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1.
Regul Toxicol Pharmacol ; 108: 104476, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31536773

ABSTRACT

Tildrakizumab (also known as MK-3222), is a high-affinity, humanized, immunoglobin G1κ monoclonal antibody targeting the p19 subunit of interleukin-23 recently approved for the treatment of moderate to severe plaque psoriasis in the US, Europe, and Australia. The safety profile of tildrakizumab was characterized in nonclinical studies using a pharmacologically relevant cynomolgus monkey model. In repeat-dose toxicity studies, cynomolgus monkeys were chronically treated with subcutaneous (SC) injections of 100 mg/kg of tildrakizumab every 2 weeks up to 9 months. Tildrakizumab was well tolerated, with no toxicological findings (including assessment of reproductive organs; hormonal effects; and cardiovascular, respiratory, and central nervous system function) at systemic exposures approximately 90 times higher than the recommended human dose of 100 mg. An embryofetal developmental study conducted in pregnant monkeys revealed no treatment-related effects to the developing fetus following SC administration of tildrakizumab 100 mg/kg. In a pre- and postnatal development study, 2 neonatal deaths due to potential viral infection at 100 mg/kg were considered of uncertain relationship to the treatment based on a lack of historical data on the occurrence of viral infection in neonate cynomolgus monkeys. The results of this comprehensive nonclinical safety program support the safe use of tildrakizumab.


Subject(s)
Antibodies, Monoclonal, Humanized/toxicity , Animals , Antibodies, Monoclonal, Humanized/blood , Antibodies, Monoclonal, Humanized/pharmacokinetics , Embryonic Development/drug effects , Female , Fetal Development/drug effects , Interleukin-23 Subunit p19/blood , Interleukin-23 Subunit p19/immunology , Macaca fascicularis , Male , Maternal-Fetal Exchange , Milk/chemistry , Pregnancy , Psoriasis/drug therapy , Toxicity Tests, Chronic
2.
Anal Chem ; 90(1): 866-871, 2018 01 02.
Article in English | MEDLINE | ID: mdl-29206445

ABSTRACT

Large molecule quantitation by LC-MS/MS commonly relies on bottom-up or so-called surrogate peptide measurements to infer the whole-molecule concentration. This can lead to questions about what is actually being measured in the assay (intact drug and/or other drug related material). An intact sequential affinity capture (ISAC) assay was developed utilizing two different immunoaffinity (IA) reagents. The reagents were selective for the heavy and light chain of a monoclonal antibody, which when used consecutively, ensures that only the intact form of the antibody is represented by the surrogate peptide. The approach provided comparable results to a traditional sandwich IA assay indicating similar capture populations. The use of an initial ISAC assessment of affinity capture purification, should add a degree of confidence in the use of a single IA-LC-MS/MS quantitation assay.


Subject(s)
Antibodies, Monoclonal/blood , Biological Assay/methods , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods , Animals , Antibodies, Monoclonal/chemistry , Macaca mulatta , Proteolysis , Trypsin/chemistry
3.
Toxicol Pathol ; 40(6): 899-917, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22552394

ABSTRACT

AMG X, a human neutralizing monoclonal antibody (mAb) against a soluble human protein, caused thrombocytopenia, platelet activation, reduced mean arterial pressure, and transient loss of consciousness in cynomolgus monkeys after first intravenous administration. In vitro, AMG X induced activation in platelets from macaque species but not from humans or baboons. Other similar mAbs against the same pharmacological target failed to induce these in vivo and in vitro effects. In addition, the target protein was known to not be expressed on platelets, suggesting that platelet activation occurred through an off-target mechanism. AMG X bound directly to cynomolgus platelets and required both the Fab and Fc portion of the mAb for platelet activation. Binding to platelets was inhibited by preincubation of AMG X with its pharmacological target or with anti-human Fc antibodies or by preincubation of platelets with AMG X F(ab')(2) or human immunoglobulin (IVIG). AMG X F(ab')(2) did not activate platelets. Thus, platelet activation required both recognition/binding of a platelet ligand with the Fab domain and interaction of platelet Fc receptors (i.e., FcγRIIa) with the Fc domain. These findings reflect the complexity of the mechanism of action of mAbs and the increasing awareness of potential for unintended effects in preclinical species.


