Crown Bioscience Inc.
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San Diego, California, US
Crown Bioscience Inc. is a leading preclinical translational technology provider with a specialization in Oncology, Cardiovascular and Metabolic Disease, and Inflammation. We are helping to bring clarity to drug discovery around the world, by helping biopharmaceutical companies solve some of today's most advanced drug development challenges.
CrownBio are known for the breadth and quality of our in vitro, ex vivo, and in vivo model portfolios, as well as our ability to help clients quantify the real efficacy and pharmacological profile of their candidate before they move into the clinic. As drug discovery continues to rapidly evolve, there is a growing desire to screen candidates earlier, and with more patient-relevant disease models. Models which more closely reflect the patient situation in the clinic and therefore help improve the selection of candidates that are taken into the clinic. Our unique collection of ready-to-run, well-validated platforms, model development expertise, comprehensive drug discovery platforms, and global capacity enable us to deliver the results you need, today.
Our team of experts includes highly trained PhD and MS scientists from around the world. Most CrownBio scientists have a deep understanding of the pharmaceutical industry having lead major departments within the top US pharmaceutical R&D and pre-clinical programs. At CrownBio, our scientists engage with you in the design and execution of your preclinical drug development program using our AAALAC approved animal facilities, proprietary animal models, and in vivo surgical expertise. We pride ourselves on the quality of our work and completing projects swiftly and cost-effectively.
We are headquartered in the heart of Silicon Valley, with wholly-owned research facilities around the world in San Diego, Indiana, and Louisiana (USA), Beijing and Taicang near Shanghai (China) and Loughborough (UK). Our state-of-the-art animal vivaria cover over 150,000 square feet and are AAALAC accredited. A truly global operation providing local service and support for your drug discovery needs.
Standard shipping requirements: Please contact us before shipping any materials to obtain full instructions for shipments. If you are shipping to our UK laboratories, please contact us first for full address, contact and shipping details.
Certifications: AAALAC accreditation
CrownBio provides a wide range of liver disease animal models, specifically within NAFLD/NASH and liver fibrosis:
CrownBio provides a wide range of NAFLD/NASH animal models:
CrownBio offers the world's largest collection of spontaneously obese, diabetic and dysmetabolic non-human primates (NHPs). We specialize in preclinical NHP studies in the areas of:
CrownBio provides a wide range of NAFLD/NASH and fibrosis rodent models:
The MS-NASH (formerly called FATZO) mouse model is an inbred polygenic animal model for obesity, metabolic syndrome, diabetes, and NAFLD/NASH research. Unlike other rodent models of metabolic disease, the MS-NASH mouse has a functional leptin pathway, which more closely mimics the human condition, and results in a more translatable choice for testing the efficacy of metabolic disease compounds. On Western diet + fructose, the MS-NASH model develops steatosis (by 4-8 weeks), hepatocyte ballooning (by 16 weeks), inflammation (by 16 weeks), and fibrosis (by 20 weeks), which can be accelerated and exacerbated with the addition of CCl4.
Rapidly and cost-effectively evaluate your NASH and anti-fibrotic agent effects rodent models with liver fibrosis rapidly induced by carbon tetrachloride (CCl4) or a cholesterol added choline deficient fibrosis diet (CCDF).
Carbon Tetrachloride (CCl4) Induction Mouse Models
Cholesterol Added, Choline Deficient Fibrosis (CCDF) Diet Induction Rodent Models
Evaluate a range of endpoints using our liver fibrosis rodent models. Key study endpoints include:
At CrownBio we routinely run a variety of in vitro assays to evaluate glucose stimulated insulin secretion using:
CrownBio provides the pcy mouse, a genetically relevant rodent PKD model with a close correlation to human disease for use in novel agent efficacy evaluation. The pcy mouse model develops PKD associated with the gene that causes human disease, providing a translatable rodent model, which closely mirrors human PKD development. It has been thoroughly characterized at CrownBio for disease progression and response to treatment. It responds positively to reference compounds, providing a high level of confidence in your drug discovery studies.
Endpoints include:
Evaluate the physiological effects and safety of your preclinical compounds with our comprehensive non-GLP NHP platform. Our models provide you with quick, cost-effective, and robust data to guide future GLP work and clinical trials.
Analyze your samples as part of your in vivo study, or as a standalone service with Beckman-Coulter AU480 Chemical System using a comprehensive portfolio of clinical chemistry assays:
| Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Albumin (ALB) Alkaline Phosphatase (ALP) Beta-2-Microglobulin (B2M) Bicarbonate (CO2) Calcium Cholesterol C-Reactive Protein (CRP) Creatine Kinase Creatinine CYSC Direct Bilirubin GGT (Gamma-Glutamyltransferase) Glucose HDL Cholesterol |
Hemoglobin A1C (HBA1c) Homocysteine Ion-specific electrode (ISE: Na, K, CL) Iron Lactate dehydrogenase (LDH) LDL Cholesterol Lipemia, Icterus, Hemolysis (LIH) Lipase Magnesium Urine Total Protein (MTP) Phosphorus Total Bilirubin Triglyceride Urea Nitrogen (BUN) Uric Acid Urine Albumin |
Blood Pressure Monitoring in Rodents For CVD studies. BP can be measured in our rat or mouse models via: Tail-cuff technology for a rapid, non-invasive BP read Radio telemetry providing continuous BP measurement for a higher definition BP evaluation, including mean arterial pressure (MAP), systolic and diastolic pressures, and heart rate, over several months if needed.
For cardiovascular and metabolic disease research: Our experienced scientific team can perform a wide range of in vivo assays, to evaluate the efficacy and PK/PD effects of your compound. Our in vivo pharmacology capabilities include the evaluation of:
Non-GLP Toxicology Rodent Studies
CrownBio provides a wide range of toxicity studies using rodent models. Assays can be performed in any commercially available rodent model, or in our proprietary highly translatable models of obesity type 2 diabetes (MS-NASH mouse, ZDSD rat) or PKD (pcy mouse). Main endpoints in rodents include necropsy, gross organ weight, and fixation for histology or rtPCR.
Non-GLP Toxicology NHP Studies
Comprehensive NHP toxicology assay platform for evaluating drug physiological and pathological effects.
Studies can be rapidly initiated within 2 weeks (dependent on test article availability), with study duration optimized to fit individual client and project needs.
As part of our General Toxicology Platform, we also provide Safety Pharmacology studies to assess the potential side effects of your new agents, either as standalone assessments, or embedded within our overall toxicological profiling
Our comprehensive Safety Pharmacology evaluations in rodents and non-human primates include assessments of:
Cardiovascular System:
Rodents - BP, HR including continuous telemetry monitoring, cardiac injury biomarker panel (MSD)
NHPs - BP, HR including continuous telemetry monitoring, ECG, cardiac function via noninvasive echocardiography
Hepatic System:
Rodent - Blood chemistry, biomarker panel
NHP - Echo evaluation of fatty liver (for long term study)
Metabolic System
Rodent - Long-term continuous monitoring of glucose via telemetry device, biomarker assessment (Std. ELISA and MSD)
NHP - Long-term continuous monitoring of blood or interstitial glucose via telemetry device
Renal/Urinary System
Rodent - Renal function, blood chemistry, kidney injury biomarker panel (MSD)
NHP - Renal function, blood chemistry, protein assays
This can include continuous telemetry monitoring for both CVD and metabolic assessments to provide high definition data.
IMMUNO-ONCOLOGY Humanized Models: MiXeno Platform of Transient Human Immunity
Simplified approach to model humanization for immunotherapeutic assessment – a platform of transient human immunity
• Created by mixing human peripheral blood mononucleated cells (PBMC) with xenograft models
• PBMC injection route is subcutaneous (where the PBMC are admixed with tumor cells) or intravenous or
intraperitoneal, followed by tumor cell inoculation
• Models are fully validated to show that the partial reconstitution of human hemopoiesis occurs, and in
specific models the significant replenishment of the human T cell population coincides with the
appearance of immunotherapeutic efficacy
• Range of models available including:
o Breast cancer (BT-474)
o Colorectal cancer (COLO 205, HCT 116, SW480)
o Lung cancer (HCC827)
o Lymphoma (KARPAS-299, Jeko-1)
o Melanoma (A375)
• For a range of functions and I/O applications e.g.
o CD19, HER2, EGFR, and EpCAM BiTE®-like antibodies
o Evaluation of immune checkpoint inhibitors/agonists e.g. PD-1, PD-L1 inhibitors
o Antibody-dependent cellular cytotoxicity (ADCC) effects including evalution of cetuximab effect
o NK modulating agent testing
CrownBio provides a large well-characerized panel of synegeneic models for in vivo immunotherapy evaluation:
IMMUNO-ONCOLOGY Murine Efficacy/PD Models: Murine Allograft Models
We provide a range of GEMM and GEMM-derived models for immunotherapeutic assessment:
• GEMM and carcinogen-induced primary mouse tumor models
• Covering multiple disease indications and a variety of mutations
• Used to interrogate the complete process of cancer progression, and to assess where stimulating the
immune system is most beneficial
MuPrime mouse allograft models, derived from spontaneous tumors from GEMM, spontaneous or carcinogen-induced tumors or pseudo GEMM, or tumors from non-germline GEMM using in vivo gene editing:
• Tumors/models never manipulated or adapted to grow in vitro (similar to parental models)
• Mirror original mouse tumor histopathology and genetic profiles, with different differentiation phenotypes,
rich microenvironments, and cancer stem cell driven disease
• Fully validated through immunohistochemistry, RNAseq to confirm gene expression and mutational status,
treatment with immunotherapeutics, and immuno-oncology profiling
• Combines the improved predictive power of the parental models with an operational simplicity,
consistency, and robust growth for pharmacology research, including efficacy and PD assessment
MuScreen™ in vivo Syngeneic Model Screening
The world’s first large-scale in vivo screening platform for immunotherapeutics
• Simultaneously screen 13 or 21 syngeneic models in vivo
• Included syngeneic models have all been well-characterized and validated with checkpoint inhibitors for
PD-1, PD-L1 and CTLA-4 and their complete RNA sequence and FACS data is available via our on-line
database: MuBase (http://mubase.crownbio.com/)
• Efficacy screening panel available, TGI as primary endpoint (FACS/IHC optional)
• Models run on a large scale, preset schedule, with shared vehicle and common groups to improve
efficiency, reproducibility, and cost-effectiveness.
CrownBio offers the largest commercially available PDX collection of 2,500 well-characterized models. PDX provide the most predictive xenograft model available for preclinical studies to:
• Prioritize lead compounds
• Narrow down possible disease indication
• Identify biomarkers to stratify patient populations in clinical trials
therefore lowering drug attrition rate and reducing development costs.
Our PDX platform encompasses both solid tumors and blood cancers, covering over 30 cancer types, with large panels (>100 models) of colorectal, esophageal, gastric, head and neck, liver, lung, melanoma, pancreatic, and sarcoma cancer models.
