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Preclinical Antitumor Activity of a Novel Anti–c-KIT Antibody–Drug Conjugate against Mutant and Wild-type c-KIT–Positive Solid Tumors
No full textPurpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non–small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti–c-KIT ADC approach to evaluate the anticancer activity in multiple disease models. Experimental Design: A humanized anti–c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models. Results: LOP628 exhibited potent antiproliferative activity on c-KIT–positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT–directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/ lymphatic system. Conclusions: The preclinical findings suggest that the c-KIT–directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT–positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients
Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective
No full textThis work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted
Sost deficiency leads to reduced mechanical strains at the tibia midshaft in strain-matched in vivo loading experiments in mice
No full textSclerostin, a product of the Sost gene, is a Wnt-inhibitor and thus negatively regulates bone accrual. Canonical Wnt/β-catenin signalling is also known to be activated in mechanotransduction. Sclerostin neutralizing antibodies are being tested in ongoing clinical trials to target osteoporosis and osteogenesis imperfecta but their interaction with mechanical stimuli on bone formation remains unclear. Sost knockout (KO) mice were examined to gain insight into how long-term Sost deficiency alters the local mechanical environment within the bone. This knowledge is crucial as the strain environment regulates bone adaptation. We characterized the bone geometry at the tibial midshaft of young and adult Sost KO and age-matched littermate control (LC) mice using microcomputed tomography imaging. The cortical area and the minimal and maximal moment of inertia were higher in Sost KO than in LC mice, whereas no difference was detected in either the anterior-posterior or medio-lateral bone curvature. Differences observed between age-matched genotypes were greater in adult mice. We analysed the local mechanical environment in the bone using finite-element models (FEMs), which showed that strains in the tibiae of Sost KO mice are lower than in age-matched LC mice at the diaphyseal midshaft, a region commonly used to assess cortical bone formation and resorption. Our FEMs also suggested that tissue mineral density is only a minor contributor to the strain distribution in tibial cortical bone from Sost KO mice compared to bone geometry. Furthermore, they indicated that although strain gauging experiments matched strains at the gauge site, strains along the tibial length were not comparable between age-matched Sost KO and LC mice or between young and adult animals within the same genotype
A Novel Microplate 3D Bioprinting Platform for the Engineering of Muscle and Tendon Tissues
No full textTwo-dimensional (2D) cell cultures do not reflect the in vivo situation thus it is important to develop predictive 3D in vitro models with enhanced reliability and robustness for drug screening applications. Treatments against muscle-related diseases are becoming more prominent due to the growth of the aging population worldwide. Therefore, in this study, we describe a novel drug screening platform with automated production of 3D musculoskeletal-tendon-like tissues. With 3D bioprinting alternating layers of photo-polymerized gelatin-methacryloyl-based bioink and cells are deposited in a dumbbell shape onto novel post holder cell culture inserts in 24-well plates. Monocultures of human primary skeletal muscle cells and rat tenocytes were printed around and in between the posts that showed high viability and tissue differentiation in culture, based on marker gene and protein expressions. Different printing patterns of bioink and cells were explored and calcium signalling with Fluo4-loaded cells under electrical stimulation was shown. Finally, controlled co-printing of tenocytes and myoblasts around the posts and between the posts, respectively, was demonstrated followed by co-culture and co-differentiation.
This screening platform combining 3D bioprinting with a novel microplate represents a promising tool to address musculoskeletal diseases
Reactive carbon species tamed for synthesis
No full textThe basis of organic chemistry is the study of carbon-containing compounds with the aim of manipulating carbon atoms to generate new molecules through the formation of carbon–carbon (C–C) bonds. In a paper in Nature, Wang et al. report a method for harnessing a reactive form of carbon known as a carbyne (Fig. 1a), which has been underused in synthetic chemistry. The findings open the door to new types of C–C bond-formation reaction
A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development Under the “Metabolites in Safety Testing” Regulatory Guidances
No full textSince the introduction of MIST guidance by FDA in 2008 there have been major changes in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and non-clinical studies to generate these information. In this cross-industry article we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radiochromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated which has led to more frequent determination of human metabolite profiles from multiple ascending dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. This, together with technological advances, led to a general shift of the focus towards earlier human metabolism studies, using high resolution mass spectrometry, and to a reduction in animal radiolabel ADME studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industr
Non-clinical safety assessment of CFZ533, a Fc-silent anti-CD40 antibody, in non-human primates
No full textCFZ533 is a pathway blocking, non-depleting anti-CD40 antibody that is in clinical development for inhibition of transplant organ rejection and therapy for autoimmune diseases. A 26-week GLP toxicity study in sexually mature Cynomolgus monkeys was conducted in order to support chronic application of CFZ533. CFZ533 was subcutaneously administered at doses up to 150 mg/kg/week and was safe and generally well tolerated . CFZ533 showed no adverse effects for cardiovascular, respiratory and neurobehavioral endpoints, and no changes were observed for blood lymphocyte and platelet counts or blood coagulation markers. In line with the non-depleting nature of CFZ533, CD20+ B cells in the blood were only marginally reduced. A complete suppression of germinal center (GC) development in lymph nodes and spleen was the most prominent result of post-mortem histological investigations. This was corroborated by an abrogated T dependent antibody response (TDAR) to the antigen Keyhole Limpet Hemocyanin (KLH) in the absence of B cell depletion as seen with immunophenotyping and histology. When serum levels of CFZ533 in recovery animals dropped below the level necessary for full CD40 occupancy on B cells, all animals were able to mount primary TDAR to KLH. All histological changes also reverted to normal appearance after recovery. In summary, CFZ533 was shown to be well tolerated and safe in the 26-week toxicity study with a distinct pharmacodynamic profile in histology and immune function
Yeast Chemogenomic Profiling Reveals Iron Chelation to Be the Principle Cell Inhibitory Mode of Action of Gossypol
No full textGossypol is an inhibitor of eukaryotic cells with an undetermined mode of action. Here we show that the chemogenomic profile of gossypol is strikingly similar to that of the iron chelators deferasirox and desferricoprogen. Iron import channels Fet1 and Fet3 are prominent in all three profiles. Furthermore, yeast inhibited by gossypol and deferasirox is rescued by the addition of Fe2+. We propose that Fe2+ chelation is in fact the principle mode of action of gossypol
U-BIOPRED: evaluation of the value of a public–private partnership to industry
No full textThe U-BIOPRED program within the Innovative Medicine Initiatives (IMI) attempted to address fundamental issues around the lack of disease understanding in asthma. This review summarises key issues, learnings, and successes of running the U-BIOPRED program from the industry perspective.
Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-’omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective. We list some of the key advantages and learnings from the perspective of the authors, and also improvements that we feel could be made in future projects
Cross - site comparison of excitation-contraction coupling using impedance and field potential recordings in hiPSC cardiomyocytes
No full textIntroduction: Since 2005 the S7B and E14 guidances from ICH and FDA have been in place to assess a potential drug candidate’s ability to cause long QT syndrome. To refine these guidelines, the FDA proposed the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, where the assessment of drug effects on cardiac repolarization was one subject of investigation. Within the myocyte phase II study, effects of pharmaceutical compounds on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were assessed and this article will focus on an evaluation of the proarrhythmic potential of 23 drugs in four hiPSC-CM cell lines.
Methods: Experiments were performed on the CardioExcyte 96 at different sites. A combined readout of contractility (via impedance) and electrophysiology endpoints (field potentials) was performed.
Results: Our data demonstrates that hERG blockers such as Dofetilide and further high risk categorized compounds prolong the field potential duration. Arrhythmic events were detected in both impedance as well as EFP recordings. Intermediate risk compounds induced arrhythmia in almost all cases at the highest dose. In the case of low risk compounds, either a decrease in FPDmax was observed, or not a significant change.
Discussion: All sources of hiPSC-CMs are sensitive enough to detect delayed or shortened repolarization and arrhythmia after drug application and can provide predictive cardiac electrophysiology data. However, the baseline electrophysiological parameters vary between iPS cells from different sources