Subject(s)
Antibodies, Monoclonal/toxicity , Blood Platelets/drug effects , Platelet Activation/drug effects , Administration, Intravenous , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/pharmacokinetics , Blood Platelets/metabolism , Humans , Hypotension/blood , Hypotension/chemically induced , Immunoglobulin Fab Fragments/metabolism , Immunoglobulin Fc Fragments/metabolism , Macaca fascicularis , Male , Papio , Platelet Aggregation/drug effects , Protein Binding , Serotonin/metabolism , Syncope/blood , Syncope/chemically induced , Thrombocytopenia/blood , Thrombocytopenia/chemically induced , Thromboxane B2/metabolism
4.
Bioorg Med Chem Lett ; 19(22): 6307-12, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19819693

ABSTRACT

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Apoptosis/physiology , Neovascularization, Physiologic/physiology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Animals , Cell Survival , Humans , Mice , Mice, Nude , Phosphorylation , Xenograft Model Antitumor Assays
6.
Int J Toxicol ; 24(5): 313-25, 2005.
Article in English | MEDLINE | ID: mdl-16257851

ABSTRACT

This study was conducted as part of the International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist following oral administration to Tg.AC (transgenic) and wild-type FVB (nontransgenic) mice for a minimum for 6 months. Clofibrate was well tolerated at doses up to 500 (males) and 650 (females) mg/kg/day. Oral administration of clofibrate to Tg.AC or FVB (wild-type) male and female mice for 6 months did not result in the increased formation of neoplastic lesions. Epithelial hyperplasia in the urinary bladder (Tg.AC and FVB) and prostate gland (Tg.AC only), and interstitial-cell hyperplasia in the testes (Tg.AC) were noted at 500 mg/kg/day. Non-neoplastic nonproliferative findings included hepatic hypertrophy and hematopoietic changes (myeloid hyperplasia, myelodysplasia, lymphoid depletion, and erythropoiesis) in Tg.AC and FVB mice of both sexes; reproductive (cystic degeneration and dilatation, hypospermia, spermatocele, dilated inspissated protein) and urogenital (tubular-cell hypertrophy, degenerative/regenerative nephropathy, necrosis/fibrosis) changes in Tg.AC and FVB male mice; congestion in the lung in male Tg.AC mice; gall bladder dilatation in female Tg.AC mice; and adrenal (intracellular lipofuscinosis and atrophy) and heart (eosinophillic myofibers) findings in Tg.AC mice of both sexes and in female FVB mice. The results of this study indicate that the clofibrate is not carcinogenic when administered to Tg.AC mice by oral gavage for 6 months at doses up to 500 (males) and 650 (females) mg/kg/day, which did produce liver hypertrophy.


Subject(s)
Clofibrate/toxicity , Liver/drug effects , Peroxisome Proliferators/toxicity , Animals , Carcinogenicity Tests/methods , Clofibrate/administration & dosage , Dose-Response Relationship, Drug , Female , Genes, ras , Hypertrophy/chemically induced , Intubation, Gastrointestinal , Liver/pathology , Male , Mice , Mice, Transgenic , Peroxisome Proliferators/administration & dosage , Risk Assessment , Time Factors
7.
Int J Toxicol ; 24(5): 341-8, 2005.
Article in English | MEDLINE | ID: mdl-16257853

ABSTRACT

This study was conducted in support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of clofibrate, a nongenotoxic peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to neonatal mice. Male and female neonatal CD-1 mice were dosed with clofibrate at doses of 100, 250, and 500 mg/kg or with the positive control, diethylnitrosamine (DEN), at 2 mg/kg by oral gavage on days 9 and 16 post birth and observed for approximately 1 year for the development of tumors. Plasma levels of clofibric acid after the second administration increased with dose, but were not dose proportional. Clofibrate administered by gavage on litter days 9 and 16 to neonatal mice at doses of 100, 250, or 500 mg/kg did not produce a carcinogenic effect. The positive control DEN did produce tumors in the liver and lung (single and multiple adenomas and carcinomas) and harderian gland (adenoma) of both sexes. Non-neoplastic lesions related to DEN treatment were confined to myocardial degeneration/fibrosis and testicular interstitial hyperplasia in males, and to glomerulonephrosis and gastritis in both sexes.


Subject(s)
Clofibrate/pharmacokinetics , Clofibrate/toxicity , Peroxisome Proliferators/toxicity , Animals , Animals, Newborn , Carcinogenicity Tests , Clofibrate/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Intubation, Gastrointestinal , Male , Mice , Models, Animal , Peroxisome Proliferators/administration & dosage , Peroxisome Proliferators/pharmacokinetics , Risk Assessment , Time Factors
8.
Int J Toxicol ; 24(5): 349-56, 2005.
Article in English | MEDLINE | ID: mdl-16257854

ABSTRACT

Studies conducted under the auspices of International Life Sciences Institute (ILSI) have suggested that an alternative mouse carcinogenicity study may be substituted for the traditional 2-year mouse bioassay typically conducted to support the development of drug candidates. The purpose of this study was to characterize the carcinogenic potential of N-methyl-N-nitrosourea (MNU), a DNA alkylating agent, in p53+/- knockout mice to determine its suitability as a positive control agent in an alternative carcinogenicity model. p53+/- knockout mice were administered a single oral dose of 90 mg/kg and maintained for up to 13 weeks prior to evaluation of neoplasms. Treatment was generally well tolerated; however, 4 of 30 mice died between the days of 75 and 92 due to neoplasms. MNU-related macroscopic observations included enlargement of the thymus, spleen, mandibular and mesenteric lymph nodes; and pale liver, heart, kidney, and bone marrow, which correlated with the diagnosis of lymphoma of the hematopoietic system, noted in the thymus of all affected animals and in the spleen, liver, lungs, and kidneys of some animals. Other treatment-related single neoplasms included a squamous-cell carcinoma in the nonglandular stomach and leiomyosarcoma in the glandular stomach. Non-neoplastic proliferative lesions included acanthosis and hyperkeratosis in the nonglandular stomach, focal papillary hyperplasia of the nonglandular stomach, glandular hyperplasia of the stomach, and adenomatous hyperplasia of the duodenum or ileum. The increased incidence of neoplastic and proliferative changes in MNU-treated mice suggests MNU could serve as a positive control in alternative carcinogenicity studies conducted in p53+/- knockout mice.


Subject(s)
Alkylating Agents/toxicity , Gastrointestinal Tract/drug effects , Genes, p53 , Lymphoma/chemically induced , Methylnitrosourea/toxicity , Stomach Neoplasms/chemically induced , Administration, Oral , Alkylating Agents/administration & dosage , Animals , Carcinogenicity Tests , Disease Models, Animal , Female , Gastrointestinal Tract/pathology , Hyperplasia/chemically induced , Male , Methylnitrosourea/administration & dosage , Mice , Mice, Inbred C57BL , Mice, Knockout , Risk Assessment
9.
Int J Toxicol ; 24(5): 289-99, 2005.
Article in English | MEDLINE | ID: mdl-16257849

ABSTRACT

This study was conducted as part of International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to p53+/- heterozygous mice for a minimum of 26 weeks. p-Cresidine, a urinary bladder carcinogen, was given orally at 400 mg/kg/day as a positive control. Initial clofibrate doses were 50, 250, and 400 mg/kg/day for males and 50, 200, and 500 mg/kg/day for females. Due to unexpected mortality during the first week of dosing, clofibrate doses were lowered to 25, 75, and 100 mg/kg/day for males and 25, 75, and 125 mg/kg/day for females. Clinical signs and mortality were greater in p53+/- than wild-type (WT) mice. With the exception of liver weights, no marked differences in any other parameters either between the sexes or between WT and p53+/- mice were noted. Moderate increases in liver weights noted in WT males given 100 mg/kg/day clofibrate were not associated with any microscopic changes. No neoplastic response was observed in p53+/- mice after 6 months of exposure to clofibrate at doses up to 100 mg/kg/day for males and 125 mg/kg/day for females. Transitional-cell hyperplasia and carcinoma of the urinary bladder were noted in both sexes given p-cresidine, demonstrating that the p53+/- mouse responded to a known mouse carcinogen as expected. Clofibrate produced non-neoplastic findings in the adrenals, pancreas, and prostate, whereas p-cresidine affected the kidney, liver, pancreas, and spleen.


