A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy.

Although recent methods for the engineering of antibody-drug conjugates (ADCs) have gone some way to addressing the challenging issues of ADC construction, significant hurdles still remain. There is clear demand for the construction of novel ADC platforms that offer greater stability, homogeneity and flexibility. Here we describe a significant step towards a platform for next-generation antibody-based therapeutics by providing constructs that combine site-specific modification, exceptional versatility and high stability, with retention of antibody binding and structure post-modification. The relevance of the work in a biological context is also demonstrated in a cytotoxicity assay and a cell internalization study with HER2-positive and -negative breast cancer cell lines

MARLI: a mobile application for regional landslide inventories in Ecuador

[EN] The regions of Central and South America most susceptible to the occurrence of landslides will become even more vulnerable in the context of climate change. The Josefina disaster, in 1993, demonstrated both the vulnerability of local infrastructures and communities in the Paute River basin (Ecuador). Since this natural phenomena, several landslide inventories and susceptibility studies were developed, revealing the vulnerability of the Paute River basin to unstable terrain and the need for further studies throughout the basin. Despite this, no studies have been done since then to update the information generated. This paper describes a Mobile Application for Regional Landslide Inventories (MARLI), a simple but efficient open-access platform to report landslide events using the Open Data Kit system. Its design makes reporting fast, simple and cost-effective with an added benefit, and a specialized knowledge is not required for its use. MARLI was tested for the collection of landslides in Cuenca (Ecuador). From the data taken in the field, it was possible to analyze the performance and suitability of collected data and compare the results with regional inventories in the same area. Additionally, these results can be used for the elaboration and update of large-scale inventories or the training of automatic identification systems of landslides and later evaluation of their precision in a small-medium scale. Likewise, this product constitutes a fundamental input for the formulation of mitigation strategies, to formulate the appropriate response and in time, also the elaboration of reconstruction plans before the increase in the occurrence of such phenomenaSIThis study was supported by the Land Laboratory Research Group (G.I.-1934-TB) (Universidade de Santiago de Compostela, Spain) and the University of Azuay (Cuenca, Ecuador) (Project No: 2016-53)

Models of school breakfast program implementation in Western Australia and the implications for supporting disadvantaged students

A substantial body of literature points to the educational and social benefits of school breakfast programs. Most high-income countries provide free or subsidized school breakfasts to support disadvantaged children. Australia does not have a nationally-funded school meal program. Instead, charitable organizations offer school breakfast programs on a voluntary basis, often with funding support from state/territory governments. Decisions about participating in a school breakfast program (SBP), which students to support, and the degree of integration with other strategies to support disadvantaged students are made at the school level. This large-scale, multi-year study examined models of SBP implementation in Western Australian (WA) schools and stakeholder perceptions of the impact of SBPs at the classroom and whole school level. Findings indicate that the approaches adopted by WA schools reflect the extent to which SBPs are part of an integrated approach to supporting disadvantaged students. Minimalist approaches were evident where the focus was limited to alleviating hunger. More inclusive, resource‐intensive models were apparent where the SBP was positioned within a whole school approach to student wellbeing and/or community capacity-building. All schools reported benefits for disadvantaged students, however, the social benefits of SBPs that manifested at the classroom and whole school level were more pronounced in schools that had adopted more integrated, whole school approaches. The findings have implications for Australian schools and other countries that seek to optimize the role of SBPs to provide more holistic support for vulnerable students and reduce the impact of social and economic disadvantage

Homogeneous Bispecifics by Disulfide Bridging

We report on a chemical platform to generate site-specific, homogeneous, antibody-antibody conjugates by targeting and bridging disulfide bonds. A bispecific antibody construct was produced in good yield through simple reduction and bridging of antibody fragment disulfide bonds, using a readily synthesized bis-dibromomaleimide cross-linker. Binding activity of antibodies was maintained, and in vitro binding of target antigens was observed. This technology is demonstrated through linking scFv and Fab antibody fragments, showing its potential for the construction of a diverse range of bispecifics

Development of the designed ankyrin repeat protein (DARPin) G3 for HER2 molecular imaging

s funded by the Seventh Framework Programme (FP7) for HER Imaging and Molecular Interaction Mapping in Breast Cancer (Imagint EC grant 259881) and the Breast Cancer Campaign. The research was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre

Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation

In this communication we describe a novel acid-cleavable linker strategy for antibody-drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody-drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload

Enzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase

Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients

Molecular targets of alcohol action: translational research for pharmacotherapy development and screening.

Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology