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Surfactant + water: efficient solution to trigger undirected & mild C–H activation of (oligo)thiophenes at challenging β-position.
No full textUnexpected potential of micellar medium to achieve challenging β-selective direct arylation of (oligo)thiophenes is reported. Thanks to the use of water/surfactant solution in combination with natural feedstock derived undecanoic acid additive, this high-yielding C–H coupling could be performed regioselective at room temperature. Broad functional group tolerance was shown with respect to the coupling partners and the synthetic value of this catalytic system has been exemplified by the late-stage diversification of Ticlopidine. Remarkably, this protocol is also compatible with oligothiophenes, allowing fully selective functionalization of such molecules of interest exclusively at their external positions, thus allowing late-stage diversification of important motifs for organic materials
Comprehensive assessment of pharmacokinetics, pharmacodynamics and tolerability of ligelizumab in healthy volunteers and patients with chronic spontaneous urticaria to optimize its subcutaneous delivery system
No full textLigelizumab is a highly potent, humanized IgG1 anti-IgE monoclonal antibody. To explore its opti-mal subcutaneous delivery, pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of ligelizumab from two Phase 1 studies in healthy volunteers (HVs) and four Phase 2 and 3 studies in patients with chronic spontaneous urticaria (CSU) were assessed. Using different in-jection volume or duration of liquid-in-vial (LIVI) formulation or different formulations [LIVI vs. pre-filled syringe (PFS)], single-dose ligelizumab showed comparable PK exposure in HVs. Steady-state exposure of ligelizumab was also comparable between LIVI and PFS following mul-tiple dosing in CSU patients. Total IgE level (PD marker) and tolerability were similar between the two formulations in both HVs and patients. Furthermore, PK, total IgE and tolerability were comparable for PFS administered ei-ther by patients or health care providers (HCPs). Collective evidence demonstrated that injection duration or volume, formulation, or administrator had no apparent impact on PK, PD and tolerabil-ity of ligelizumab, supporting no clinically relevant difference between that LIVI and PFS of ligelizumab and PFS can be administered by patients or HCP. This report provides a comprehensive assessment based on data of multiple clinical endpoints from both HVs and patients to inform formulation develop-ment and commercial use of a monoclonal antibody
A universal tool for stability predictions of biotherapeutics, vaccines and in vitro diagnostic products.
No full textIt is of particular interest for biopharmaceutical companies developing and distributing fragile biomolecules to warrant the stability and activity of their products during long-term storage and shipment. In accordance with quality by design principles, advanced kinetic modeling (AKM) has been successfully used to predict long-term product shelf-life and relies on data from short-term accelerated stability studies that are used to generate Arrhenius-based kinetic models that can, in turn, be exploited for stability forecasts. The AKM methodology was evaluated through a cross-company perspective on stability modeling for key stability indicating attributes of different types of biotherapeutics, vaccines and biomolecules combined in in vitro diagnostic kits. It is demonstrated that stability predictions up to 3 years for products maintained under recommended storage conditions (2-8 °C) or for products that have experienced temperature excursions outside the cold-chain show excellent agreement with experimental real-time data, thus confirming AKM as a universal and reliable tool for stability predictions for a wide range of product types
Systematic Analyses of the Resistance Potential of Drugs Targeting SARS-CoV-2 Main Protease.
No full textDrugs that target the main protease (Mpro) of SARS-CoV-2 are effective therapeutics that have entered clinical use. Wide-scale use of these drugs will apply selection pressure for the evolution of resistance mutations. To understand resistance potential in Mpro, we performed comprehensive surveys of amino acid changes that can cause resistance to nirmatrelvir (Pfizer), and ensitrelvir (Xocova) in a yeast screen. We identified 142 resistance mutations for nirmatrelvir and 177 for ensitrelvir, many of which have not been previously reported. Ninety-nine mutations caused apparent resistance to both inhibitors, suggesting likelihood for the evolution of cross-resistance. The mutation with the strongest drug resistance score against nirmatrelvir in our study (E166V) was the most impactful resistance mutation recently reported in multiple viral passaging studies. Many mutations that exhibited inhibitor-specific resistance were consistent with the distinct interactions of each inhibitor in the substrate binding site. In addition, mutants with strong drug resistance scores tended to have reduced function. Our results indicate that strong pressure from nirmatrelvir or ensitrelvir will select for multiple distinct-resistant lineages that will include both primary resistance mutations that weaken interactions with drug while decreasing enzyme function and compensatory mutations that increase enzyme activity. The comprehensive identification of resistance mutations enables the design of inhibitors with reduced potential of developing resistance and aids in the surveillance of drug resistance in circulating viral populations
Duration of and time to response in oncology clinical trials from the perspective of the estimand framework.
No full textDuration of response (DOR) and time to response (TTR) are typically evaluated as secondary endpoints in early-stage clinical studies in oncology when efficacy is assessed by the best overall response and presented as the overall response rate. Despite common use of DOR and TTR in particular in single-arm studies, the definition of these endpoints and the questions they are intended to answer remain unclear. Motivated by the estimand framework, we present relevant scientific questions of interest for DOR and TTR and propose corresponding estimand definitions. We elaborate on how to deal with relevant intercurrent events which should follow the same considerations as implemented for the primary response estimand. A case study in mantle cell lymphoma illustrates the implementation of relevant estimands of DOR and TTR. We close the paper with practical recommendations to implement DOR and TTR in clinical study protocols
Potential of measured relative shifts in collision cross section values for biotransformation studies.