Subject(s)
Clofibrate/toxicity , Genes, p53 , Peroxisome Proliferators/toxicity , Administration, Oral , Adrenal Glands/pathology , Animals , Carcinogenicity Tests , Clofibrate/administration & dosage , Dose-Response Relationship, Drug , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pancreas/pathology , Peroxisome Proliferators/administration & dosage , Prostate/pathology , Risk Assessment , Time Factors
10.
Int J Toxicol ; 24(5): 327-39, 2005.
Article in English | MEDLINE | ID: mdl-16257852

ABSTRACT

This study was conducted as part of the International Life Sciences Institute (ILSI) Alternatives to Carcinogenicity Testing program and evaluated the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist following dermal application to transgenic Tg.AC and nontransgenic FVB mice for a minimum of 26 weeks. Clofibrate doses of 12, 28, or 36 mg/200 microl/day were used. Positive controls for papilloma formation were benzene (174.8 mg/200 microl), and 12-o-tetradecanoylphorbol-13-acetate (TPA [0.00250 mg/200 microl]). Clofibrate was tolerated at doses up to 36 mg/200 microl. In Tg.AC mice, clofibrate produced a dose-related increase in the incidence of mice with cutaneous papillomas; and dose-related decreases in mean time to first tumor, mean multiplicity of tumors per mouse, and mean weeks to maximal yield, as well as numerous nonneoplastic microscopic lesions in the liver, kidney, spleen, and skin. Benzene and TPA induced both neoplastic and/or non-neoplastic proliferative lesions in Tg.AC mice. Clofibrate did not increase the incidence or multiplicity of papillomas, or any other tumors in FVB mice. These data show that the Tg.AC dermal model has increased sensitivity in detecting skin papillomas caused by the nongenotoxic rodent carcinogen, clofibrate, compared to wild type FVB mice, at systemic exposures that are 3x higher than the systemic exposure observed in humans taking clofibrate (AUC = 1100 microg.h/ml) at the recommended maximum therapeutic dose of 500 mg. In addition, this study supports the proposed concept that Tg.AC model may detect compounds with nongenotoxic carcinogenic potential in a shorter timeframe than conventional mouse carcinogenicity bioassays.


Subject(s)
Clofibrate/toxicity , Papilloma/chemically induced , Peroxisome Proliferators/toxicity , Skin Neoplasms/chemically induced , Administration, Cutaneous , Animals , Carcinogenicity Tests , Clofibrate/administration & dosage , Dose-Response Relationship, Drug , Female , Genes, ras , Male , Mice , Mice, Transgenic , Peroxisome Proliferators/administration & dosage , Risk Assessment , Time Factors
11.
Int J Toxicol ; 24(5): 301-11, 2005.
Article in English | MEDLINE | ID: mdl-16257850

ABSTRACT

The purpose of the study was to support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of the nongenotoxic carcinogen, clofibrate, a peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to rasH2 mice. Peroxisome proliferators are one of the most widely studied of the nongenotoxic carcinogens and have diverse industrial and therapeutic uses (Gonzalez et al. J. Nat. Cancer Inst. 90: 1702-1709, 1998); however, the nongenotoxic mechanism of carcinogenicity is currently unknown. Male mice were administered doses of clofibrate at 50, 100, or 200 mg/kg/day and female mice were administered doses of 50, 150, or 250 mg/kg/day by oral gavage at 10 ml/kg for 27 weeks. In addition, rasH2 male and female mice were treated with N-nitroso-N-methylurea (NMU). Nontransgenic male and female mice were treated with 200 and 250 mg/kg/day, respectively, of clofibrate. The NMU-treated mice were given a single intraperitoneal dose of 75 mg/kg, which was followed by a 90-day observation period; all others were sacrificed after 6 months of daily dosing. Hepatocellular neoplasms were observed in clofibrate-treated rasH2 male mice after 6 months of treatment but not in nontransgenic males or females. Clofibrate treatment (250 mg/kg/day) of female rasH2 mice was associated with a slight increase in the incidence of various neoplasms (harderian gland, lungs, skin, spleen, tail, thymus, and uterus) compared with untreated transgenic mice and with similarly treated nontransgenic mice. Non-neoplastic changes were found in the liver of transgenic and nontransgenic mice of both sexes and in the kidneys of male mice. NMU produced findings are consistent with previous studies. The data suggest that the rasH2 mice are a good model for testing epigenetic carcinogens in a shorter timeframe than conventional mouse carcinogenicity bioassays.


Subject(s)
Clofibrate/toxicity , Eye Neoplasms/chemically induced , Genes, ras , Liver Neoplasms, Experimental/chemically induced , Peroxisome Proliferators/toxicity , Animals , Carcinogenicity Tests , Clofibrate/administration & dosage , Dose-Response Relationship, Drug , Eye Neoplasms/pathology , Female , Harderian Gland/pathology , Humans , Intubation, Gastrointestinal , Liver Neoplasms, Experimental/blood , Liver Neoplasms, Experimental/physiopathology , Male , Mice , Mice, Transgenic , Peroxisome Proliferators/administration & dosage , Risk Assessment , Time Factors
12.
Carcinogenesis ; 25(9): 1757-69, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15131011

ABSTRACT

There is little primate risk factor data in the literature evaluating the relationship between proposed mechanisms of PPAR agonist-induced hepatocarcinogenesis at clinically relevant therapeutic exposures. These studies were conducted to characterize the hepatic effects of fenofibrate and ciprofibrate in the cynomolgus monkey. Male cynomolgus monkeys were given fenofibrate (250, 1250 or 2500 mg/kg/day) or ciprofibrate (3, 30, 150 or 400 mg/kg/day) for up to 15 days. The highest doses used were approximately 4 times (fenofibrate) and 9.4 times (ciprofibrate) the human therapeutic exposure for these agents based on AUC (area under the curve). For both compounds, there was a treatment-related increase in liver weight and periportal hepatocellular hypertrophy, which was related to increases in peroxisomes (up to 2.8 times controls) and mitochondria (up to 2.5 times controls). An increase in smooth endoplasmic reticulum probably contributed to the hypertrophy. There was no indication of cell proliferation as determined by the number of mitotic figures and this was confirmed by evaluating cell proliferation by immunohistochemical staining for the Ki-67 antigen. Consistent with the findings by light microscopy, there was no treatment-related effect on the level of mRNA for proteins known to be involved in the control of hepatocyte cell division or apoptosis (e.g. P21, Cyclin D1, PCNA, CDKN1A). Furthermore, there was minimal indication of oxidative stress. Thus, there was no evidence of lipofuscin accumulation, and there was no remarkable increase in the mRNA levels for most proteins known to respond to oxidative stress (e.g. catalase, glutathione peroxidase). A mild induction in the mRNA levels of cellular beta-oxidation and detoxification enzymes (e.g. acyl CoA oxidase, thioredoxin reductase) was observed. Collectively, the data from these studies suggest that the primate responds to PPARalpha agonists in a manner that is different from the rodent suggesting that the primate may be refractory to PPAR-induced hepatocarcinogenesis.


Subject(s)
Clofibric Acid/analogs & derivatives , Clofibric Acid/toxicity , Fenofibrate/toxicity , Liver/metabolism , Mitochondria/metabolism , Oxidative Stress/drug effects , Peroxisomes/metabolism , Acyl-CoA Oxidase/metabolism , Animals , Apoptosis , Area Under Curve , Catalase/genetics , Catalase/metabolism , Cell Division/drug effects , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Endoplasmic Reticulum, Smooth/drug effects , Endoplasmic Reticulum, Smooth/metabolism , Fibric Acids , Gene Expression Profiling , Glutathione Peroxidase/genetics , Glutathione Peroxidase/metabolism , Liver/cytology , Macaca fascicularis , Male , Mitochondria/drug effects , Mitotic Index , Organ Size/drug effects , Peroxisomes/drug effects , Proliferating Cell Nuclear Antigen/metabolism , RNA, Messenger/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Thioredoxin-Disulfide Reductase/metabolism , Transcription Factors/metabolism
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