7196 research outputs found
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Towards Efficient Time-to-Event Dose-Escalation Guidance of Multi-Cycle Cancer Therapies.
No full textTreatment of cancer has rapidly evolved over time in quite dramatic ways, for example, from chemotherapies, targeted therapies to immunotherapies and chimeric antigen receptor T-cells. Nonetheless, the basic design of early phase I trials in oncology still follows predominantly a dose-escalation design. These trials monitor safety over the first treatment cycle to escalate the dose of the investigated drug. However, over time, studying additional factors such as drug combinations and/or variation in the timing of dosing became important as well. Existing designs were continuously enhanced and expanded to account for increased trial complexity. With toxicities occurring at later stages beyond the first cycle and the need to treat patients over multiple cycles, the focus on the first treatment cycle only is becoming a limitation in nowadays multi-cycle treatment therapies. Here, we introduce a multi-cycle time-to-event model (TITE-CLRM: Time-Interval-To-Event Complementary-Loglog Regression Model), allowing guidance of dose-escalation trials studying multi-cycle therapies. The challenge lies in balancing the need to monitor the safety of longer treatment periods with the need to continuously enroll patients safely. The proposed multi-cycle time-to-event model is formulated as an extension to established concepts like the escalation with overdose control principle. The model is motivated by a current drug development project and evaluated in a simulation study
Setting the Standard Cleanliness Grades Behind Every Sterility Test Isolator
No full textSterility testing is a critical quality control measure in pharmaceutical manufacturing, ensuring the absence of viable microorganisms in sterile products. Traditionally performed in grade A laminar airflow cabinets within grade B cleanrooms, the industry is transitioning toward isolator-based systems that offer superior contamination control. This shift has prompted debate over the required environmental classification for the background in which sterility test isolators are located.
This paper explores the regulatory landscape surrounding this issue, highlighting the lack of harmonized guidance. While pharmacopoeial chapters emphasize aseptic conditions and environmental monitoring, they do not mandate specific background classifications. Regulatory documents vary in specificity, with some dismissing the need for classified environments, while manufacturing guidelines like EU GMP Annex 1 prescribe grade D for closed isolators and grade C for open ones.
The distinction between sterility testing and aseptic manufacturing is crucial. Sterility testing, a quality control activity, poses minimal direct risk to patient safety compared to manufacturing failures. However, aligning sterility testing environments with manufacturing standards can facilitate root cause investigations and regulatory discussions.
Ultimately, the requirement for a grade D background is not universally mandatory but should be justified through risk assessment and contamination control strategy (CCS). Cleanliness of the isolator, test samples, and consumables is paramount, and environmental monitoring alone does not prevent false positives. The paper advocates for a balanced approach, recognizing both regulatory flexibility and the importance of robust contamination control practices
Sample-level modeling of single‑cell data at scale with tinydenseR
No full textHere, we present tinydenseR, a landmark-based platform for single‑cell data analysis. tinydenseR identifies differentially abundant cell types and differentially expressed features, including subtle within-cluster changes. We applied it to a preclinical xenograft model and two immuno-oncology clinical trials to uncover treatment-associated cell states. Modeling samples instead of cells as biological replicates, tinydenseR enhances analytic efficiency and reproducibility while preserving the richness of single‑cell data across technologies
Palladium-Catalyzed α‑Arylation of Boc-Protected Lactams Using 2,2,6,6-Tetramethylpiperidine·ZnCl·LiCl
No full textWe report general conditions for the palladium-catalyzed α-arylation of Boc-protected lactams using TMP·ZnCl·LiCl as base, eliminating the need for preformed zinc amides. The method is compatible with various 5- and 6-membered lactams and a broad range of aryl bromides. These operationally simple conditions enable efficient access to α-arylated lactams, streamlining SAR exploration in medicinal chemistry
Considerations for creating effective academic-industrial partnerships.
No full textOn 12 February 2025, a joint meeting of the UK Aging Networks was held in Liverpool, UK. It was convened by the ECMage (extracellular matrix aging) network and EuroAgeNet, an initiative led by ECMage but involving four other UK aging networks — namely, the building links in aging science and translation network (BLAST), the cognitive frailty interdisciplinary network (CFIN), the aging and nutrient sensing network (AGENTS) and the food systems for older people (Food4Years) network — together with industrial and European partners. In this Meeting Report, we summarize the opinions of an industrial panel and round-table discussions on barriers and opportunities related to academic–industrial partnerships
Assessing the adjuvant potential of CHO host cell proteins using an in vitro dendritic cell assay
No full textHost cell proteins (HCPs) are process-related impurities of therapeutic protein production and may affect product quality or patient safety. In clinical trials, certain HCPs (e.g., PLBL2 or CCL2) that co-purify with the therapeutic protein have been associated with immune reactions in patients. In this study, we examined the adjuvant potential of six commonly detected HCPs from CHO cells (YWHAE, S100A4, PRDX1, PLBL2, CCL2, and CLU) using an in vitro dendritic cell (DC) maturation assay. Recombinant HCPs were expressed in CHO cells to mimic manufacturing conditions. PRDX1, S100A4, and PLBL2 caused a slight increase in the expression of maturation markers on DCs, while YWHAE, CLU, and CCL2 did not. Interestingly, CLU and CCL2 reduced the DC maturation induced by rituximab. In addition, we observed that process parameters such as elution conditions during chromatographic purification can influence HCP aggregation, which in turn can mask or enhance the intrinsic adjuvant potential of an HCP. These findings not only provide initial insights into the adjuvant potential of individual HCPs but also indicate that the quantity as well as the degree of aggregation of HCPs might influence adjuvanticity
Defining immune reset: achieving sustained remission in autoimmune diseases.
No full textPersonalized cell therapies for autoimmune diseases - such as autologous haematopoietic stem cell transplantation and chimeric antigen receptor-expressing T cells - have the potential to achieve sustained remission in patients with certain autoimmune diseases. The effective elimination of pathogenic lymphocytes and their subsequent repopulation with naive cells has been termed 'immune reset'. In this Perspective, we trace the origins of the immune reset concept and its clinical, cellular and molecular definitions, and we review current attempts to identify biomarkers for long-term clinical remission in autoimmune diseases. Emerging data from clinical trials support the concept that higher probabilities of long-term remission can be achieved with therapies that can more deeply and broadly deplete B cells than the anti-CD20 antibody rituximab. A better understanding of the cellular and molecular basis for immune reset and the biomarkers associated with this state should accelerate progress towards the goal of restoring a non-autoimmune state and sustaining remission, while reducing the need for chronic immunosuppression
Factor B as a therapeutic target for the treatment of complement-mediated diseases.
No full textThe complement system, consisting of three initiating pathways-classical, lectin and alternative, is an important part of innate immunity. Dysregulation of the complement system is implicated in the pathogenesis of several autoimmune and inflammatory diseases. Therapeutic inhibition of the complement system has been recognized as a viable approach to drug development and has been successful with the approval of a small number of complement inhibitors for diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, neuromyelitis optica, myasthenia gravis and geographic atrophy. More recently, therapies selectively targeting the alternative pathway (AP), which drives the amplification of the complement responses, are being evaluated for these complement-mediated diseases. Complement Factor B, a serine protease, is a unique component of the AP that is essential for the catalytic activity of AP C3 convertase and AP C5 convertase. Inhibition of Factor B blocks the activity of the alternative pathway and the amplification loop, and subsequent generation of the membrane attack complex downstream; however, it has no effect on the initial activation mediated by the classical and lectin complement pathways. Therefore, Factor B is an attractive target for diseases in which the AP is overactivated. In this review, we provide an overview of Factor B and its critical role in the AP, discuss the benefit-risk of Factor B inhibition as a targeted therapeutic strategy, and describe the various Factor B inhibitors that are approved and/or in clinical development
Securing Patient Well-Being Best Practices for In-Use Stability and Compatibility Studies
No full textIn daily practice, healthcare providers and patients frequently are required to manipulate biological drugs before and during administration. Procedures can include dilution of a drug into admixtures for infusion, short-term storage, transportation to a hospital, or exposure to new contact materials such as intravenous bags. A drug manufacturer provides such instructions for use based on studies of in-use stability and compatibility with administration components, simulating drug handling and hold times throughout a defined in-use period. Such studies are complex because a wide range of in-use conditions and administration components are used globally. In addition, regulators provide only limited guidance on expected in-use stability data.
There is significant interest and value in capturing best practices for in-use stability and compatibility studies. To advance this goal, we summarize herein the findings of the CASSS chemistry, manufacturing, and controls (CMC) Strategy Forum, which was held on 22 January 2024 in Washington, DC. The forum, entitled “Securing Patient Well-being: Best Practices for In-Use Stability and Compatibility Studies,” addressed classic biological products and emerging trends. The forum was structured into four 90-minute workshops. Each workshop began with two presentations, followed by a discussion with the presenters and additional panel members:
• Workshop 1: Established Best Practices for In-Use Stability Study Design and Testing
• Workshop 2: Microbial In-Use Studies and Closed System Transfer Devices
• Workshop 3: Product In-Use: Meeting Patient and User Needs
• Workshop 4: Emerging Trends in Compatibility and In-Use Stability Studie