vascular disease, and hypertension were significantly correlated with lipid-lowering drug use, whereas age showed an inverse correlation. Diabetes was not associated with drug treatment. Conclusions In this in-hospital cohort, the use of lipid-lowering agents was mainly driven by patients’ clinical history, most notably the presence of clinically overt manifestations of atherosclerosis. Increasing age seems to be associated with lower prescription rates. This might be indicative of cautious behavior towards a potentially toxic treatment regimen.