Regulation of genome edited organisms in Australia.

Whether organisms developed with the use of genome editing techniques, or food derived from such organisms, are, or should be, regulated as genetically modified organisms (GMOs) or genetically modified (GM) food, respectively, remains a subject of debate globally. Much of the discussion has been scientific and focussed on the similar genetic outcomes of some genome editing techniques and 'conventional' or natural mutagenesis. Many jurisdictions, including Australia, have considered, or are considering, how their regulatory frameworks will deal with such organisms and products.

Infliximab biosimilar-to-biosimilar switching in patients with inflammatory rheumatic disease: clinical outcomes in real-world patients from the DANBIO registry.

Objective: Successful uptake of biosimilars in rheumatology is limited by lack of real-world evidence regarding effectiveness of biosimilar-to-biosimilar switching. We investigated infliximab biosimilars CT-P13-to-GP1111 switching among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA).

Methods: Observational cohort study from the DANBIO registry.

CTLA4-Ig prevents development of neutralizing antibody formation after continuous treatment with human FVIII in HA rats.

Introduction: Immunogenicity causing development of anti-drug antibodies (ADAs) are major challenges in the treatment of haemophilia, as well as other diseases where proteins are used for treatment. Furthermore, it is a complication for preclinical testing of such therapies in animal models.

Aim: To investigate if the immunosuppressive drug CTLA4 immunoglobulin (CTLA4-Ig) can induce tolerance in haemophilia A (HA) rats receiving recombinant human coagulation factor VIII (rhFVIII) treatment.

Structure identification of circulating metabolites from somapacitan, a long-acting growth hormone derivative, and pharmacokinetics after single and multiple subcutaneous dosing in rats.

Somapacitan is a growth hormone derivative approved for once-weekly treatment of growth hormone deficiency in adults and currently in clinical development for once-weekly dosing in children. The purpose of this study was to obtain non-clinical data from rats to support the safety evaluation of the most abundant metabolites of somapacitan in humans. The aims were to identify somapacitan metabolites and their relative proportions in rat plasma, identify the structure of abundant metabolites and measure the systemic metabolite exposure at the no-observed-adverse-effect level in the rat.

A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice.

Hemophilia A is a bleeding disorder resulting from deficient factor VIII (FVIII), which normally functions as a cofactor to activated factor IX (FIXa) that facilitates activation of factor X (FX). To mimic this property in a bispecific antibody format, a screening was conducted to identify functional pairs of anti-FIXa and anti-FX antibodies, followed by optimization of functional and biophysical properties. The resulting bispecific antibody (Mim8) assembled efficiently with FIXa and FX on membranes, and supported activation with an apparent equilibrium dissociation constant of 16 nM.

Identification of Binding Sites on Human Serum Albumin for Somapacitan, a Long-Acting Growth Hormone Derivative.

Somapacitan, a human growth hormone derivative that binds reversibly to albumin, was investigated for human serum albumin (HSA) and HSA domain binding. Isothermal titration calorimetry (ITC) binding profiles showed high-affinity binding (∼100-1000 nM) of one somapacitan molecule and low-affinity binding (∼1000-10000 nM) of one to two somapacitan molecules to HSA. The high-affinity site was identified in HSA domain III using size exclusion chromatography (SEC) and ITC.

Identification and preclinical development of an anti-proteolytic uPA antibody for rheumatoid arthritis.

Blocking the proteolytic capacity of urokinase-type plasminogen activator (uPA) with a monoclonal antibody (mAb) reduces arthritis progression in the collagen-induced mouse arthritis model to an extent that is on par with the effect of blocking tumor necrosis factor-alpha by etanercept. Seeking to develop a novel therapy for rheumatoid arthritis, a humanized mAb, NNC0266-0043, was selected for its dual inhibition of both the zymogen activation and the proteolytic capacity of human uPA. The antibody revealed nonlinear elimination kinetics in cynomolgus monkeys consistent with binding to and turnover of endogenous uPA.

Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative.

Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA).

Towards a Göttingen minipig model of adult onset growth hormone deficiency: evaluation of stereotactic electrocoagulation method.

Background: Adult onset growth hormone (GH) deficiency (AGDH) is a potentially underdiagnosed condition, caused by damage to the pituitary gland. AGHD is treated with growth hormone replacement therapy. A large variety of clinical symptoms and changes in the metabolic homeostasis can be observed and quantified.

Clarifying the regulation of genome editing in Australia: situation for genetically modified organisms.

Australia's gene technology regulatory scheme (GT Scheme) regulates activities with genetically modified organisms (GMOs, organisms modified by gene technology), including environmental releases. The scope of regulation, i.e.

Inorganic co-crystal formation and thermal disproportionation in a dicyanometallate 'superperovskite'.

We report the synthesis, crystal structure, and thermally-driven phase transformation of the dicyanometallate superperovskite co-crystal [NBu4]Mn[Au(CN)2]3·[NBu4]ClO4. This phase is understandable in terms of the conventional ABX3 perovskite structure type, but with the NBu4+ A-site cation displaced onto the perovskite cage face and 1-dimensional AX' chains included within framework pores opened up by these displacements. On heating to 380 K, the co-crystal disproportionates into its two inorganic components: a bcs-structured ABX3 phase and [NBu4]ClO4.

