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People of TM: Video of Craig Boulton
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featuring stories of people in TM.
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Preclinical Characterization and Phase 1 Study of the Anti-HER2-TLR7 Immune Stimulator Antibody Conjugate NJH395 in Patients with HER2-positive Malignancies
No full textImmune stimulator antibody conjugates (ISACs) combining tumor-targeting monoclonal antibodies with potent immunostimulatory agents allow targeted delivery of immune activators in tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll‐like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a non-cleavable linker-payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase 1, multicenter, open-label study in patients with HER2-positive malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7 agonist payload in HER2-positive tumor cells and induction of type I IFN response, which interrelated with preferential immune modulation in the tumor microenvironment. Cytokine release syndrome was a common but manageable drug-related adverse event. Antidrug antibody formation and neuroinflammation at high doses represented significant clinical challenges
β‐secretase inhibition prevents structural spine plasticity deficits in App NL-G-F mice
No full textAll clinical BACE1-inhibitor trials for the treatment of Alzheimer´s Disease (AD) have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. However, the scientific evidence to date suggests that BACE1-inhibition could be an effective preventative measure if applied prior to the accumulation of amyloid‐beta (Aβ)‐peptide and resultant impairment of synaptic function. Preclinical studies have associated BACE1-inhibition induced cognitive deficits with decreased dendritic spine density. Therefore, we investigated dose-dependent effects of BACE1-inhibition on hippocampal dendritic spine dynamics in an APP knock-in mouse line for the first time. We conducted in vivo two-photon microscopy in the stratum oriens layer of hippocampal CA1 neurons in 3.5-month-old AppNL�G-FGFP-M mice over 6 weeks to monitor the effect of potentially preventive treatment with a high and low-dose of the BACE1-inhibitor NB-360 on dendritic spine dynamics. Structural spine plasticity was severely impaired in untreated AppNL-G-FGFP-M mice, although spines were not yet showing signs
of degeneration. Prolonged high-dose BACE1-inhibition significantly enhanced spine formation, improving spine dynamics in the AD mouse model. We conclude that in an early AD stage characterized by low Aβ‐accumulation and no irreversible spine loss, BACE1‐inhibition could hold the progressive synapse loss and cognitive decline by improving structural spine dynamics
Discovery of compounds with viscosity-reducing effects on biopharmaceutical formulations with monoclonal antibodies
No full textFor the development of concentrated monoclonal antibody formulations for subcutaneous administration, the main challenge is the high viscosity of the solutions. To compensate for this, viscosity reducing agents are commonly used as excipients. Here, we applied two computational chemistry approaches to discover new viscosity-reducing agents: fingerprint similarity searching, and physicochemical property filtering. In total, 94 compounds were selected and experimentally evaluated on two model monoclonal antibodies, which led to the discovery of 44 new viscosity-reducing agents. Analysis of the results showed that using a simple filter that selects only compounds with three or more charge groups is a good ‘rule of thumb’ for selecting potential viscosity-reducing agents for two model monoclonal antibody formulations
The SGLT2i dapagliflozin reduces RV mass independent of changes in RV pressure induced by pulmonary artery banding
No full textBACKGROUND
Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored.
HYPOTHESIS
We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle.
METHODS
Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses.
RESULTS
PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05).
SIGNIFICANCE
Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined
Sustainable and Bench-Stable Photoactive Aqueous Nanoaggregates of Cu(II) for ppm Cu(I) Catalysis in Water
No full textThe nanomaterial containing amphiphilic Cu(II) nanoparticles (NPs) stabilized with proline unit of the amphiphile SS-550-M is reported. The material is characterized using various spectroscopic techniques, such as XAS, HRTEM, NMR, UV-Vis, and IR spectroscopy. DFT calculations and NMR spectroscopic analyses support that the tertiary amide group in the amphilphile is a binding site to the NP surface. Upon light irradiation, Cu(II) changes to Cu(I) assisted by ligand to metal charge transfer process, genrating robust catalytically active species. The catalytic activity is investigated for domino azidation and 1,4-cycloaddition in water. The catalytic protocol is applicable on a wide variety of substrates and catalytic material is stable under ambient conditions for upto six months
IL-17A is a pertinent therapeutic target for moderate-to-severe hidradenitis suppurativa: Combined results from a pre-clinical and phase II proof-of-concept study.
No full textHidradenitis Suppurativa (HS) is a chronic, recurrent, inflammatory, follicular skin disease whose pathology is complex and not fully understood. The objective of this study was to elucidate the role of IL-17A in moderate-to-severe HS. Transcriptomic and histological analyses were conducted on ex vivo HS (n = 19; lesional and non-lesional) and healthy control (n = 8) skin biopsies. Further, a Phase II exploratory, randomized, double-blind, placebo-controlled study was carried out in moderate-to-severe HS patients. Patients were treated with either CJM112 300 mg (n = 33), a fully human anti-IL-17A IgG1/κ monoclonal antibody, or placebo (n = 33). The main outcome of the translational analyses was to identify IL-17A-producing cells and indications of IL-17A activity in HS lesional skin. The primary objective of the clinical study was to determine the efficacy of CJM112 in moderate-to-severe HS patients by HS-Physician Global Assessment (HS-PGA) responder rate at Week 16. Transcriptomic and histopathologic analyses revealed the presence of heterogeneous cell types in HS lesional skin; IL-17A gene signatures were increased in HS lesional vs non-lesional or healthy skin. High expression of IL-17A was localized to T cells, neutrophils, and mast cells, confirming the transcriptional data. Clinically, the proportion of Week 16 HS-PGA responders was significantly higher (p = 0.03) in the CJM112 group vs placebo (32.3% vs 12.5%). This study elucidated the role of the IL-17A pathway in HS pathogenesis and clinically validated the IL-17A pathway in moderate-to-severe HS patients in a proof-of-concept study using the anti-IL-17A-specific antibody CJM112
Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
No full textMalaria is among the tropical diseases that cause the most deaths in Africa. Around 500,000 malaria deaths are reported yearly among African children under the age of five. Chloroquine (CQ) is a low-cost antimalarial used worldwide for the treatment of Plasmodium vivax malaria. Due to resistance mechanisms, CQ is no longer effective against most malaria cases caused by P. falciparum. The World Health Organization recommends artemisinin combination therapies for P. falciparum malaria, but resistance is emerging in Southeast Asia and some parts of Africa. Therefore, new medicines for treating malaria are urgently needed. Previously, our group identified the 4-aminoquinoline DAQ, a CQ analog containing an acetylenic bond in its side chain, which overcomes CQ resistance in K1 P. falciparum strains. In this work, the antiplasmodial profile, drug-like properties, and pharmacokinetics of DAQ were further investigated. DAQ showed no cross-resistance against standard CQ-resistant strains (e.g., Dd2, IPC 4912, RF12) nor against P. falciparum and P. vivax isolates from patients in the Brazilian Amazon. Using drug pressure assays, DAQ showed a low propensity to generate resistance. DAQ showed considerable solubility but low metabolic stability. The main metabolite was identified as a mono N-deethylated derivative (DAQM), which also showed significant inhibitory activity against CQ-resistant P. falciparum strains. Our findings indicated that the presence of a triple bond in CQ-analogues may represent a low-cost opportunity to overcome known mechanisms of resistance in the malaria parasite
An Automatic Foot and Shank IMU Synchronization Algorithm: Proof-of-concept
No full textWhen using wearable sensors for measurement and analysis of human performance, it is often necessary to integrate and synchronise data from separate sensor systems. This paper describes a synchronization technique between IMUs attached to the shanks and insoles attached at the feet and aims to solve the need to compute the ankle joint angle, which relies on synchronized sensor data. This will additionally enable concurrent analysis using gait kinematic and kinetic features. A proof-of-concept of the algorithm, which relies on cross-correlation of gyroscope sensor data from the shank an foot, to align the sensor systems is demonstrated. The algorithm output is validated against those signals synchronized using manually annotated heel-strike and toe-off ground-truth signal landmarks, identified in both the shank and feet signals using previously published definitions. Results demonstrate that the developed algorithm is capable of synchronizing both sensor systems, based on IMU data from both healthy participants and participants suffering from knee osteoarthritis, with a mean lag time bias of 25.56ms when compared to the ground truth. A proof-of-concept of technique to synchronise IMUs attached to the shanks and insoles attached at the feet is demonstrated and offers an alternative approach to sensor system synchronisation
Aqueous Micelle-Driven Spontaneously Formed Ligand-Free Pal-ladium(0) Nanoparticles are Efficient Catalyst for Cross-Couplings Enabling Biaryl Ketones
No full textA novel strategy has been developed to spontaneously form ligand-free Pd(0) nanoparticles from water- and air-sensitive Pd2dba3 in water. These nanoparticles are thoroughly characterized by IR, NMR, and mass spectrometry, revealing that the metal-micelle binding play a critical role in their stability and activity. HRTEM supported the ultrasmall nature of nanopar-ticles, while XPS analysis confirmed the zero-oxidation state of Pd. The shielding effect of micelle and enhanced stability of nanoparticles enabled fast cross-couplings of water-sensitive triazene adducts of carboxylic acid to form non-symmetrical biaryl ketones. These naturally formed nanoparticles are more efficient than new synthetic nanoparticles formed under a hydrogen atmosphere. The activity of naturally formed nanoparticles is compared with synthetic nanoparticles over 34 sub-strates revealing that naturally formed nanoparticles are much more efficient than synthetic nanoparticles