Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is ...maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favorable expression profile, CD19 has rapid internalization kinetics and is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies. ADCT-402 (loncastuximab tesirine) is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand crosslinking pyrrolobenzodiazepine (PDB) dimer warhead. It showed potent and highly targeted in vitro cytotoxicity in CD19-expressing human cell lines. ADCT-402 was specifically bound, internalized, and trafficked to lysosomes in CD19-expressing cells and, following release of the PBD warhead, resulted in formation of DNA crosslinks that persisted for 36 hours. Bystander killing of CD19− cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent antitumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA crosslinks and γ-H2AX DNA damage response were measured in tumors by 24 hours after single dose administration, whereas matched peripheral blood mononuclear cells showed no evidence of DNA damage. Pharmacokinetic analysis in rat and cynomolgus monkey showed excellent stability and tolerability of ADCT-402 in vivo. Together, these impressive data were used to support the clinical testing of this novel ADC in patients with CD19-expressing B-cell malignancies.
•ADCT-402 is a CD19-targeted ADC delivering SG3199, a cytotoxic DNA minor groove interstrand crosslinking PDB dimer warhead.•ADCT-402 has potent and selective antitumor activity against CD19-expressing hematological malignancies warranting clinical development.
SummaryBackgroundTrastuzumab duocarmazine is a novel HER2-targeting antibody–drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies ...showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. MethodsWe did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. FindingsBetween Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3–4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two 1%) and dyspnoea (two 1%). The most common treatment-related adverse events (grades 1–4) were fatigue (48 33% of 146 patients), conjunctivitis (45 31%), and dry eye (45 31%). Most patients (104 71% of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4–48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8–46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3–67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2–30·2) of 16 patients with gastric cancer, four (25%, 7·3–52·4) of 16 patients with urothelial cancer, and five (39%, 13·9–68·4) of 13 patients with endometrial cancer. InterpretationTrastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. FundingSynthon Biopharmaceuticals.
Abstract
We report the discovery of six ultra-faint Milky Way satellites identified through matched-filter searches conducted using Dark Energy Camera (DECam) data processed as part of the second ...data release of the DECam Local Volume Exploration (DELVE) survey. Leveraging deep Gemini/GMOS-N imaging (for four candidates) as well as follow-up DECam imaging (for two candidates), we characterize the morphologies and stellar populations of these systems. We find that these candidates all share faint absolute magnitudes (
M
V
≥ −3.2 mag) and old, metal-poor stellar populations (
τ
> 10 Gyr, Fe/H < −1.4 dex). Three of these systems are more extended (
r
1/2
> 15 pc), while the other three are compact (
r
1/2
< 10 pc). From these properties, we infer that the former three systems (Boötes V, Leo Minor I, and Virgo II) are consistent with ultra-faint dwarf galaxy classifications, whereas the latter three (DELVE 3, DELVE 4, and DELVE 5) are likely ultra-faint star clusters. Using data from the Gaia satellite, we confidently measure the proper motion of Boötes V, Leo Minor I, and DELVE 4, and tentatively detect a proper-motion signal from DELVE 3 and DELVE 5; no signal is detected for Virgo II. We use these measurements to explore possible associations between the newly discovered systems and the Sagittarius dwarf spheroidal, the Magellanic Clouds, and the Vast Polar Structure, finding several plausible associations. Our results offer a preview of the numerous ultra-faint stellar systems that will soon be discovered by the Vera C. Rubin Observatory and highlight the challenges of classifying the faintest stellar systems.
Echinoidea is a clade of marine animals including sea urchins, heart urchins, sand dollars and sea biscuits. Found in benthic habitats across all latitudes, echinoids are key components of marine ...communities such as coral reefs and kelp forests. A little over 1000 species inhabit the oceans today, a diversity that traces its roots back at least to the Permian. Although much effort has been devoted to elucidating the echinoid tree of life using a variety of morphological data, molecular attempts have relied on only a handful of genes. Both of these approaches have had limited success at resolving the deepest nodes of the tree, and their disagreement over the positions of a number of clades remains unresolved.
We performed de novo sequencing and assembly of 17 transcriptomes to complement available genomic resources of sea urchins and produce the first phylogenomic analysis of the clade. Multiple methods of probabilistic inference recovered identical topologies, with virtually all nodes showing maximum support. In contrast, the coalescent-based method ASTRAL-II resolved one node differently, a result apparently driven by gene tree error induced by evolutionary rate heterogeneity. Regardless of the method employed, our phylogenetic structure deviates from the currently accepted classification of echinoids, with neither Acroechinoidea (all euechinoids except echinothurioids), nor Clypeasteroida (sand dollars and sea biscuits) being monophyletic as currently defined. We show that phylogenetic signal for novel resolutions of these lineages is strong and distributed throughout the genome, and fail to recover systematic biases as drivers of our results.
Our investigation substantially augments the molecular resources available for sea urchins, providing the first transcriptomes for many of its main lineages. Using this expanded genomic dataset, we resolve the position of several clades in agreement with early molecular analyses but in disagreement with morphological data. Our efforts settle multiple phylogenetic uncertainties, including the position of the enigmatic deep-sea echinothurioids and the identity of the sister clade to sand dollars. We offer a detailed assessment of evolutionary scenarios that could reconcile our findings with morphological evidence, opening up new lines of research into the development and evolutionary history of this ancient clade.
Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor ...groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI
of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.