Long-Acting Human Growth Hormone Analogue by Noncovalent Albumin Binding.

The present work describes a series of human growth hormone (hGH) albumin binder conjugates with an extended in vivo half-life. A broad range of different conjugates were studied by varying the albumin binder structure and conjugation site. Conjugates were conveniently obtained by reductive alkylation or by alkylation to introduced cysteines using functionalized albumin-binding side chains.

Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models.

Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis.

Validity and completeness of rheumatoid arthritis diagnoses in the nationwide DANBIO clinical register and the Danish National Patient Registry.

Objectives: In Denmark, patients with rheumatoid arthritis (RA) are registered in the nationwide clinical DANBIO quality register and the Danish National Patient Registry (DNPR). The aim was to study the validity of the RA diagnosis and to estimate the completeness of relevant RA cases in each registry.

Study Design And Setting: Patients registered for the first time in 2011 with a diagnosis of RA were identified in DANBIO and DNPR in January 2013.

Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis.

Growth hormone (GH) resistance may develop as a consequence of inflammation during conditions such as inflammatory bowel disease, encompassing ulcerative colitis (UC). However, the specific role of the GH-insulin growth factor (IGF)-1-axis and/or the functional consequences of GH resistance in this condition are unclear. In situ hybridization targeting the GH receptor (GHR) and relevant transcriptional analyses were performed in patients with UC and in IL-10 knock-out mice with piroxicam accelerated colitis (PAC).

Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone.

Objective: Somapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys.

Potential exposure to endocrine disrupting chemicals and selected adverse pregnancy outcomes: a follow-up study of pregnant women referred for occupational counselling.

Background: Experimental evidence indicates that fetal exposure to xenobiotics with the potential to interfere with the endogenous steroid hormone regulation of fetal development may reduce birth weight. However, epidemiological studies are limited. The aim of the study was to investigate whether potential occupational exposure to endocrine disrupting chemicals (EDC) of the mother during pregnancy is associated with preterm birth and low birth weight.

Orbital Dimer Model for the Spin-Glass State in Y_{2}Mo_{2}O_{7}.

The formation of a spin glass generally requires that magnetic exchange interactions are both frustrated and disordered. Consequently, the origin of spin-glass behavior in Y_{2}Mo_{2}O_{7}-in which magnetic Mo^{4+} ions occupy a frustrated pyrochlore lattice with minimal compositional disorder-has been a longstanding question. Here, we use neutron and x-ray pair-distribution function (PDF) analysis to develop a disorder model that resolves apparent incompatibilities between previously reported PDF, extended x-ray-absorption fine structure spectroscopy, and NMR studies, and provides a new and physical explanation of the exchange disorder responsible for spin-glass formation.

Control of Multipolar and Orbital Order in Perovskite-like [C(NH2)3]CuxCd1-x(HCOO)3 Metal-Organic Frameworks.

We study the compositional dependence of molecular orientation (multipolar) and orbital (quadrupolar) order in the perovskite-like metal-organic frameworks [C(NH2)3]CuxCd1-x(HCOO)3. Upon increasing the fraction x of Jahn-Teller-active Cu(2+), we observe an orbital disorder/order transition and a multipolar reorientation transition, each occurring at distinct critical compositions xo = 0.45(5) and xm = 0.

The kidneys play a central role in the clearance of rhGH in rats.

The kidneys are thought to play an important role in the clearance of recombinant human growth hormone (rhGH), but the relative importance is not clear. Obtaining knowledge of clearance pathway is an important prerequisite for the development of new long acting growth hormone analogues targeted at treatment of patients with growth hormone disorders. The purpose of this study was to investigate the relative importance of the kidneys in the clearance of rhGH.

Translational mixed-effects PKPD modelling of recombinant human growth hormone - from hypophysectomized rat to patients.

Background And Purpose: We aimed to develop a mechanistic mixed-effects pharmacokinetic (PK)-pharmacodynamic (PD) (PKPD) model for recombinant human growth hormone (rhGH) in hypophysectomized rats and to predict the human PKPD relationship.

Experimental Approach: A non-linear mixed-effects model was developed from experimental PKPD studies of rhGH and effects of long-term treatment as measured by insulin-like growth factor 1 (IGF-1) and bodyweight gain in rats. Modelled parameter values were scaled to human values using the allometric approach with fixed exponents for PKs and unscaled for PDs and validated through simulations relative to patient data.

N-glycosylation increases the circulatory half-life of human growth hormone.

Therapeutic use of recombinant GH typically involves daily sc injections. We examined the possibilities for prolonging the in vivo circulation of GH by introducing N-glycans. Human GH variants with a single potential N-glycosylation site (N-X-S/T) introduced by site-directed mutagenesis were expressed in HEK293 cells.

Physiologically-based PK/PD modelling of therapeutic macromolecules.

Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules.

An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma.

Purpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8(+) T cells and natural killer cells. We report a phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT).