Sensor macrophages derived from human induced pluripotent stem cells to assess pyrogenic contaminations in parenteral drugs.

Ensuring the safety of parenteral drugs before injection into patients is of utmost importance. New regulations around the globe and the need to refrain from using animals however, have highlighted the need for new cell sources to be used in next-generation bioassays to detect the entire spectrum of possible contaminating pyrogens. Given the current drawbacks of the Monocyte-Activation-Test (MAT) with respect to the use of primary peripheral blood mono-nuclear cells or the use of monocytic cell lines, we here demonstrate the manufacturing of sensor monocytes/macrophages from human induced pluripotent stem cells (iMonoMac), which are fully defined and superior to current cell products. Using a modern and scalable manufacturing platform, iMonoMac showed typical macrophage-like morphology and stained positive for several Toll like receptor (TLRs) such as TLR-2, TLR-5, TLR-4. Furthermore, iMonoMac derived from the same donor were sensitive to endotoxins, non-endotoxins, and process related pyrogens at a high dynamic range and across different cellular densities. Of note, iMonoMac showed increased sensitivity and reactivity to a broad range of pyrogens, demonstrated by the detection of interleukin-6 at low concentrations of LPS and MALP-2 which could not be reached using the current MAT cell sources. To further advance the system, iMonoMac or genetically engineered iMonoMac with NF-κB-luciferase reporter cassette could reveal a specific activation response while correlating to the classical detection method employing enzyme-linked immunosorbent assay to measure cytokine secretion. Thus, we present a valuable cellular tool to assess parenteral drugs safety, facilitating the future acceptance and design of regulatory-approved bioassays.

Programmable multispecific DNA-origami-based T-cell engagers.

Multispecific antibodies have emerged as versatile therapeutic agents, and therefore, approaches to optimize and streamline their design and assembly are needed. Here we report on the modular and programmable assembly of IgG antibodies, F(ab) and scFv fragments on DNA origami nanocarriers. We screened 105 distinct quadruplet antibody variants in vitro for the ability to activate T cells in the presence of target cells. T-cell engagers were identified, which in vitro showed the specific and efficient T-cell-mediated lysis of five distinct target cell lines. We used these T-cell engagers to target and lyse tumour cells in vivo in a xenograft mouse tumour model. Our approach enables the rapid generation, screening and testing of bi- and multispecific antibodies to facilitate preclinical pharmaceutical development from in vitro discovery to in vivo proof of concept.

Secukinumab Demonstrated High Effectiveness in Vietnamese Patients with Moderate-To-Severe Plaque Psoriasis in a Real-World Clinical Setting: 16 Week Results from an Observational Study.

INTRODUCTION: Plaque psoriasis (PsO), characterized by demarcated, erythematous, scaly skin, can have a substantial negative impact on patients' quality of life. This observational (non-interventional) retrospective study was conducted to characterize treatment patterns and response among patients with plaque PsO treated with secukinumab under routine medical practice in Vietnam. METHODS: Patient medical records from the specialized clinic of the Ho Chi Minh City Hospital of Dermato-Venereology (N = 236) were collected. Patients (male or female) aged ≥ 18 years with moderate-to-severe chronic plaque PsO, defined as > 10% involvement of the body surface area (BSA > 10) or a Psoriasis Area and Severity Index (PASI) score > 10 and a Dermatology Life Quality Index (DLQI) score > 10, were included. RESULTS: In total, 230 patients met the inclusion criteria and were included in the intention-to-treat (ITT) population, the majority of whom were men (66.1%). At baseline, the mean ± standard deviation (SD) age of the ITT population was 41.46 ± 14.29 years, mean disease duration was 7.91 ± 7.91 years, and 27% (n = 62) were obese. More than 90% of the patients were biologic naïve prior to initiation of secukinumab therapy. At week 4, 54.6% patients (n = 124) achieved ≥ 75% reduction in PASI scores from baseline (PASI 75). By week 16, 81.1, 68.9, and 36.5% of the overall population (n = 180, 153, and 81) achieved PASI scores of 75, 90, and 100, respectively; 66.1% of the overall population (n = 154) reported DLQI scores of 0/1 by week 16. The effectiveness of secukinumab was validated in subgroups of patients with or without obesity, concomitant conditions (hepatitis B virus, hepatitis C virus, diabetes, high blood pressure, gout, and/or obesity [body mass index ≥ 30 kg/m2]), and concomitant psoriatic arthritis (PsA). CONCLUSION: The study validated the real-world effectiveness of secukinumab in Vietnamese patients irrespective of obesity, concomitant conditions, and concomitant PsA status.