Melanin is a ubiquitous biological pigment found in bacteria, fungi, plants, and animals. It has a diverse range of ecological and biochemical functions, including display, evasion, photoprotection, ...detoxification, and metal scavenging. To date, evidence of melanin in fossil organisms has relied entirely on indirect morphological and chemical analyses. Here, we apply direct chemical techniques to categorically demonstrate the preservation of eumelanin in two > 160 Ma Jurassic cephalopod ink sacs and to confirm its chemical similarity to the ink of the modern cephalopod, Sepia officinalis . Identification and characterization of degradation-resistant melanin may provide insights into its diverse roles in ancient organisms.
Abstract
We present a spectroscopic analysis of Eridanus IV (Eri IV) and Centaurus I (Cen I), two ultrafaint dwarf galaxies of the Milky Way. Using IMACS/Magellan spectroscopy, we identify 28 member ...stars of Eri IV and 34 member stars of Cen I. For Eri IV, we measure a systemic velocity of
v
sys
=
−
31.5
−
1.2
+
1.3
km
s
−
1
, and velocity dispersion
σ
v
=
6.1
−
0.9
+
1.2
km
s
−
1
. Additionally, we measure the metallicities of 16 member stars of Eri IV. We find a metallicity of
Fe
/
H
=
−
2.87
−
0.07
+
0.08
, and resolve a dispersion of
σ
Fe/H
=0.20 ± 0.09. The mean metallicity is marginally lower than all other known ultrafaint dwarf galaxies, making it one of the most metal-poor galaxies discovered thus far. Eri IV also has a somewhat unusual right-skewed metallicity distribution. For Cen I, we find a velocity
v
sys
= 44.9 ± 0.8 km s
−1
, and velocity dispersion
σ
v
=
4.2
−
0.5
+
0.6
km
s
−
1
. We measure the metallicities of 27 member stars of Cen I, and find a mean metallicity Fe/H = −2.57 ± 0.08, and metallicity dispersion
σ
Fe
/
H
=
0.38
−
0.05
+
0.07
. We calculate the systemic proper motion, orbit, and the astrophysical J-factor for each system, the latter of which indicates that Eri IV is a good target for indirect dark matter detection. We also find no strong evidence for tidal stripping of Cen I or Eri IV. Overall, our measurements confirm that Eri IV and Cen I are dark-matter-dominated galaxies with properties largely consistent with other known ultrafaint dwarf galaxies. The low metallicity, right-skewed metallicity distribution, and high J-factor make Eri IV an especially interesting candidate for further follow-up.
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Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. Spontaneous bleeding shows a predilection for joints, and repeated ...hemarthroses lead to a disabling condition called hemophilic arthropathy. Treatment of this condition consists of preventing joint bleeding on the one hand and orthopedic surgery as a last resort on the other. Up till now, there is no disease modifying therapy available to fill the gap between these extremes. This review provides an overview of the pathogenesis of hemophilic arthropathy in order to identify potential targets for therapy. Joint bleeding induces synovial inflammation, cartilage degeneration and bone damage. These processes interact with each other and result in a vicious circle. Hemarthrosis promotes synovial hypertrophy and neoangiogenesis, increasing the susceptibility to mechanical damage and subsequent bleeding. The inflamed synovium affects the cartilage, while cartilage is also directly affected by blood via the release of cytokines and metalloproteinases, and via hydroxyl radical formation inducing chondrocyte apoptosis. Apart from the inflammatory pathways, iron plays a pivotal role in this process, as does the fibrinolytic system.
Considering its pathogenesis, potential targets for disease modifying therapy in hemophilic arthropathy are iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration. So far, iron chelators, anti-inflammatory therapy, anti-fibrinolytics and bone remodeling agents have demonstrated beneficial effects, predominantly in a preclinical setting. There is still a long way to go before these interventions will translate into clinical practice. The most important challenges are: establishing a universal outcome measure to predict efficacy in humans, and determination of the optimal route and timing to administer disease modifying therapy.
Abstract Objective: To test the effectiveness of two programmes to improve the treatment of acute depression in primary care. Design: Randomised trial. Setting: Primary care clinics in Seattle. ...Patients: 613 patients starting antidepressant treatment. Intervention: Patients were randomly assigned to continued usual care or one of two interventions: feedback only and feedback plus care management. Feedback only comprised feedback and algorithm based recommendations to doctors on the basis of data from computerised records of pharmacy and visits. Feedback plus care management included systematic follow up by telephone, sophisticated treatment recommendations, and practice support by a care manager. Main outcome measures: Blinded interviews by telephone 3 and 6 months after the initial prescription included a 20 item depression scale from the Hopkins symptom checklist and the structured clinical interview for the current DSM-IV depression module. Visits, antidepressant prescriptions, and overall use of health care were assessed from computerised records. Results: Compared with usual care, feedback only had no significant effect on treatment received or patient outcomes. Patients receiving feedback plus care management had a higher probability of both receiving at least moderate doses of antidepressants (odds ratio 1.99, 95% confidence interval 1.23 to 3.22) and a 50% improvement in depression scores on the symptom checklist (2.22, 1.31 to 3.75), lower mean depression scores on the symptom checklist at follow up, and a lower probability of major depression at follow up (0.46, 0.24 to 0.86). The incremental cost of feedback plus care management was about $80 (£50) per patient. Conclusions: Monitoring and feedback to doctors yielded no significant benefits for patients in primary care starting antidepressant treatment. A programme of systematic follow up and care management by telephone, however, significantly improved outcomes at modest cost.
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