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Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors.
No full textNIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors.Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1).As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1-77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8+ T cells), increased CD16+ monocytes, and increased CD163+ macrophages at injection sites.Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy.NCT02452268
Simultaneous Monitoring of Monoclonal Antibody Variants by Strong Cation-Exchange Chromatography Hyphenated to Mass Spectrometry to Assess Quality Attributes of Rituximab-Based Biotherapeutics.
No full textDifferent manufacturing processes and storage conditions of biotherapeutics can lead to a significant variability in drug products arising from chemical and enzymatic post-translational modifications (PTMs), resulting in the co-existence of a plethora of proteoforms with different physicochemical properties. To unravel the heterogeneity of these proteoforms, novel approaches employing strong cation-exchange (SCX) high-performance liquid chromatography (HPLC) hyphenated to mass spectrometry (MS) using a pH gradient of volatile salts have been developed in recent years. Here, we apply an established SCX-HPLC-MS method to characterize and compare two rituximab-based biotherapeutics, the originator MabThera® and its Indian copy product Reditux™. The study assessed molecular differences between the two drug products in terms of C-terminal lysine variants, glycosylation patterns, and other basic and acidic variants. Overall, MabThera® and Reditux™ displayed differences at the molecular level. MabThera® showed a higher degree of galactosylated and sialylated glycoforms, while Reditux™ showed increased levels of oligomannose and afucosylated glycoforms. Moreover, the two drug products showed differences in terms of basic variants such as C-terminal lysine and N-terminal truncation, present in Reditux™ but not in MabThera®. This study demonstrates the capability of this fast SCX-HPLC-MS approach to compare different drug products and simultaneously assess some of their quality attributes
Envisioning Post-Pandemic Neurological, Psychiatric and Mental Health Care
No full textThe SARS-Cov-2 pandemic has placed a dramatic burden on managed healthcare and perhaps nowhere as evident as in neurological and psychiatric disease care. Attenuated access to hospital services and changes in prescribing practices have had a marked impact system wide. The severity of the pandemic has also required renormalization of social interactions at a population level placing additional stresses on society at large and an increased anxiety burden on vulnerable patient groups and the broader community. This said, the duration of the pandemic has mandated adaptability of the entire care system and the oft-vaunted benefits of telehealth have now been subjected to deep scrutiny at scale. Positive experiences have been reported by both patients and providers all the way from routine check-ups, to use of cognitive behavioral therapy associated with mental disorders, and management of complex diseases such as multiple sclerosis and other neurological and psychiatric conditions. Integration into standard care looks likely in the post pandemic era with many healthcare systems moving to expand reimbursement categories and develop equitable incentive models for both developers and providers. Equally, as fuller vaccination rates are achieved, hesitation and aversion to prescription of potentially immunomodulating therapeutics will abate, allowing a degree of normalcy to return for some of the most afflicted and at risk patient populations. In this commentary we share perspective on how the future of care may evolve through hybrid delivery models, and the advent of new therapeutic approaches which can address pain points identified during the pandemic
Promoter-driven overexpression in Chromobacterium vaccinii facilitates access to FR900359 and yields novel low abundance analogs
No full textThe access to the cyclic depsipeptide FR900359 (FR), a selective Gq protein inhibitor of high pharmacological interest and a potential lead molecule for targeted therapy of cancers with oncogenic Gαq/11 mutations, has been challenging ever since its initial discovery more than three decades ago. The recent discovery of Chromobacterium vaccinii as cultivable FR producer enables the development of approaches leading to a high-yielding, scalable and sustainable biotechnological process for production of FR, thereby removing this bottleneck. Here we characterize different promoters in exchange of the native promoter of the FR assembly line, resulting in a mutant with significantly increased production of FR. Thereby, the isolation and structure elucidation of novel FR analogs of low abundance was enabled. Further, we explored the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gαq/11 mutations and characterized the major metabolite of FR formed in plasma
CHARACTERIZING THE PHARMACOKINETICS AND BIODISTRIBUTION OF THERAPEUTIC PROTEINS: AN INDUSTRY WHITE PAPER
