Abstract：
:The HER2 pathway plays a pivotal role in cell proliferation and differentiation, while the receptor overexpression caused by amplification of HER2 gene is associated with the growth of several tumors. Previously published clinical trials have demonstrated that antibody-conjugated drugs (ADCs) remarkably improved clinical effects compared with antibodies alone for the same target. In order to provide more effective drugs, we developed Disitamab vedotin based on ADC. The antibody part was a humanized monoclonal antibody targeting HER2, the small molecule toxin was monomethyl auristatin E (MMAE), a synthetic antineoplastic agent. A protease cleavable linker covalently attached MMAE to the antibody. In this study, we characterized the toxicity profile of Disitamab vedotin through single- and repeat-dose toxicity studies in monkeys. The toxicities of small molecules and naked antibody (Disitamab) were also assessed in these studies. Monkeys were well tolerated with Disitamab vedotin at doses of 6 mg/kg, while equivalent MMAEs resulted in severe myelosuppression. This finding proves that ADCs improve the therapeutic effect. In addition, the safety profiles of Disitamab vedotin and MMAE were similar and consistent with the activation mechanism of MMAE. Toxicology finding included bone marrow/hematology toxicity and lymphoid organ toxicity, while no significant toxicity was observed in animals treated with naked antibody. These side effects were found to be consistent with data acquired from clinical phase I/II patients treated with Disitamab vedotin.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Jiang J,Li S,Shan X,Wang L,Ma J,Huang M,Dong L,Chen Fdoi
10.1016/j.toxlet.2019.12.027subject
Has Abstractpub_date
2020-05-15 00:00:00pages
30-37eissn
0378-4274issn
1879-3169pii
S0378-4274(19)30421-7journal_volume
324pub_type
杂志文章abstract：:Stoichiometric conversion of methyl acetate to methanol in vitro was detected when methyl acetate was incubated with blood for 2 to 8 h. The velocity of the reaction was so fast that almost all of methyl acetate disappeared in 8 h. The methanol formation was further confirmed by means of gas-chromatography-mass spectr...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(92)90028-i
更新日期：1992-09-01 00:00:00
abstract：:Rats surviving various single dose of the organophosphorus anticholinesterase nerve agents Soman and Sarin were examined by light microscopy at intervals up to 35 days post-exposure. Brain lesions, identical to those that have been reported elsewhere were present, as well as a previously unreported finding associated ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(87)90192-5
更新日期：1987-05-01 00:00:00
abstract：:Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mea...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(92)90094-z
更新日期：1992-12-01 00:00:00
abstract：:Methanol remains to be a major public and environmental health hazard. Formic acid is the toxic metabolite responsible for the metabolic acidosis observed in methanol poisoning in humans, in non-human primates and in folate-depleted rodents. Cytochrome oxidase inhibition by formate leads to lactic acid accumulation, w...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2005.07.017
更新日期：2006-02-20 00:00:00
abstract：:Low concentrations of arachidonic acid monoepoxides protect against ischemia/reperfusion injury. This study examined whether low concentrations of the linoleic acid monoepoxide, cis-12,13-epoxy-9-octadecenoic acid (12,13-EOA), protect renal cells against decreases in mitochondrial and transport functions induced by hy...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2003.11.002
更新日期：2004-03-01 00:00:00
abstract：:Activation of the cold-receptor TRPM8 by menthol or other tobacco additives can suppress natural defense reactions such as coughing that usually would become effective as involuntary resistance against the inhalation of fumes. In Europe menthol is only regulated as flavor, but can be used as additive as long as no cha...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2017.02.020
更新日期：2017-04-05 00:00:00
abstract：:Primary cultures of rat hepatocytes were exposed to various concentrations of L-asparaginase derived from Escherichia Coli. Protein synthesis was inhibited by about 33% and cellular glutamine was reduced proportionally to the enzyme concentration. However, protein synthesis was inhibited only by amounts of enzyme able...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(86)90113-x
更新日期：1986-09-01 00:00:00
abstract：:Lindane administration to rats (60 mg/kg b.w.) led to an enhancement in the oxidative stress status of the liver at 4 h after treatment, characterized by increases in hepatic thiobarbituric acid reactants (TBARS) formation and chemiluminescence, reduced glutathione (GSH) depletion, and diminution in the biliary conten...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/s0378-4274(00)00172-7
更新日期：2000-04-10 00:00:00
abstract：:The skin is an immunologically active tissue. Epidermal cells, both keratinocytes and Langerhans cells (LC), produce constitutively or can be stimulated to produce a variety of cytokines, many of which play important roles in the induction and regulation of allergic responses to sensitizing chemicals. Tumor necrosis f...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/0378-4274(95)03497-8
更新日期：1995-12-01 00:00:00
abstract：:Skin esterases serve an important pharmacological function as they can be utilised for activation of topically applied ester prodrugs. Understanding the nature of these enzymes, with respect to their role and local activity, is essential to defining the efficacy of ester prodrugs. Minipigs are used as models to study ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2007.07.004
更新日期：2007-09-10 00:00:00
abstract：:Doxorubicin (DOX) is a chemotherapeutic agent of which the medical use is limited due to cardiotoxicity. While acute cardiotoxicity is reversible, chronic cardiotoxicity is persistent or progressive, dose-dependent and irreversible. While DOX mechanisms of action are not fully understood yet, 3 toxicity processes are ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2018.05.029
更新日期：2018-09-15 00:00:00
abstract：:The activities of vanadium oxide (V2O3), vanadyl sulfate (VOSO4) and ammonium metavanadate (NH4VO3) in inducing sister chromatid exchange (SCE) and chromosomal aberrations (CAb) were assayed in Chinese hamster ovary cells. The toxic concentrations (TC50) for these compounds were found to be 25, 23 and 16 micrograms el...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(90)90026-i
更新日期：1990-02-01 00:00:00
abstract：:The involvement of neurotrophins after radiation injury during brain development were studied in pregnant mice (C 57/B1) exposed on gestation day 15 to X-ray doses of 0.02-2 Gy. Nerve growth factor protein (NGF) and different cholinergic markers were investigated on postnatal day 1 (P1) and day 21 (P21); in situ hybri...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/s0378-4274(96)03827-1
更新日期：1997-01-15 00:00:00
abstract：:Voltage-activated sodium channels and GABAA receptor-chloride channel complex are among the most important target sites of various environmental neurotoxicants. Pyrethroids keep the sodium channels open for prolonged periods of time leading to hyperexcitation of the entire nervous system. In rat cerebellar Purkinje ne...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/0378-4274(95)03482-x
更新日期：1995-12-01 00:00:00
abstract：:The proceedings in this volume suggest several important future research needs. Research is needed to validate modeling in toxicology in order to support the use of the general approach of modeling, either for structure-activity relationships (SAR) or physiologically based pharmacokinetics (PBPK), by regulators. Resea...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/0378-4274(95)03382-u
更新日期：1995-09-01 00:00:00
abstract：:Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dos...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2020.07.020
更新日期：2020-10-10 00:00:00
abstract：:Citrinin (CIT), a fungal metabolite causing nephrotoxicity, has a tolerable daily intake (TDI) value of 0.2μg/kg bw. Contamination of food with CIT is not sufficiently known to allow dietary exposure assessment. Urinary biomonitoring data are available from cohorts of several countries. However, kinetic information is...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2017.10.006
更新日期：2018-01-05 00:00:00
abstract：:Humans are typically exposed to mixtures of substances, whereby their bioactivity can be significantly altered by co-occurring compounds. Thus, over the last years, research on combinatory effects has gained increasing attention. In particular, several xenoestrogens have been recently reported to interact synergistica...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2019.10.025
更新日期：2020-02-01 00:00:00
abstract：:Male Swiss Webster mice were given an intravenous dose of 50 mg/kg, or an oral gavage dose of 5, 50 or 500 mg/kg [1, 2-(14)C]-ethylenediamine dihydrochloride, and its fate was followed for 48 h. Ethylenediamine (EDA) was readily absorbed from the gut (bioavailability, 87% measured at 50 mg/kg). Absorption was rapid as...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/s0378-4274(00)00252-6
更新日期：2000-09-30 00:00:00
abstract：:Potentiality of a protective effect of methionine against hepatotoxic action of vinyl chloride (VC) was assessed on rats, induced with phenobarbital and thereafter exposed to 50 000 ppm VC for 5 h. This extremely high dosage of VC warranted the appearance of drastic symptoms of liver injury in the course of 20 h poste...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(81)90043-6
更新日期：1981-05-01 00:00:00
abstract：:A low-Mr copper (Cu) and zinc (Zn)-binding protein was present in the liver of a control water lizard Triturus pyrrhogaster. Cadmium (Cd) accumulated in the liver of the animals after intramuscular injections of Cd salt and was bound to Cu- and Zn-binding protein of a single isoform that had properties characteristic ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(84)90203-0
更新日期：1984-05-01 00:00:00
abstract：:The effect of chlordimeform (CDM) treatment on the hepatic microsomal drug metabolizing enzymes was examined in male and female rats following either acute or repeated treatment. After acute administration of chlordimeform (100 mg/kg, i.p., 1 hour before killing) differential effects were observed in various parameter...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(83)90072-3
更新日期：1983-08-01 00:00:00
abstract：:Effects of intestinal damage on thyroid carcinogenesis due to amitrole (AT) were examined in F344 male rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). In experiment 1, rats were provided with diet containing 0.03% AT for 20 weeks after a single subcutaneous injection of DHPN (2800 mg/kg body weight), and...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2005.11.012
更新日期：2006-06-20 00:00:00
abstract：:There are multiple lines of evidence showing that environmental toxicants including pesticides may contribute to neuronal cell death. Fipronil (FPN) is a phenylpyrazole insecticide that acts on insect GABA receptors. Although the action of FPN is restricted to insect neuronal or muscular transmitter systems, a few stu...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2012.02.022
更新日期：2012-05-20 00:00:00
abstract：:Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well as blister inducing chemical warfare agent. We evaluated the cytoprotective efficacy of amifostine, DRDE-07 and their analogues, and other antidotes of mustard agents against HN-2. Administration of 1 LD(50) of HN-2 (20mg...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2009.04.015
更新日期：2009-08-10 00:00:00
abstract：:Cholestasis represents pathophysiologic syndromes defined as impaired bile flow from the liver. As an outcome, bile acids accumulate and promote hepatocyte injury, followed by liver cirrhosis and liver failure. Glycochenodeoxycholic acid (GCDCA) is relatively toxic and highly concentrated in bile and serum after chole...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2020.05.017
更新日期：2020-10-01 00:00:00
abstract：:The relative deposition of inhaled heterodisperse particles of the size of environmental tobacco smoke (ETS, mass median aerodynamic diameter 0.2 micron, geometric standard deviation 1.5) is about the same in the tracheobronchial tree and is lower in the pulmonary region of the rat than in the same regions of humans. ...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/0378-4274(87)90093-2
更新日期：1987-01-01 00:00:00
abstract：:The blood-brain barrier (BBB) is critical to maintain cerebral homeostasis. In this study, we examined the effects of exposure to electromagnetic pulse (EMP) on the functional integrity of BBB and, on the localization and expression of tight junction (TJ) proteins (occludin and ZO-1) in rats. Animals were sham or whol...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2010.04.011
更新日期：2010-07-15 00:00:00
abstract：:Cadmium specifically modify amine metabolism at the central nervous system and pituitary hormone secretions. Thus, the physiological functions controlled by these hormones can be modulated by cadmium. This xenobiotic is associated with deleterious effects on the gonadal function and with changes in the secretory patte...
journal_title：Toxicology letters
pub_type： 杂志文章,评审
doi：10.1016/s0378-4274(99)00159-9
更新日期：1999-11-22 00:00:00
abstract：:Anthocyanins are plant pigments occurring in flowers and berry fruits. Since a phenomenon of food-drug interactions is increasingly emerging, we examined the effects of 21 major anthocyanins and the extracts from 3 food supplements containing anthocyanins on the aryl hydrocarbon receptor (AhR)-cytochrome P450 CYP1A1 s...
journal_title：Toxicology letters
pub_type： 杂志文章
doi：10.1016/j.toxlet.2013.05.007
更新日期：2013-07-31 00:00:00
