The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine- and anthracycline-based chemotherapy induction regimens (7 + 3) remain the standard of care, and ...most patients have poor long-term survival. The reapproval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next-generation ADC for AML to improve upon the initial success of Mylotarg.
The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti-CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys.
We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33-targeted ADCs. Our anti-CLL-1-ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys.
Collectively, our data suggest that an anti-CLL-1-ADC has the potential to become an effective and safer treatment for AML in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML.
In practice, apart from the problem of vehicle routing, schedulers also face the problem of finding feasible driver schedules complying with complex restrictions on drivers' driving and working ...hours. To address this complex interdependent problem of vehicle routing and break scheduling, we propose a restricted dynamic programming heuristic for the vehicle routing problem with time windows and the full European social legislation on drivers' driving and working hours. The problem we consider includes all rules in this legislation, whereas in the literature only a basic set of rules has been addressed. In addition to this basic set of rules, the legislation contains a set of modifications that allow for more flexibility. To include the legislation in the restricted dynamic programming heuristic, we propose a break scheduling heuristic. Computational results show that our method finds solutions to benchmark instances-which only consider the basic set of rules-with 18% fewer vehicles and 5% less travel distance than state-of-the-art approaches. Moreover, our results are obtained with significantly less computational effort. Furthermore, the results show that including a set of rules on drivers' working hours-which has been generally ignored in the literature-has a significant impact on the resulting vehicle schedules: 3.9% more vehicle routes and 1.0% more travel distances are needed. Finally, using the modified rules of the legislation leads to an additional reduction of 4% in the number of vehicles and of 1.5% in travel distances. Therefore, the modified rules should be exploited in practice.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does ...not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.
Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and ...characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti-GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both
and
The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line-derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker-payload based ADCs. Overall, these data suggest that anti-GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients.
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The Hippo pathway is a critical regulator of cell and organ growth and has emerged as a target for therapeutic intervention in cancers. Its signaling is thought to play an important role in various ...physiological processes including homeostasis and tissue regeneration. To date there has been limited information about potential pharmacology-related (on-target) safety liabilities of Hippo pathway inhibitors in the context of cancer indications. Herein, we review data from human genetic disorders and genetically engineered rodent models to gain insight into safety liabilities that may emerge from the inhibition of Hippo pathway. Germline systemic deletion of murine Hippo pathway effectors (Yap, Taz, and Teads) resulted in embryonic lethality or developmental phenotypes. Mouse models with tissue-specific deletion (or mutant overexpression) of the key effectors in Hippo pathways have indicated that, at least in some tissues, Hippo signaling may be dispensable for physiological homeostasis; and appears to be critical for regeneration upon tissue damage, indicating that patients with underlying comorbidities and/or insults caused by therapeutic agents and/or comedications may have a higher risk. Caution should be taken in interpreting phenotypes from tissue-specific transgenic animal models since some tissue-specific promoters are turned on during development. In addition, therapeutic agents may result in systemic effects not well-predicted by animal models with tissue-specific gene deletion. Therefore, the development of models that allows for systemic deletion of Yap and/or Taz in adult animals will be key in evaluating the potential safety liabilities of Hippo pathway modulation. In this review, we focus on potential challenges and strategies for targeting the Hippo pathway in cancers.
Highlights • The here studied rapid antigen detection test (RADT) BinaxNOW RSV has a high sensitivity and positive predictive value. • RADT BinaxNOW Influenza A&B has a relatively low sensitivity and ...positive predictive value. • We advise a restricted use of RADT BinaxNOW Influenza A&B in a tertiary paediatric care setting
Daily traffic congestion forms a major problem for businesses such as logistic service providers and distribution firms. It causes late arrivals at customers and additional costs for hiring the truck ...drivers. Such costs caused by traffic congestion can be reduced by taking into account and avoiding predictable traffic congestion within vehicle route plans. In the literature, various strategies are proposed to avoid traffic congestion, such as selecting alternative routes, changing the customer visit sequences, and changing the vehicle-customer assignments. We investigate the impact of these and other strategies in off-line vehicle routing on the performance of vehicle route plans in reality. For this purpose, we develop a set of vehicle routing problem instances on real road networks, and a speed model that reflects the key elements of peak hour traffic congestion. The instances are solved for different levels of congestion avoidance using a modified Dijkstra algorithm and a restricted dynamic programming heuristic. Computational experiments show that 99% of late arrivals at customers can be eliminated if traffic congestion is accounted for off-line. On top of that, about 87% of the extra duty time caused by traffic congestion can be eliminated by clever congestion avoidance strategies.
In 2005 human bocavirus (HBoV) was discovered in respiratory tract samples of children. The role of HBoV as the single causative agent for respiratory tract infections remains unclear. Detection of ...HBoV in children with respiratory disease is frequently in combination with other viruses or bacteria. We set up an algorithm to study whether HBoV alone can cause severe acute respiratory tract infection (SARI) in children. The algorithm was developed to exclude cases with no other likely cause than HBoV for the need for admission to the paediatric intensive care unit (PICU) with SARI. We searched for other viruses by next-generation sequencing (NGS) in these cases and studied their HBoV viral loads. To benchmark our algorithm, the same was applied to respiratory syncytial virus (RSV)-positive patients. From our total group of 990 patients who tested positive for a respiratory virus by means of RT-PCR, HBoV and RSV were detected in 178 and 366 children admitted to our hospital. Forty-nine HBoV-positive patients and 72 RSV-positive patients were admitted to the PICU. We found seven single HBoV-infected cases with SARI admitted to PICU (7/49, 14%). They had no other detectable virus by NGS. They had much higher HBoV loads than other patients positive for HBoV. We identified 14 RSV-infected SARI patients with a single RSV infection (14/72, 19%). We conclude that our study provides strong support that HBoV can cause SARI in children in the absence of viral and bacterial co-infections.
In earlier studies, we demonstrated the efficacy of indole-3-carbinol (I3C) against lung adenocarcinoma in A/J mice. However, these effects were accompanied by reductions in body weight gain. We ...therefore assessed if combinations of low doses of I3C with silibinin could inhibit lung tumorigenesis without causing undesirable side effects. In in vitro assays with A549 and H460 lung cancer cells, exposure of the cells to a mixture of low concentrations of I3C (50 μM) plus silibinin (50 μM) for 72 h caused inhibition of cell growth and extracellular signal-regulated kinase (ERK) and Akt activation and induction of apoptosis, whereas the individual agents did not have any effect. In mice pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and given I3C (10 μmol/g diet) plus silibinin (7 μmol/g diet), multiplicities of tumors on the surface of the lung and adenocarcinoma were reduced by 60 and 95%, respectively. The individual effects of I3C and silibinin were relatively weaker: 43 and 36% reductions, respectively, in the multiplicity of tumors on the surface of the lung and 83 and 50% reductions, respectively, in the number of adenocarcinoma. Also, the expression of phospho-Akt, phospho-ERK and cyclin D1 and poly (ADP-ribose) polymerase cleavage were strongly modulated by I3C plus silibinin than by I3C or silibinin alone, suggesting that the chemopreventive activities of the mixture could be mediated, at least partly, via modulation of the level of these proteins. Taken together, our findings showed that mixtures of I3C and silibinin are more potent than the individual compounds for the chemoprevention of lung cancer in A/J mice.
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