No full textCharacterization of the pharmacokinetics (PK) and biodistribution of therapeutic proteins (TPs) is a hot topic within the pharmaceutical industry, particularly with an ever-increasing catalog of novel modality TPs. Here, we review the current practices, and provide a summary of extensive cross-company discussions as well as a survey completed by International Consortium for Innovation and Quality (IQ consortium) members on this theme. A wide variety of in vitro, in vivo and in silico techniques are currently used to assess PK and biodistribution of TPs, and we discuss the relevance of these from an industry perspective, focusing on PK/PD understanding at the preclinical stage of development, and translation to human. We consider that the ‘traditional in vivo biodistribution study’ is becoming insufficient as a standalone tool, and thorough characterization of the interaction of the TP with its target(s), target biology, and off-target interactions at a microscopic scale are key to understand the overall biodistribution at a full-body scale. Our summary of the current challenges and our recommendations to address these issues could provide a guide to the implementation of best practices in this area of drug development, and continued cross-company collaboration will be of tremendous value
Water in organic chemistry:from our worst enemy to our best friend
No full textAlthough water is Nature’s solvent, it has long been regarded by organic chemists, at least until recently,
as their worst enemy. From introductory organic chemistry courses to multi-kilo labs of contract
manufacturing organizations (CMOs), chemists are taught that the presence of water in most organic
reactions should be avoided at all cost. Historically, the paradigm that “like dissolves like”, implying that
dissolution is a prerequisite for high conversion, led to the obvious conclusion that water is a “no-go.” This
notion may have arisen from the observation that for some catalysts, reagents, and/or reaction conditions,
there is a definite element of moisture-sensitivity. Thus, organic solvents, and when necessary, very dry
organic solvents, have always been the norm, with most subsequent developments made with this in mind.
However, toxicity issues such as mutagenicity, teratogenicity, carcinogenicity, and/or reprotoxicity can be
ascribed to many of these same solvents. The risk to operators in the plant due to flammability, explosivity,
and exposure, in general, is not trivial, whether arising from their industrial applications, transportation, or
storage. Their impact on the environment must not be overlooked either. Volatile organic compounds
(VOCs) can contribute to smog, air pollution, ground-level ozone production and yes, climate change. The
persistence of chlorinated solvents in soils and aquatic environments represents yet another non-negligible
environmental threat.1 For these reasons, regulations are becoming increasingly severe regarding
production and use of organic solvents, forcing chemists to find greener and safer alternatives. While the
Montreal Protocol2 aims to control usage of nearly 100 man-made ozone-depleting substances since 1987,
the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH)3 regulation has been
more recently adopted in Europe, looking to protect both human health and the environment from the risks
posed by chemicals
Special Issue on Digital Pathology, Tissue Image Analysis, Artificial Intelligence, and Machine Learning: Approximation of the Effect of Novel Technologies on Toxicologic Pathology
No full textFor decades, it has been postulated that digital pathology is the future. By now it is safe to say that we are living that future. Digital pathology has expanded into all aspects of pathology, including human diagnostic pathology, veterinary diagnostics, research, drug development, regulatory toxicologic pathology primary reads, and peer review. Digital tissue image analysis has enabled users to extract quantitative and complex data from digitized whole-slide images. The following editorial provides an overview of the content of this special issue of Toxicologic Pathology to highlight the range of key topics that are included in this compilation. In addition, the editors provide a commentary on important current aspects to consider in this space, such as accessibility of publication content to the machine learning-novice pathologist, the importance of adequate test set selection, and allowing for data reproducibility
CYP27A1 dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism
No full textThree limonoid natural products with selective anti-proliferative activity against BRAF(V600E) and NRAS(Q61K)-mutation dependent melanoma cell lines were identified. Differential transcriptome analysis revealed dependency of compound activity on expression of the mitochondrial cytochrome P450 oxidase CYP27A1, a transcriptional target of MITF. We determined that CYP27A1 activity is necessary for the generation of a reactive metabolite that proceeds to inhibit cellular proliferation. A genome-wide siRNA screen in combination with chemical proteomics experiments revealed genedrug functional epistasis, suggesting that these compounds target mitochondrial biogenesis and inhibit tumor bioenergetics. Our work suggests a strategy for melanoma specific targeting by exploiting the expression of MITF target gene CYP27A1 and inhibiting mitochondrial oxidative phosphorylation in BRAF mutant melanomas
Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360
No full textStarting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens
Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity Against Fluoroquinolone-Resistant Gram-positive Bacteria
No full textHerein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water–metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones