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QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life.
No full textAntibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling. Using a PK-TGI model, we identified a composite exposure-above-tumorostatic concentration (AUCTSC) metric as the PK-driver of efficacy. To underpin the mechanisms behind AUCTSC as the driver of efficacy, we performed quantitative systems pharmacology (QSP) modeling of DYP688 intratumoral pharmacokinetics and pharmacodynamics. Through exploratory simulations, we show that by deviating from canonical ADC design dogma, DYP688 has optimal FR900359 activity despite its transient inactivation. Finally, we performed the successful preclinical to clinical translation of DYP688 PK, including the payload inactivation kinetics, evidenced by good agreement of the predicted PK to the observed interim clinical PK. Overall, this work highlights early quantitative pharmacokinetics as a missing link in the ADC design-developability chasm
Intestinal Cells-on-Chip for Permeability Studies
No full textBackground: To accurately measure permeability of compounds in the intestine, here is a need for preclinical in vitro models that accurately represent the specificity, integrity and complexity of the human small intestinal barrier. Intestine-on-chip systems hold considerable promise as testing platforms, but several characteristics still require optimization and further development.
Methods: An established intestine-on chip model for tissue explants was here adopted for intes-tinal cell monolayer culture. Besides, membrane characteristics and standardized read-outs were further investigated.
Results: By starting cultures outside the chip in conventional wells plates, the new cell disc design could support accurate cell monolayer formation for both Caco-2 and human enteroids. When transferred to the chip with laminar flow, there was accurate detection of barrier integrity (FD4 and Cascade Blue) and permeability (atenolol/antipyrine).
Conclusions: This novel intestinal cell-on-chip system offers large flexibility for intestinal per-meability studies, although it still requires validation with more compounds to reveal its full potentia
Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease.
No full textBIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD
Data sharing of Ames test data for Intermediates database
No full textThe molecule has been previously shared with the data sharing consortium and is already in the Vitic database. The request is now to share the raw data. This is a small chemical that cannot be related to any Novartis compound. It has a CAS number and is in public domain
No Novartis compounds are disclosed
A description paragraph to call for submission of papers for a special issue
No full textSummary*: Issues related to drug safety remain a major bottleneck in drug discovery and development. Recent technological advancements in metabolomics have enabled researchers to measure a large number of compounds in large sets of samples, as well as in single cells. These new advancements have helped to gain insights into the mechanisms of drug toxicity, translatability to humans, prediction of safety events, mitigation of side effects, and development of safety biomarkers. Metabolomics applied to drug metabolism, drug-endobiotic interactions, and drug-drug (food) interactions offers an ideal opportunity to study toxicological effects of drugs.
This special issue is devoted to metabolomics in drug metabolism, drug-drug (food) interactions, and drug toxicity. The topics that will be covered include studies on the metabolomic analyses of the fate of drugs, host responses to drugs (including new modalities such as peptides, antibody-drug conjugates, protein therapeutics, and oligonucleotide therapeutics), as well as endogenous probes for drug-drug (food) interactions. Additional topics include metabolomic analyses of studying mechanism, prediction, and safety biomarkers of drug toxicity. Other topics with similar focus will also be considered
Meeting report of the 4th European Biotransformation Workshop
No full textChallenges, strategies and new technologies in the field of biotransformation were presented and discussed at the fourth European Biotransformation Workshop which was held in collaboration with the joint ISSX/DMDG meeting on June 15, 2023 at the University of Hertfordshire in Hatfield, UK. In this meeting report we summarise the presentations and discussions from this workshop.
The topics covered are listed below:
• Unusual biotransformation reactions
• Biotransformation Workflows in Discovery utilizing various softwares for structure elucidation
• Biotransformation software for the identification of peptide metabolites
• Accelerator Mass Spectrometry (AMS) for endogenous and xenobiotic metabolite profiling
• Metabolite profiling using quantitative Nuclear magnetic resonance (NMR) and liquid chromatography coupled to inductively coupled plasma-mass spectrometry (LC-ICP-MS)
Keywords: unusual biotransformation reactions, Mass Metasite, biotransformation softwares, AMS, F-NMR for metabolite profiling, LC-ICP-MS for metabolite profiling
Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors.
No full textNLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1β and IL-18, as well as cleavage of Gasdermin-d and pyroptotic cell death. The NLRP3 inflammasome has been implicated in a plethora of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, and cancer. In this publication, we describe the discovery of a novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. The hit (1) could be optimized into an advanced compound NP3-562 demonstrating excellent potency in human whole blood and full inhibition of IL-1β release in a mouse acute peritonitis model at 30 mg/kg po dose. An X-ray structure of NP3-562 bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, NP3-562 shows also a good overall development profile
2023 White Paper on Recent Issues in Bioanalysis: Deuterated Drugs; LNP; Tumor/FFPE Biopsy; Targeted Proteomics; Small Molecule Covalent Inhibitors; Chiral Bioanalysis; Remote Regulatory Assessments; Sample Reconciliation/Chain of Custody (PART 1A - Recommendations on Mass Spectrometry, Chromatography, Sample Preparation Latest Developments, Challenges, and Solutions and BMV/Regulated Bioanalysis PART 1B - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV, Biomarkers/IVD/CDx/BAV, Immunogenicity, Gene & Cell Therapy and Vaccine).
No full textThe 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on June 19-23, 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with this NEW Regulation" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication covers the recommendations on Mass Spectrometry Assays, Regulated Bioanalysis/BMV (Part 1A) and Regulatory Inputs (Part 1B). Part 2 (Biomarkers, IVD/CDx, LBA and Cell-Based Assays) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 7 and 8 (2024), respectively
Data sharing of an Ames test for tert-Butyl 2-bromo-acetate
No full textThe result of the Ames test was already shared with the Intermediates consortium in 2013. We are now asked to share the Ames test result raw data. It is a small chemical with CAS number. No Novartis project disclosed
Calpain Inhibition Protects against UVB-Induced Degradation of Dermal-Epidermal Junction-Associated Proteins.
No full textTo the Editor
The skin is a highly regenerative tissue that harbors multiple reservoirs of stem cells, enabling it to efficiently repair and regenerate (
Fuchs, 2008
). However, despite its regenerative capacity, the skin undergoes aging, leading to compromised barrier function, reduced mechanoresilience, and impaired wound healing (
Quan, 2023
). Histological analyses have indicated that alterations in the extracellular matrix of the skin are key features of aging (
Quan, 2023
). These alterations affect the load-bearing dermal interstitial extracellular matrix through reduced collagen levels and increased fragmentation of collagen and elastin fibers (
Quan, 2023
). In addition, the dermal–epidermal junction (DEJ) is significantly affected during skin aging (
Langton et al, 2016
). Hemidesmosomes (HDs) are multiprotein attachment structures, which at the DEJ are composed of integrin ⍺6β4, collagen XVII, and CD151 at the basal keratinocyte plasma membrane and intracellularly; plectin; and BPAG1, BP230, or dystonin (
Ewald and Nyström, 2023
)