Fit-for-purpose validation of a drug-tolerant immunogenicity assay for a human mAb drug in animal safety studies.

A modified biotin-drug extraction and acid dissociation (BEAD) immunogenicity assay was developed to detect anti-drug-antibodies (ADA) against the human anti-FXIIa monoclonal antibody (mAb) drug, Garadacimab (previously called CSL312). Multiple strategies were tested to optimize the signal-to-background (S/B) ratio, assay sensitivity and the drug tolerance. The modified BEAD assay was found to be highly drug tolerant (>500 μg/ml) with a sensitivity of 100 ng/ml, in line with current FDA regulatory guidelines.

Airway inflammation and dysbiosis in antibody deficiency despite the presence of IgG.

Background: Patients with antibody deficiency suffer chronic respiratory symptoms, recurrent exacerbations, and progressive airways disease despite systemic replacement of IgG. Little is known about the respiratory tract biology of these patients.

Objective: We sought to measure immunoglobulin levels, inflammatory cytokines, and mediators of tissue damage in serum and sputum from patients with antibody deficiency and healthy controls; to analyze the respiratory microbiome in the same cohorts.

Pharmacokinetics and pharmacodynamics of a recombinant fusion protein linking activated coagulation factor VII with human albumin (rVIIa-FP) in patients with congenital FVII deficiency.

Recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) is a therapeutic option designed to prevent and treat bleeding events in patients with congenital FVII deficiency with reduced infusion frequency compared to current FVII treatments. This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of rVIIa-FP. A phase I multicenter, randomized, open-label, parallel-arm, single-dose study (NCT02470871) was conducted in nine patients with severe congenital FVII deficiency.

International comparative field study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories.

Unlabelled: Essentials AFSTYLA exhibits ≈50% underestimation in activity when the one-stage (OS) assay is utilized. A field study compared the performance of AFSTYLA with Advate in factor VIII activity assays. AFSTYLA activity can be monitored with both the chromogenic substrate and the OS assay.

Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

Unlabelled: Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios.

Population pharmacokinetics of a new long-acting recombinant coagulation factor IX albumin fusion protein for patients with severe hemophilia B.

Essentials The new recombinant factor IX (FIX) albumin fusion protein (rIX-FP) has a prolonged half-life. A population pharmacokinetic (PK) model was based on FIX activity levels of hemophilia B patients. The model was used to simulate different dosing scenarios of rIX-FP to help guide dosing.

Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A.

Background: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII.

Aim: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII.

Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate.

Background: The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban's effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC).

Methods And Results: This was a phase 1 study conducted at a single site.

Biochemical comparison of four commercially available C1 esterase inhibitor concentrates for treatment of hereditary angioedema.

Background: For safe and efficacious treatment of hereditary angioedema, C1 esterase inhibitor (C1-INH) concentrates should have high purity and high amounts of functional protein. As no pharmacopoeia requirements exist for C1-INH concentrate lot release, biochemical characteristics as declared by the manufacturers may not be compared directly. This study compared the characteristics and purity profiles of four commercially available C1-INH concentrates.

Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study.

Background: Hereditary angioedema (HAE) is a rare disease caused by C1-esterase inhibitor (C1-INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1-INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1-INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety.

123I-IMT SPECT for evaluation of the response to radiation therapy in high grade gliomas: a feasibility study.

Assessing response to radiation therapy in patients with high grade gliomas is needed upon making decisions toward further therapy strategies. Currently used standard imaging tools such as CT and MRI are not sensitive enough to detect early therapy effects. We prospectively investigated if single photon emission computed tomography (SPECT) using radiolabelled amino acid derivate (123)I-methyltyrosine (IMT) would be useful for this aim.

Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme.

We aimed to evaluate the feasibility and tolerability of the newly developed thermotherapy using magnetic nanoparticles on recurrent glioblastoma multiforme. Fourteen patients received 3-dimensional image guided intratumoral injection of aminosilane coated iron oxide nanoparticles. The patients were then exposed to an alternating magnetic field to induce particle heating.

18F-FET PET for planning of thermotherapy using magnetic nanoparticles in recurrent glioblastoma.

Purpose: Thermotherapy using magnetic nanoparticles (nano cancer therapy) is a new concept of local tumour therapy, which is based on controlled heating of intra-tumoural injected magnetic nanoparticles. The aim of this study was to evaluate the usefulness of PET with a recently introduced amino acid tracer O-(2-[18F]fluoroethyl)-]L-tyrosine (FET) for targeting the nanoparticles implantation.

Materials And Methods: Eleven patients with glioblastoma recurrences underwent MR and FET-PET imaging for planning of the nano cancer therapy.

Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique.

The aim of this pilot study was to evaluate whether the technique of magnetic fluid hyperthermia can be used for minimally invasive treatment of prostate cancer. This paper presents the first clinical application of interstitial hyperthermia using magnetic nanoparticles in locally recurrent prostate cancer. Treatment planning was carried out using computerized tomography (CT) of the prostate.

Methods and potentials of magnetic resonance imaging for monitoring radiofrequency hyperthermia in a hybrid system.

Introduction: Non-invasive thermometry (NIT) is a valuable and probably indispensable tool for further development of radiofrequency (RF) hyperthermia. A hybridization of an MRI scanner with a hyperthermia system is necessary for a real-time NIT. The selection of the best thermographic method is difficult, because many parameters and attributes have to be considered.

123I-IMT SPECT and 1H MR-spectroscopy at 3.0 T in the differential diagnosis of recurrent or residual gliomas: a comparative study.

The aim of this investigation was to compare two current non-invasive modalities, single photon emission tomography (SPECT) using 123-iodine-alpha-methyl tyrosine (123I-IMT) and single-voxel proton magnetic resonance spectroscopy (1H-MRS) at 3.0 T, with regard to their ability to differentiate between residual/ recurrent tumors and treatment-related changes in patients pretreated for glioma. The patient population comprised 25 patients in whom recurrent glioma was suspected based on MR imaging.

Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia.

Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability.

The frequent Marburg I polymorphism impairs the pro-urokinase activating potency of the factor VII activating protease (FSAP).

The recently reported plasmatic, Factor Seven Activating Protease (FSAP), has also been found to be a potent activator of pro-urokinase [single-chain plasminogen activator, urinary type (scuPA)]. An initial epidemiological study surprisingly showed that plasmas of 5-10% of healthy blood donors had an impaired potential to activate scuPA. Analysis of the respective genomic DNAs revealed one particular single nucleotide polymorphism of FSAP resulting in an identical amino acid exchange (G511E), which correlates with the reduced activities.

Quantitation of the factor VII- and single-chain plasminogen activator-activating protease in plasmas of healthy subjects.

Plasma samples of 189 healthy subjects were investigated for antigen levels of the recently reported factor VII- and single-chain plasminogen activator-activating protease (FSAP) and the corresponding pro-urokinase activating potencies. While the age of donors had no significant effect on the investigated parameters, female plasmas revealed a trend to higher antigen contents and activity levels. Surprisingly, as much as 9% of all samples contained significantly reduced single-chain urinary plasminogen activator activating potential, whereas antigen concentrations were normal.

Factor VII and single-chain plasminogen activator-activating protease: activation and autoactivation of the proenzyme.

Structural and biological characteristics of a recently described plasma serine protease, which displayed factor VII as well as pro-urokinase-activating properties in vitro, indicated a dual role for this factor VII-activating protease (FSAP) in hemostasis. Only the active protease (two-chain FSAP) has been isolated from plasma and from a prothrombin complex concentrate, whereas activators of the proenzyme have not been identified so far. After purification of the FSAP proenzyme from cryo-poor plasma by adsorption to an immobilized mAb and subsequent ion-exchange chromatography, activation to generate two-chain FSAP was followed by a direct chromogenic assay as well as by the ability of two-chain FSAP to activate pro-urokinase.

The FVII activating protease cleaves single-chain plasminogen activators.

A serine protease isolated from plasma sharing structural characteristics with a hepatocyte growth factor activator-like protease has been demonstrated recently to activate FVII. Accordingly, it was named 'FVII activator'. Until now an impact of this protease on the fibrinolytic system has not been reported.

A protease isolated from human plasma activating factor VII independent of tissue factor.

An activity detected in a prothrombin complex concentrate, termed 'thrombin-like' due to its amidolytic properties, was recently reported by another working group. This serine-protease revealed partial structural homology with a 'hepatocyte growth factor activator'. An impact of this protease on coagulation has not yet been described.