No full textIon mobility spectrometry-mass spectrometry (IMS-MS) separates gas phase ions due to differences in drift time from which reproducible and analyte-specific collision cross section (CCS) values can be derived. Internally conducted in vitro and in vivo metabolism (biotransformation) studies indicated repetitive shifts in measured CCS values (CCSmeas) between parent drugs and their metabolites. Hence, the purpose of the present article was (i) to investigate if such relative shifts in CCSmeas were biotransformation-specific and (ii) to highlight their potential benefits for biotransformation studies. First, mean CCSmeas values of 165 compounds were determined (up to n = 3) using a travelling wave IMS-MS device with nitrogen as drift gas (TWCCSN2, meas). Further comparison with their predicted values (TWCCSN2, pred, Waters CCSonDemand) resulted in a mean absolute error of 5.1%. Second, a reduced data set (n = 139) was utilized to create compound pairs (n = 86) covering eight common types of phase I and II biotransformations. Constant, discriminative, and almost non-overlapping relative shifts in mean TWCCSN2, meas were obtained for demethylation (- 6.5 ± 2.1 Å2), oxygenation (hydroxylation + 3.8 ± 1.4 Å2, N-oxidation + 3.4 ± 3.3 Å2), acetylation (+ 13.5 ± 1.9 Å2), sulfation (+ 17.9 ± 4.4 Å2), glucuronidation (N-linked: + 41.7 ± 7.5 Å2, O-linked: + 38.1 ± 8.9 Å2), and glutathione conjugation (+ 49.2 ± 13.2 Å2). Consequently, we propose to consider such relative shifts in TWCCSN2, meas (rather than absolute values) as well for metabolite assignment/confirmation complementing the conventional approach to associate changes in mass-to-charge (m/z) values between a parent drug and its metabolite(s). Moreover, the comparison of relative shifts in TWCCSN2, meas significantly simplifies the mapping of metabolites into metabolic pathways as demonstrated
An Open-label, Multi-center, Phase 1/2 Study to Assess Safety, Efficacy and Cellular Kinetics of YTB323, a Rapid Manufacturing CAR-T Cell Therapy Targeting CD19 on B Cells, for Severe Refractory Systemic Lupus Erythematosus: Preliminary Results
No full textBackground/Purpose
Systemic lupus erythematosus (SLE) is characterized by pathogenic autoreactive B cells producing autoantibodies against multiple self-antigens. Recently, a series of clinical cases suggest that traditionally manufactured anti-CD19 chimeric antigen receptor T cell (CAR-T cell) therapies show potential to promote full clinical remission in severe refractory SLE (srSLE).1,2 This is the first clinical trial to evaluate the preliminary safety and efficacy of anti-CD19 CAR-T cell therapy in patients with srSLE. YTB323 is a novel, rapidly manufactured autologous CAR-T therapy that has shown preserved T cell stemness and enhanced CAR-T cell efficacy in hematological malignancies.3
Methods
An open-label, single-arm, multi-center phase I/II study, CYTB323G12101 (NCT05798117), to assess the safety, efficacy, and cellular kinetics of YTB323 in participants with srSLE is currently ongoing. A sentinel cohort of patients with srSLE (n=3), dosed with 12.5x106 cells at least 28 days apart, were enrolled. The primary endpoint is safety as measured by vital signs, adverse events, laboratory parameters and ECG evaluation. CAR-T cell kinetics were monitored by quantitative PCR and flow cytometry. Further relevant endpoints include changes from baseline levels in circulating B and T cells, autoantibody and complement levels, disease activity scores and renal outcome measures.
Results
Baseline characteristics of patients are summarized in Table 1. Adverse events are shown in Figure 1. No serious adverse events or deaths were reported. Disease worsening requiring treatment occurred in the first patient between apheresis and prior to lymphodepletion. No immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. A grade 1 cytomegalovirus reactivation occurred in one patient, which was subsequently resolved. Two patients had cytokine release syndrome (grade 1 or 2); both responded well to tocilizumab treatment and fully recovered. As expected, grade 3 and 4 transient lymphodepletion-related cytopenias were observed in all patients. Grade 2 or 3 hypogammaglobulinemia was observed in two patients; neither event required intravenous immunoglobulin treatment. Cellular kinetics studies showed peak expansion (Tmax) at 13 and 18 days post-infusion for the two patients with data characterizing the expansion phase. Transient T cell and sustained B cell depletion was observed in all patients. Preliminary efficacy data (Figure 2) suggest substantial decreases in SLE Disease Activity Index (SLEDAI) (Figure 2a) and in Physician’s Global Assessment (PhGA) (Figure 2b) in line with improvements in relevant disease biomarkers, such as dsDNA (Figure 2c), complement levels and proteinuria.
Conclusion
Preliminary data from this clinical trial including the first three sentinel patients suggest favorable safety, CAR-T cell expansion, B cell depletion and initial efficacy supporting continuation of the study to evaluate YTB323 in srSLE
Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon.
No full textThe design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4
People of TM: Video of Arzu Granberg
No full textThe video will be used for external social media engagement campaign on platforms like LinkedIn and YouTube etc.featuring stories of people in TM. No IP related content