Synthon (Netherlands)

Introduction: Hyperphosphatemia (HPFT) is a complication that is exacerbated proportionally to the degree of kidney damage, and leads to vascular calcification and increased cardiovascular risk. The objective of the present study is to determine the frequency of hyperphosphatemia in patients with chronic dialysis treatment. Material and methods: This is a cross-sectional, observational, retrospective and analytical study. Real-life national multicenter study, conducted from January 1 to March 31, 2022. It includes subjects with chronic dialysis (>3 months stay), >16 years, from the public and private sectors. Does not include patients treated with phosphate binders or vitamin D receptor analogs; only treated with calcium derivatives in different formulations. Gender, age, causes of kidney failure, serum phosphorus values (mg/dL), calcium (mg/dL) and parathyroid hormone (pg/mL) are identified. Results: 2,176 subjects, 1,205 from the public sector (55%) and 971 private (45%). 1,063 (49%) male and 1,113 female (51%), with a mean age of 51.4 years (range 16-88). 794 with diabetes (36%), 559 arterial hypertension (26%) and 823 unknown (38%). The mean serum calcium values were 8.75 mg/dL (SD ± 1.01; range: 6.1-12.7) and phosphorus 5.15 mg/dL (SD ± 3.04; range: 2.5-18.1). 1,435 subjects presented HPFT (66%), 903 mild (41%), 450 moderate (21%, mean 5.7 mg/dL) and 82 severe (4%, mean: 9.2 mg/dL). Parathyroid hormone was determined in 33% (mean 614.87 pg/ mL, SD 628.64; range: 53.3 -3,803). Conclusions: HPFT is frequent in patients with chronic dialysis, it affects regardless of gender, age, primary cause of kidney disease and even after receiving adequate dialysis treatment. Significant increase in HPFT was observed in peritoneal dialysis patients.

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action. To determine the effect of one of these novel ADCs, SYD985, on tumors resistant to T-DM1, we developed several patient-derived models of resistance to T-DM1. Characterization of these models showed that previously described mechanisms—HER2 downmodulation, impairment of lysosomal function and upregulation of drug efflux pumps—account for the resistances observed, arguing that mechanisms of resistance to T-DM1 are limited, and most of them have already been described. Importantly, SYD985 was effective in these models, showing that the resistance to first generation ADCs can be overcome with an improved design.

The psychoactive properties of lysergic acid diethylamide (LSD) have fascinated scientists across disciplines and the exploration of other analogues and derivatives has been motivated by deepening the understanding of ligand-receptor interactions at the molecular level as well as by the search for new therapeutics. Several LSD congeners have appeared on the new psychoactive substances (NPS) market in the form of blotters or powders. Examples include 1-propionyl-LSD (1P-LSD), AL-LAD, and LSZ. The absence of analytical data for novel compounds is a frequent challenge encountered in clinical and toxicological investigations. Two newly emerging lysergamides, namely N6 -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1P-ETH-LAD, were characterized by gas chromatography-mass spectrometry (GC-MS), low and high mass accuracy electrospray MS(/MS), GC solid-state infrared analysis, high performance liquid chromatography diode array detection as well as nuclear magnetic resonance spectroscopy. Limited analytical data for ETH-LAD were previously available, whereas information about 1P-ETH-LAD has not previously been encountered in the scientific literature. This study extends the characterization of lysergamides distributed on the NPS market, which will help to make analytical data available to clinicians, toxicologists, and other stakeholders who are likely to encounter these substances. The analysis of a test incubation of 1P-ETH-LAD with human serum at 37°C by LC single quadrupole MS at various time points (0-6h, once per hour and one measurement after 24h) revealed the formation of ETH-LAD, suggesting that 1P-ETH-LAD might serve as a pro-drug. 1P-ETH-LAD was still detectable in serum after 24h. Copyright © 2017 John Wiley & Sons, Ltd.

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide-based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900-9. ©2016 AACR.

The correlation between the dimensionless retention times (DRT) of proteins in hydrophobic interaction chromatography (HIC) and their surface properties were investigated. A ternary atomic-level hydrophobicity scale was used to calculate the distribution of local average hydrophobicity across the proteins surfaces. These distributions were characterized by robust descriptive statistics to reduce their sensitivity to small changes in the three-dimensional structure. The applicability of these statistics for the prediction of protein retention behaviour was looked into. A linear combination of robust statistics describing the central tendency, heterogeneity and frequency of highly hydrophobic clusters was found to have a good predictive capability (R2 = 0.78), when combined a factor to account for protein size differences. The achieved error of prediction was 35% lower than for a similar model based on a description of the protein surface on an amino acid level. This indicates that a robust and mathematically simple model based on an atomic description of the protein surface can be used for the prediction of the retention behaviour of conformationally stable globular proteins with a well determined 3D structure in HIC. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:372-381, 2016.

Activation of inflammatory pathways is known to accompany development of obesity-induced non-alcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive pro-inflammatory mediators IL-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In the present study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human alpha-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3 deficient mice showed strongly reduced levels of lipids in the liver after fed a high fat diet. Moreover, these mice were resistant to high fat diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1(-/-) mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with alpha-1 antitrypsin during the last 10 days of a 16 week high fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.

e16527 Background: Uterine serous carcinoma (USC) is an aggressive endometrial cancer that carries a poor prognosis. Up to 35% of USC overexpress HER2/neu oncogene at strong (3+) levels while 45% d...

Abstract We have built a linker-drug platform based on a cleavable linker-duocarmycin payload for the development of novel generation antibody-drug conjugates. SYD983, a lead ADC originating from that platform, is a cysteine-coupled HER2-targeting ADC based on trastuzumab. SYD983 is a heterogeneous product that consists of a mixture of naked Ab and ADCs with a drug-to-antibody ratio (DAR) of 2, 4, 6, the mean DAR being 2.0. We have shown that SYD983 binds to HER2, induces antibody-dependent cell-mediated cytotoxicity, and is efficiently internalized into HER2-expressing cells. SYD983 very potently kills HER2-expressing cells in vitro and is inactive in cells that don't express HER2. SYD983 is stable in human and cynomolgus monkey (CM) plasma in vitro but has relatively poor stability in mouse plasma. The latter is due to mouse-specific carboxylesterase (CES1c) since stability of SYD983 in plasma of CES1c knockout mice is similar to that in human and CM plasma. SYD983 could be dosed up to 30 mg/kg in CM in vivo with high exposure and stable kinetics and without severe toxic effects. The CM safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, which both commonly occur in studies with ADCs based on tubulin inhibitors. Finally, to reduce heterogeneity we have further fractionated SYD983 by hydrophobic interaction chromatography resulting in an ADC predominantly containing DAR2 and DAR4 species and we designated the resulting purified and more homogeneous ADC as SYD985. In line with its increased average DAR and the absence of naked Ab, SYD985 (average DAR of 2.7) shows increased potency in vitro compared to SYD983. In vivo, SYD985 showed high anti-tumor activity in two patient-derived xenograft models of HER2 positive metastatic breast cancers which underscores the potential for SYD985 in this indication. We have further initiated a program to directly compare SYD985 to T-DM1 for anti-tumor activity in a series of tumors with different HER2 status of which the results are published in a separate accompanying abstract. In conclusion, the data obtained indicates great potential for SYD985 to become an effective drug for patients with HER2-positive cancers. Clinical studies will further elucidate how the characteristics revealed in the preclinical studies, will translate into a benefit for patients. Taken more generally, we conclude that this novel generation duocarmycin-based LD technology could be used on other mAbs to create effective and safe ADCs to treat different forms of cancer. Citation Format: Willem Dokter, Ruud Ubink, Miranda van der Lee, Monique van der Vleuten, Tanja van Achterberg, Daniëlle Jacobs, Diels van den Dobbelsteen, David Egging, Ellen Mattaar, Patrick Groothuis, Patrick Beusker, Ruud Coumans, Ronald Elgersma, Michel Eppink, Guy de Roo, Gijs Verheijden, Marco Timmers. Impressive efficacy and safety profile of a novel generation duocarmycin-based HER2-targeting ADC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2651. doi:10.1158/1538-7445.AM2014-2651