In vitro model for predicting bioavailability of subcutaneously injected monoclonal antibodies

Monoclonal antibodies (mAbs), which are now more frequently administered by subcutaneous (SC) injection rather than intravenously, have become a tremendously successful drug format across a wide range of therapeutic areas. Preclinical evaluations of mAbs to be administered by SC injection are typically performed in species such as mice, rats, minipigs, and cynomolgus monkeys to obtain critical information regarding formulation performance and prediction of PK/PD outcomes needed to select clinical doses for first-in-human studies. Despite extensive efforts, no preclinical model has been identified to date that accurately predicts clinical outcomes for these SC injections. We have addressed this deficiency with a novel in vitro instrument, termed Scissor, to model events occurring at the SC injection site and now further validated this approach using a set of eight mAbs for which clinical PK/PD outcomes have been obtained. Diffusion of these mAbs from the Scissor system injection cartridge into a large volume physiological buffer, used to emulate mAb movement from the SC injection site into the systemic circulation, provided distinct profiles when monitored over a 6 h period. Curve-fitting analysis of these profiles using the Hill equation identified parameters that were used, along with physicochemical properties for each mAb, in a partial least squares analysis to define a relationship between molecule and formulation properties with clinical PK outcomes. The results demonstrate that parameters of protein charge at neutral pH and isoelectric point (pI) along with combined formulation properties such as viscosity and mAb concentration can dictate the movement of the mAb from the injection cartridge to infinite sink compartment. Examination of profile characteristics of this movement provided a strong predictive correlation for these eight mAbs. Together, this approach demonstrates the feasibility of this in vitro modelling strategy as a tool to identify drug and formulation properties that can define the performance of SC injected medicines and provide the potential for predicting clinical outcomes that could be useful for formulation selection and a first-in-human clinical dosing strategy

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Yrittäjät Green Care - palveluiden tuottajina

Millaisia Green Care -palveluihin liittyviä kehittämistarpeita on lappilaisilla yrittäjillä? Miten Lapin elinkeinorakenteiden muutokset vaikuttavat Green Care -yritystoiminnan suuntaamiseen? Artikkelikokoelma tarjoilee tietoa luonnon hyvinvointia hyödyntävien palveluiden kehittämisestä ja elinkeinorakenteiden muutosvaikutuksista, joita rikastuttavat yrittäjätarinat sekä eri asiantuntijoiden näkemykset. Monialaiset näkökulmat Green Care -palveluiden tuottamisesta ja yrittäjyyden kehittämisestä painottuvat Lapin luonnonvara-, sosiaali- ja terveys-, taide- ja kulttuuri- sekä matkailualoille. Julkaisu on suunnattu Green Care -palveluiden tuottamisesta kiinnostuneille yrittäjille, päättäjille sekä luontolähtöisten palveluiden kehittäjille. Tiedot on koottu Green Care -yrittämisen kehittämistarpeet Lapissa -hankkeessa vuosina 2017-2019, jonka toimintaa ja tuloksia on myös artikkeleissa esitelty

A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components

Subcutaneous (SC) injection is becoming a more common route for the administration of biopharmaceuticals. Currently, there is no reliable in vitro method that can be used to anticipate the in vivo performance of a biopharmaceutical formulation intended for SC injection. Nor is there an animal model that can predict in vivo outcomes such as bioavailability in humans. We address this unmet need by the development of a novel in vitro system, termed Scissor (Subcutaneous Injection Site Simulator). The system models environmental changes that a biopharmaceutical could experience as it transitions from conditions of a drug product formulation to the homeostatic state of the hypodermis following SC injection. Scissor uses a dialysis-based injection chamber, which can incorporate various concentrations and combinations of acellular extracellular matrix (ECM) components that may affect the release of a biopharmaceutical from the SC injection site. This chamber is immersed in a container of a bicarbonate-based physiological buffer that mimics the SC injection site and the infinite sink of the body. Such an arrangement allows for real-time monitoring of the biopharmaceutical within the injection chamber, and can be used to characterize physicochemical changes of the drug and its interactions with ECM components. Movement of a biopharmaceutical from the injection chamber to the infinite sink compartment simulates the drug migration from the injection site and uptake by the blood and/or lymph capillaries. Here, we present an initial evaluation of the Scissor system using the ECM element hyaluronic acid and test formulations of insulin and four different monoclonal antibodies. Our findings suggest that Scissor can provide a tractable method to examine the potential fate of a biopharmaceutical formulation after its SC injection in humans and that this approach may provide a reliable and representative alternative to animal testing for the initial screening of SC formulations

Overlap in the Genetic Architecture of Stroke Risk, Early Neurological Changes, and Cardiovascular Risk Factors

[Background and Purpose] The genetic relationships between stroke risk, stroke severity, and early neurological changes are complex and not completely understood. Genetic studies have identified 32 all stroke risk loci. Polygenic risk scores can be used to compare the genetic architecture of related traits. In this study, we compare the genetic architecture of stroke risk, stroke severity, and early neurological changes with that of 2 stroke risk factors: type 2 diabetes mellitus (T2DM) and hypertension.[Methods] We assessed the degree of overlap in the genetic architecture of stroke risk, T2DM, hypertension, and 2 acute stroke phenotypes based on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 for no stroke symptoms to 21 to 42 for a severe stroke: baseline (within 6 hours after onset) and change in NIHSS (ΔNIHSS=NIHSS at baseline−NIHSS at 24 hours). This was done by (1) single-nucleotide polymorphism by single-nucleotide polymorphism comparison, (2) weighted polygenic risk scores with sentinel variants, and (3) whole-genome polygenic risk scores using multiple P thresholds.[Results] We found evidence of genetic architecture overlap between stroke risk and T2DM (P=2.53×10−169), hypertension (P=3.93×10−04), and baseline NIHSS (P=0.03). However, there was no evidence of overlap between ΔNIHSS and stroke risk, T2DM, or hypertension.[Conclusions] The genetic architecture of stroke risk is correlated with that of T2DM, hypertension, and initial stroke severity (NIHSS within 6 hours of stroke onset). However, the genetic architecture of early neurological change after stroke (ΔNIHSS) is not correlated with that of ischemic stroke risk, T2DM, or hypertension. Thus, stroke risk and early neurological change after stroke have distinct genetic architectures.This study was supported by Emergency Medicine Foundation Career Development Grant; American Heart Association (AHA) Mentored Clinical and Population Research Award (14CRP18860027); NIH/NINDS-R01-NS085419; NIH/NINDS-K23-NS099487-01; Barnes-Jewish Hospital Foundation; Helsinki University Central Hospital; Finnish Medical Foundation; Finland government subsidiary funds; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (grants Registro Base de Datos de Ictus del Hospital del Mar (BASICMAR) Funding for Research in Health [PI051737], Genome Wide Association Study in Spanish Population (GWALA Project) from Fondos de Investigación Sanitaria Instituto de Salud Carlos III [PI10/02064, PI12/01238, and PI15/00451]); Fondo Europeo de Desarrollo Regional (FEDER/EDRF) Red de Investigación Cardiovascular (RD12/0042/0020); Fundació la Marató TV3; Genestroke Consortium (76/C/2011); and Recercaixa’13 (JJ086116). Dr Fernandez-Cadenas is supported by Miguel Servet II Program, Generacion project (PI15/01978), Pretest project (PMP15/00022), Invictus plus Network (RD16/0019), from Instituto de Salud Carlos III and Fondos Feder; Agaur; and Epigenesis project from Marató TV3 Foundation. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html.Peer reviewe