PDX models are fully annotated by profiling of genomics/genetics (including RNAseq and WES), histopathology, growth properties, and SoCs.
Our highly experienced preclinical team work with you to choose the most appropriate models, study design, and screening method for your compounds, with our free of charge consultation service. Or start searching for the models that meet your needs through our easily searchable online collated PDX database.
Including ALL and AML models which truly represent the human disease - presenting stable disease through passages, with typical leukemia symptoms and eventual mortality. Patient relevant mutations includin FLT3-ITD(+), BCR/ABL(+).
Cell Line Derived Xenograft Studies
CrownBio has established one of the world’s largest collections of validated in vivo models to evaluate novel anticancer compounds. Conventional xenograft studies are used to evaluate novel anticancer compounds, with each model type specifically designed to understand a drug's mechanism of action, or an individual agent property.
Our highly experienced preclinical team will work with you to choose the most appropriate models, study design and screening method for your compounds. And as always, our consultation service is free of charge for you.
CrownBio’s ex vivo models are derived from our collections of highly characterized Patient-Derived Xenograft (PDX) solid tumor and blood cancer models:
Freshly isolated cells from PDX tumors, utilized in assays immediately on the day of isolation. We have
currently validated almost 70 PDX-derived primary cells for 3D cell culture assays, with cells derived from both
solid tumors and blood cancer models.
Fresh frozen PDX cells which shorten assay timelines, with no lag time required for PDX tumor donors to grow
out in vivo. Our fresh frozen PDX cells come from a range of cancer types including breast, colorectal, lung,
and ovarian cancer with further models under development.
Our ex vivo models can be used to evaluate the efficacy of anticancer agents via:
Methylcellulose clonogenic assays
Soft agar clonogenic assays
3D Tumor Growth Assays (3D TGA).
Crownbio's proprietary HuTissue bank:
CrownBio has established 3D cell cultures for >100 commercial cell lines that we have validated for in vitro drug efficacy studies, including blood, bone, brain and nerves, breast, CRC, esophageal, head and neck, lung, liver, ovary, pancreatic, prostate and stomach cancer cell lines
Focused panels of target-relevant cell lines for in vitro evaluation, making assessment of your novel agents fast and easy with our comprehensive services.
OmniPanel™, a genomically diverse collection of more than 400 cancer cell lines for drug response screening
XenoSelect™, a diverse oncogenic in vitro screening panel of over 180 well-validated cell lines, with associated xenograft models ready for in vivo efficacy studies
RNAseq Panel, more than 120 genomically characterized cell lines to correlate mutation status, copy number variation, and expression levels with drug response
PrimePanel™, a unique collection of cancer cell lines with each primary cell originating from one of our genetically defined Patient-Derived Xenograft (PDX) models
3D ex vivo panel, a unique collection of freshly isolated and fresh frozen cells from our PDX models
Select cell lines of interest using our collated online cell line and xenograft database, XenoBase.
In order to gain insights into the complex interaction between the microbiome and cancer therapy, CrownBio performs fecal collection and microbiome profiling (16S rRNA sequencing) to compare gut microbiomes across our syngeneic models, which we can correlate with response to therapy.
PBMC or human serum as effector, cancer cells as target, ADCC reporter assay to provide a high quality assay for determining the cytotoxic activity of selected antibodies against specified target cell lines.
CDC Assays
CrownBio’s CDC assay measures the lysis of target tumor cells following the addition of novel test mAbs, based on the antibody triggering complement cascade activation, which results in membrane attack complexes being inserted on the tumor causing cell death. Our CDC assays are fully optimized for complement concentration used in the serum, with optimal concentrations used to evaluate cytotoxicity of novel mAbs.
CrownBio provides high quality in vitro ADME services. Our capabilities and services include:
• Microsome metabolic stability (rat, human, mouse, dog)
• Hepatocyte metabolic stability (rat and human)
• S-9 metabolic stability (rat and human)
• Metabolite identification (microsomes, hepatocytes, plasma)
• Metabolite profiling (microsomes, hepatocytes, plasma)
• Reactive metabolite (RM) GSH trapping
• Cytochrome P450 (CYP) inhibition/induction for DDI
• CYP metabolism enzyme identification (CYP ID)
• CYP reaction phenotyping (CRP)
• Caco-2 bi-directional permeability, efflux
• P-glycoprotein (P-gp) transporter inhibition
• TDI (Time Dependent Inhibition)
• Plasma protein binding (human, rat, mouse, monkey, dog)
• Microsomal binding
• Tissue binding
• Blood/plasma ratio
We provide a comprehensive range of capabilities to support fully integrated drug discovery collaboration or standalone service for your internal projects.
CrownBio provide high quality bioanalysis services. Our capabilities and services include:
• Rapid LC/MS/MS method development and validation
• Supporting ADME screening, and preclinical PK and PD efficacy studies
• Small molecule to large biologic testing
• Biological matrices like blood, plasma, bile, urine, feces, and tumor tissue collection
• EHS compliant and GLP-like SOP, QA, and QC implemented.
We also provide a full bioanalysis platform from early physicochemical property screening, in vitro ADME profiling, through to late stage in vivo PK as well as PK/PD studies from rodents to NHPs for both small molecules and biologics.
Our service advantages include:
• High quality and complete in vitro ADME and in vivo PK package
• Experienced expertise team and strong problem-solving capacities
• GLP-like SOP, QA, QC, and in-depth knowledge for data interpretation
• New technologies and cutting-edge approaches to address DMPK issues
• Small to large molecule PK in small animals to NHPs
• Criteria and risk assessments for DDI and RM, dose, exposure, and safety margins
• Cost-effective and fast turnaround using automated high-throughput technologies
• EHS-compliant environment and drug metabolism testing according to FDA guidance
CrownBio provide high quality bioanalysis services. Our capabilities and services include:
• Rapid LC/MS/MS method development and validation
• Supporting ADME screening, and preclinical PK and PD efficacy studies
• Small molecule to large biologic testing
• Biological matrices like blood, plasma, bile, urine, feces, and tumor tissue collection
• EHS compliant and GLP-like SOP, QA, and QC implemented.
We also provide a full bioanalysis platform from early physicochemical property screening, in vitro ADME profiling, through to late stage in vivo PK as well as PK/PD studies from rodents to NHPs for both small molecules and biologics.
Our service advantages include:
• High quality and complete in vitro ADME and in vivo PK package
• Experienced expertise team and strong problem-solving capacities
• GLP-like SOP, QA, QC, and in-depth knowledge for data interpretation
• New technologies and cutting-edge approaches to address DMPK issues
• Small to large molecule PK in small animals to NHPs
• Criteria and risk assessments for DDI and RM, dose, exposure, and safety margins
• Cost-effective and fast turnaround using automated high-throughput technologies
• EHS-compliant environment and drug metabolism testing according to FDA guidance
CrownBio provides high quality in vivo PK/PD services. Our capabilities and services include:
Focused in vivo PK studies
• Uptake of drugs by the body
• Biotransformation of the drugs and their metabolites in the tissues
• Elimination of drugs and their metabolites from the body over a period of time
• Distribution of bioactive substances (especially high-molar-mass polymers that cannot cross endothelial
or epithelial physiological barriers) within the various compartments present in an animal or human body
CrownBio leverages our extensive expertise and models to provide expert PK services. Compounds can be administered to normal or disease models through various routes, and blood and/or sample collection both pre- and post-dose is optimized to meet individual client, project, and compound needs. Our laboratories are well equipped, allowing performance of LC/MS/MS bioanalysis (API 4000 + UPLC), with data analysis using WinNonlin®
Following a PK screen, discovery research typically progresses to the investigation of repeatable PD biomarkers in multiple species. We routinely conduct in vivo screening studies that generate both PK and PD endpoints.
Whatever your needs, we work with you to identify the most appropriate models and to provide the customized study designs you require. Our complete service for the in vivo evaluation of compound PK/PD properties includes:
• Study design using various model species
• Single, multiple, and cassette dose PK
• In vivo crossover studies for bioavailability (F)
• Various administration routes (i.v., p.o., i.p., s.c., i.m., etc.)
• Carotid artery and jugular vein cannulation
• Histology and pathology expertise and sample preparation
• Serial blood collection over 24 hours
• Allometric dose prediction and PK optimization
• Effects of food, gender, and formulation type
• PK tissue distribution and mass balance
• Excretion assays
• Non-GLP toxicology (single dose, single dose escalating, repeat dose)
• TK/MTD (toxicokinetics/maximum tolerated dose)
• AAALAC accredited facilities
• Standard formulation and specific formulation development
• Full bioanalytical support available
Antibody Humanization is to engineer a monoclonal antibody (MAb) raised in a nonhuman species without losing its biological function by modifying its protein sequence to increase its similarity to antibody variants produced naturally in humans. Our approach to do humanization is CDR grafting with 3D structural modeling technique for Fv region.
Additionally, various analyses can be performed for mAb characterization:
Crystallization of protein or protein complex:
*Mammalian, baculovirus and bacterial systems
*Various tags
*High throughput system available
*High quality product with Certificate of Analysis
Service Details:
Reporter assays enable monitoring of enhanced expression or nuclear localization of transcription factors. Binding of the transcription factor enables transcription and translation of the reporter gene, which can be quantified in vitro or in vivo by measuring light emitted in the presence of the substrate.
We provide a number of reporter gene assays to measure specific conditions in vitro or in vivo (e.g. hypoxia) in real time, or to follow tumor growth and metastasis over time.
CrownBio provides high quality in vitro services:
• We have one of the largest cell based assay panels.
• Offer services with 250+ cancer cell lines along with CrownBio’s unique proprietary human primary cancer cell lines.
• Designated Study Directors oversees the entire process from study design and assay validation to experimental execution and data analysis.
• Expert scientific and technical support for data interpretation.
• Cell titer Glo, cyquant, MTT or cell-titer blue format.
Huvec cells tube formation assay, calcein quantification by acuman
CrownBio provides high quality in vitro services:
• We have one of the largest cell based assay panels.
• Offer services with 250+ cancer cell lines along with CrownBio’s unique proprietary human primary cancer cell lines.
• Designated Study Directors oversees the entire process from study design and assay validation to experimental execution and data analysis.
• Expert scientific and technical support for data interpretation.
• Annexin V/PI staining or caspase 3/7-Glo format.
transwell or wound healing format
CrownBio provides high quality in vitro services:
• We have one of the largest cell based assay panels.
• Offer services with 250+ cancer cell lines along with CrownBio’s unique proprietary human primary cancer cell lines.
• Designated Study Directors oversees the entire process from study design and assay validation to experimental execution and data analysis.
• Expert scientific and technical support for data interpretation.
• Cell titer Glo, cyquant, MTT or cell-titer blue format.
CrownBio provides high quality in vitro services:
• We have one of the largest cell based assay panels and offer services with more than 250 cancer cell lines along with CrownBio’s unique proprietary human primary cancer cell lines.
• High throughput cytotoxicity screening format.
• Different assays according to your request (e.g. MTS, SRB, BrdU).
• Designated Study Directors oversees the entire process from study design and assay validation to experimental execution and data analysis.
• Expert scientific and technical support for data interpretation.
Real-time PCR (RT-PCR) provides a quantitative comparison of gene expression in cell lines or tissues, and is used to determine whether different gene expression levels are associated with a particular cell phenotype. At CrownBio we also use RT-PCR in conjunction with RNAi technology to verify changes in gene expression.
Noninvasive Echocardiography of NHPs
To monitor cardiac functions within non-human primate colonies.
Noninvasive Sonography of NHP's
CrownBio has developed an ultrasonography method for noninvasive measurement of hepatic lipidosis and other pathologic changes in correlation with multiple metabolic disorders and liver fibrosis biomarkers in our dysmetabolic non-human primates. We have also optimized the quantitative computer-aided analyses of hepatic/renal echo-intensity ratio (H/R) and hepatic echo-intensity attenuation rate (HA), which are more objective than traditional examiner ultrasound analysis.
NHP Models of Obesity - for Obesity, Dysmetabolism, and NAFLD/NASH Research
CrownBio’s portfolio of translational non-human primate obesity models provides:
The naturally occurring NHP obesity model is by far the most predictive model system for human metabolic syndrome, exhibiting in adulthood clinical features of obesity, insulin resistance, dyslipidemia, diabetes, and pancreatic pathology that are similar to those observed in humans. Evaluating drugs in such models offers tremendous value towards understanding efficacy, PK/PD relationship, biomarkers, and possible adverse effects. We have also validated the colony to demonstrate for the first time that, similar to human disease, NHPs also develop hepatic pathology with characteristics of NAFLD/NASH. Combined with high calorie (fat) diet (HCD)-induced models, our NHP models of obesity are a highly valuable resource for research and development in a variety of dysmetabolic conditions.
Rodent Models for Obesity Research
CrownBio provides a full suite of rodent models for obesity research including:
Spontaneously Diabetic NHPs - for Diabetes, Diabetic Nephropathy, and CVD Research
CrownBio provides the world’s largest collection of well-characterized naturally diabetic non-human primates including both cynomolgus and rhesus monkeys, which mirror every aspect of human diabetes including disease progression, obesity, and complications such as nephropathy, neuropathy, and dyslipidemia, making them the ideal system for preclinical investigation of next generation antidiabetic agents. Before moving your agent to successful human clinical trials, NHP models provide invaluable data on: Efficacy, PK/PD relationship, biomarkers, and adverse effects.
Our spontaneously diabetic NHP models develop diabetic nephropathy with similar phenotypic manifestations as in human patients, including hypergylcemia, glucosuria, albuminuria, and proteinuria, providing the ideal animal model for investigating the mechanisms underlying human T2DM, as well as for pharmaceutical discovery, development, and evaluation of novel therapeutic agents. CrownBio has characterized an NHP model of diabetic nephropathy that displays the same features observed in diabetic nephropathy patients with similar molecular, cellular, biochemical, and pathophysiological mechanisms. The diabetic nephropathy phenotype is observed in both genders of NHPs, and is associated with both increasing age and diabetes severity.
Spontaneously diabetic NHPs also provide the most translatable animal model for cardiovascular disease studies, allowing the study of highly human relevant disease and pathogenic mechanisms, as well as late stage research into the antihypertensive properties of novel compounds.
Diabetic Nephropathy Rat Model
The ZDSD rat is an inbred polygenic model for metabolic syndrome, obesity, diabetes, and diabetic complications, which spontaneously develops diabetic nephropathy. To study diabetic nephropathy, male ZDSD rats are allowed to become spontaneously diabetic. Control SD rats and ZDSD rats that have been diabetic from 12 to 13 weeks, and 16 to 17 weeks are terminated and perfused fixed at approximately 35 weeks of age. Glomerular capillaries and basement membrane (BM) are imaged and analyzed endpoints included measuring GBM thickness and evaluation of podocyte morphology.
Rodent Models for Diabetes Research
CrownBio provides a wide variety of rodent models for diabetes research:
The ZDSD rat is an inbred polygenic animal model for metabolic syndrome, diabetes, and obesity. This rat model more closely resembles human disease with an intact leptin pathway providing the most translatable rat model for metabolic syndrome, diabetes, and obesity.
• More closely resembles human prediabetic state with elevated biomarkers, diabetes progression, and
diabetic complications, unlike any other rodent model
• Intact leptin pathway like humans and unlike most rodent models
• Allows the evaluation of pharmacological intervention at different disease stages
• Responds to anti-diabetic standard of care treatments like humans
The ZDSD rat was developed by crossing the ZDF rat (Lean +/+) with the CD(SD) rat and selectively bred for obesity and diabetes traits, followed by inbreeding for more than 35 generations. Phenotype:
• Type 2 diabetes progression similar to the human disease - prediabetes (8-16 weeks of age), through
overt diabetes (>16 weeks of age), to diabetic complications (24 weeks of age)
• Diabetic complications including nephropathy, neuropathy, fatty liver, etc.
• Metabolic syndrome characteristics including increased body weight with abdominal fat, insulin
resistance, dyslipidemia, and hypertension
The ZDSD rat can be used to evaluate agents against all stages of diabetes – from prediabetes, through overt diabetes, and is also a valuable tool for evaluating diabetic nephropathy and naturally occurring hypertension for CVD research (which is missing from many conventional rodent models).
The FATZO mouse is an inbred polygenic animal model for obesity, metabolic syndrome, and diabetes research. This mouse model more closely resembles human metabolic syndrome with an intact leptin pathway like human disease, providing a more translatable mouse model than conventionally available models.
This strain is valuable in studying the continuum of metabolic disturbances that accompany the conditions that lead to overt diabetes: obesity, metabolic syndrome, and the overt hyperglycemic state.
The FATZO mouse was developed by crossing of the AKR/J and C57BL/6J strains followed by selective inbreeding. FATZO mouse phenotype:
Uni-Nephrectomy, Aldosterone-Induced Renal Disease Rodent Model
Renal disease can be induced in Sprague-Dawley (SD) rats by uni-nephrectomy, and the resulting model is suitable for kidney disease research.
Male SD rats are subjected to aseptic uni-nephrectomy (at CRL), and following one week acclimation at CrownBio, animals are implanted with an Alzet mini-pump containing aldosterone (0.75µg/h) for 28 days. Drinking water is supplemented with 0.3% KCl to prevent hypokalemia and a standard diet is admixed with 6% NaCl for the study duration. As the models salt intake is increased, stress on the remaining kidney also increases, leading to the animal developing renal injury and hypertension.
We have validated the model with the clinically approved, mineralocorticoid receptor antagonist eplerenone.
Energy Expenditure Assessment
For obesity research, energy expenditure is measured via indirect calorimetry (OxyMax system, Columbus Instruments). Animals are placed in a sealed unit, which has a known amount of oxygen delivered (allowing measurement of oxygen consumption, VO2) and the amount of oxygen that is converted to CO2 is recorded as it leaves the unit (VCO2). Infra-red is used to measure animal movement and activity, and body temperature can also be monitored as required. This system can be used to evaluate novel anti-obesity agents and their effects on energy expenditure.
Food Consumption Measurement
Monitoring food consumption in obesity studies is a standard endpoint, to confirm that weight loss/reduction in body fat is due to the agent under evaluation rather than a reduction in food intake. CrownBio can calculate the total food intake by weighing of provided food either daily or weekly.
For obesity research, CrownBio provides body fat measurement by qNMR (EchoMRI). This technique utilizes a low field electromagnet to measure conscious whole body composition in only three minutes, providing data on:
• Percent body fat
• Percent lean mass
• Percent water
Anti-obesity agents can then be evaluated to identify decreases in body fat and baseline body fat (via prefeeding) or to determine how much model body fat is converted into lean mass. Body weight is also recorded as standard in our assays
Platelet Aggregometry Assessment in Rodents
For CVD research, CrownBio provides platelet aggregometry assessment in rodents, to evaluate the effects of novel compounds on platelet function. We provide a range of agonists to meet your research needs (including collagen, thrombin, serotonin, or arachidonic acid). Novel agents can be added to the assay to evaluate the level with which they inhibit platelet aggregation.
Blood Pressure Monitoring in Rodents
For CVD studies.
BP can be measured in our rat or mouse models via:
Tail-cuff technology for a rapid, non-invasive BP read
Radio telemetry providing continuous BP measurement for a higher definition BP evaluation, including mean
arterial pressure (MAP), systolic and diastolic pressures, and heart rate, over several months if needed.
Rodent Models for Cardiovascular Disease Research
CrownBio provides a wide variety of rodent models for CVD research:
Any commercially available rat or mouse model
Uni-nephrectomized Sprague-Dawley (SD) rats receiving aldosterone and salt in their drinking water which develop hypertension
Rabbits fed high-cholesterol diet
Our proprietary, highly translatable ZDSD rat model of CVD, which naturally develops high blood pressure on a normal chow diet, providing a suitable model for CVD research and antihypertensive evaluation
Advanced CVD models for aneuryms and atherosclerosis studies:
Glucose and Insulin Level Monitoring in Rodents
For diabetes research.
In vivo measurement of glucose and insulin levels are the gold standard for testing your antidiabetic compound efficacy. At CrownBio we can assess the level of circulating sugar or insulin in rodent studies via:
Single point measurements via glucometer
Continuous telemetry monitoring
Glucose and insulin tolerance tests
ELISA based assays for insulin determination
Glucose clamp tests to quantify insulin resistance.
At CrownBio we also routinely run a variety of in vitro assays including the evaluation of glucose stimulated insulin secretion on isolated primary islets from various rodent models.
Gene Signature Analysis to Discover and Validate the Response to Your Therapy
A key component in reducing attrition rates in oncology drug development, and in making personalized medicine a reality, is discovering and validating gene signatures that are predictive of response and that will enable significant improvement in selecting patients who could benefit from a particular treatment regimen.
CrownBio has developed a proprietary state of the art genetic signature discovery and validation platform, HuSignature, which is changing the way we identify the right patients for the right treatment, allowing our clients to identify patients with higher probability of responding to, or not responding to, a given drug treatment in a prospective clinical trial.
The HuSignature platform (of either an evidence-based or hypothesis-free approach) is being used to generate and/or test hypotheses for our clients through analyzing their HuTrial™ (mouse clinical trial) results. The identification of a HuSignature which defines responders and non-responders allows the selection of appropriate models to accelerate the understanding of likely success of your candidate in the clinic.
PDX Population Studies - Mouse Clinical Trials
Preclinical population studies help stratify patients for clinical trials, identifying responders, partial, and non-responders before you enter the clinic.
CrownBio provides a preclinical Translational Oncology Technology Platform based around our highly predictive PDX models. Our clients use these well-characterized and genomically annotated models in HuTrials (mouse clinical trials) to identify and understand which patients will benefit from their treatment before they enter the clinic.
Within a HuTrial, each PDX subject reflects the pathology of its original patient (behaving as a patient avatar), with the cohort of patient avatars representing a diversity of the human patient population. The main functional utilities of HuTrials include:
Drug positioning or repositioning – identification of responders in a given indication, thereby facilitating a
“go or no-go” decision
Screening for lead candidates
Facilitating human trial design
Identifying optimal partner drugs for combination
Discovery and/or validation of genetic signatures predictive of response (HuSignature™) and predictive
biomarkers (HuMark™), therefore generating hypotheses for clinical testing.
1:1 Mouse Trial
HuScreen+ is the first commercial in vivo screening platform to utilize a 1:1 study design to evaluate drug response using an extensive, well-characterized, clinically relevant patient-derived xenograft (PDX) collection. This exclusive 1:1 study design provides highly reproducible results, and clinically translatable data, to inform on targeted agent and combination therapy treatment approaches in a cost effective manner across a selection of different tumor types.
Highlights of HuScreen+
Fast and efficient in vivo screening platform
Under 6-month turnaround time, utilizing live PDX models with proven robust growth
Reliable 1:1 study design enabling a cost effective way to screen many tumor types
Wide spectrum of tumor types with unique mutations, genetic features, and drug responses
Biomarker of Response Identification
As part of our Translational Oncology program, CrownBio has developed the HuMark Translational Platform to understand the relationships between:
Genes
Protein expression
Molecular interactions
And activity
that define the fundamental components of a predictive biomarker, and help clients to explain the mechanism of action of, and profile resistance mechanisms to, their particular treatment regimen.
Our platform leverages data from PDX population studies to identify biomarkers of response, improving clients understanding of their compound target population, and allowing the selection of appropriate models to accelerate their candidate success in the clinic.
Biomarkers are identified from HuTrial results via a range of techniques including:
Whole genome profiling and data analysis
Next generation genome sequencing
Mutation analysis bioinformatics
In vitro and in vivo PD marker identification
Biomarker assay development and validation
Quantitative western blot, FACS analysis
Immunohistochemistry
DNA sequencing
1:1 Mouse Trial
HuScreen+ is the first commercial in vivo screening platform to utilize a 1:1 study design to evaluate drug response using an extensive, well-characterized, clinically relevant patient-derived xenograft (PDX) collection. This exclusive 1:1 study design provides highly reproducible results, and clinically translatable data, to inform on targeted agent and combination therapy treatment approaches in a cost effective manner across a selection of different tumor types.
Highlights of HuScreen+
Fast and efficient in vivo screening platform
Under 6-month turnaround time, utilizing live PDX models with proven robust growth
Reliable 1:1 study design enabling a cost effective way to screen many tumor types
Wide spectrum of tumor types with unique mutations, genetic features, and drug responses
In Vivo/Ex Vivo Target Validation
Thanks to our unique collection of validated and well-characterized Cell Line Derived Xenograft tumor models, human primary cancer cells (PrimePanel™), and patient tumor samples we can correlate in vitro preclinical findings with in vivo data, which can be translated to clinical patient outcomes.
The effect of interfering with a gene function can be evaluated in vivo using tumors grown in mice as xenografts or ex vivo using tumor tissue or tumor derived cell suspensions. The activity of your targeted agent on tumor growth can be measured directly and target-specific biomarkers can be investigated using our unique models.
Target Protein Knockdown and Overexpression
We provide a variety of assays, including western blot analysis, flow cytometry, immunohistochemistry, and immunofluorescence to determine knockdown or overexpression of the target protein of choice.
Gene Cloning and Stable Transfection
De novo or enhanced expression of genes in mammalian cells can be achieved through molecular cloning, with genes of interest cloned and overexpressed in the cells of choice for target validation.
We utilize a variety of expression systems (both plasmid- and lentiviral-based) to deliver constitutive or inducible high level expression of wild type and mutated genes (e.g. constitutively active or kinase dead mutants).
Following establishment of stable recombinant cell lines, downstream effects of gene overexpression can be monitored through in vitro or in vivo assays.
The specific knockdown of a gene of interest by RNA interference (RNAi) is a powerful tool for target discovery or validation. Gene knockdown is achieved through the use of small interfering RNAs (siRNAs) for transient downregulation of the gene of interest in the cell line.
We have expertise using a wide variety of lipid-based transfection reagents to deliver siRNAs to the cells of interest. Our robust systems and processes ensure that expression of the target gene of choice and the protein it encodes is significantly reduced.
High-Throughput Physicochemical Property Determination
Evaluate your compound's physicochemical properties with our comprehensive services:
• Aqueous solubility in PBS buffer
• Aqueous solubility in bio-relevant media (FaSSIF)
• Chemical stability
• Plasma and whole blood stability
• Compound concentration, homogeneity, and stability in different formulations (dose formulation analysis)
• Lipophilicity (logD7.4 distribution coefficients)
We provide a comprehensive range of capabilities to support fully integrated drug discovery collaboration or standalone service for your internal projects.
Tumor Microarray including Custom TMAs
We offer ready to use TMA slides from a range of CrownBio models for Biomarker Screening and Model Selection. TMAs are available from patient-derived xenograft (PDX) models, conventional "cell line derived" xenograft models, syngeneic models and murine allograft models. We can also build custom TMA based on request.
Product Details:
Custom TMAs from PDX and cancer cell lines:
Single tissue or TMA slides
Approximately 2,500 validated PDX tumor models from a wide range of cancer types
Around 200 Cell Line Derived Xenograft models
Custom made TMAs to fit your specifications
Fast turnaround, results ready in 3-4 weeks
Flexible pricing (based on configuration, minimum 5 slides)
Model information accessible via CrownBio curated online databases:
PDX-Derived Cell Lines in 2D or 3D Functional In Vitro Assays
Primary tumor cells derived from patient tissue and grown in short-term culture can generate high-fidelity data for translating in vitro findings to in vivo models and ultimately to clinical settings. This provides more refined data sets compared to immortalized cells (which can drift significantly from the original patient disease) or tissue banks.
From our extensive portfolio of 2,500 Patient-Derived Xenograft (PDX) models CrownBio has successfully derived PrimePanel a unique collection of disease relevant cell lines from various cancer types, which our clients regularly use for rapid screening of their drug discovery/development programs.
Our cell lines are all early passage (<10) and maintain essential histopathological features and genetic profiles of the original patient tumors including genomic mutational status, biochemical signaling, and response to tumor cell autonomously targeted therapeutics.
Used in 2D or 3D functional in vitro assays:
High throughput cytotoxicity screening
In vitro drug combination studies
Adhesion, migration, and invasion assays
Colony forming cell (CFC) assays
Soft agar colony formation
3D Tumor Growth Assays (3D TGA)
To provide rapid information on the cytotoxicity and chemotherapeutic potential of your agent early in the drug development process, we have developed a cost effective approach to rapid screening, taking your lead compound to validated candidate.
OmniScreen is CrownBio’s global program for large-scale screening of client compounds against our proprietary collections of cancer cell lines, allowing you to:
Utilize multiple screening platforms including IncuCyte® ZOOM (real time) and Acumen eX3 (multiparameter)
Schedule any subpanel of 50 or more cell lines, with a screening run every 3 months
Select from quality cells STR verified and mycoplasma-proofed
Choose the models that best fit your needs with XenoBase® our curated, online database of cancer cell
lines
Customize your study thanks to out flexible template designs
Quality control your data against standard of care agents
Obtain bioinformatics support throughout the study
Review your data in real time using a secure online client account
Our OmniScreen cancer cell line panels include:
OmniPanel™, a genomically diverse and growing collection of more than 400 cancer cell lines for drug
response screening
XenoSelect™, a diverse oncogenic in vitro screening panel of almost 160 well validated cell lines with
corresponding xenograft models ready for in vivo efficacy studies
RNAseq Panel, more than 120 in-house genomically characterized cell lines to correlate mutation status,
copy number variation, and expression levels with drug response.
Novel Immuno-Oncology Target Identification
Immuno-oncology is a fast paced field, and the identification and validation of novel targets is vital to new agent development.
At CrownBio we are constantly enhancing our in vitro immuno-oncology platforms, and now provide a variety of assays to evaluate your IDO and TDO inhibitor effects on human and murine cancer cell proliferation in vitro, including validated tryptophan catabolism assays.
IDO/TDO, as tryptophan catabolizing enzymes, are overexpressed on tumor cells, and have been shown to assist cancer cells in immune evasion, providing key enzymes for targeting with immunotherapeutic inhibitors.
NK Mediated Cell Killing Flow Cytometry Based Assay
CrownBio has developed an NK mediated cell killing assay using flow cytometry analysis for cytotoxicity. Our assay is based on target cell labeling with CFSE and subsequent DNA-labeling with PI for identification of target cells with compromised cell membranes, which provides a measure of cytotoxicity of novel agents.
T Cell Killing - Lactate Dehydrogenase Assay
T cell mediated cell death can be indirectly measured through the release of lactate dehydrogenase (LDH) by cells enduring membrane damage. We have validated our T cell killing LDH assay to evaluate both single agent and combination regimens, combining T cells isolated from human PBMCs with target tumor cells .
In Vitro Immuno-Oncology Antigen Presentation and Immune System Activation Assays
CrownBio offers a variety of assays for measuring the immunogenicity of experimental proteins and peptides in vitro. Our assays are customized to target immune cells, including T and B cells, natural killer cells, macrophages, and dendritic cells, as well as tumor cells.
T Cell Targets and Activation
T cell proliferation
Recalled T cell function assay
Target expression profiling on cell subsets (resting and activated)
Screening assays for enhanced proliferation and survival (MLR, antigen driven systems)
Screening for the ability to reverse T cell exhaustion
Suppression of Treg function
Modulation of differentiation and cytokine profile
Immune cell migration assay
Macrophages and Dendritic Cell Targets
Target expression profiling on subsets (resting vs activated)
Screening for modulation of M1/M2/MDSC (e.g. differentiation)
Screening for modulation of tumor conditional response (phenotype and cytokine/chemokine production)
Effects on antigen presentation
NK Cell Targets
Target expression on NK cells
Modulation of activation and killing
B Cell Targets
Target expression profiling on B cell subsets (resting and activated)
Modulation of antibody production
Modulation of antigen presenting cell function and cytokine release
Tumor Targets
Target expression profiling on subsets
Effects on antigen presentation/killing assays
Modulation of checkpoint ligand expression
Modulation of tumor derived immune modulating factors (e.g.eicosanoids, chemokines, cytokines)
Direct cytotoxicity
In Vitro Immunophenotyping and Cell Profiling
CrownBio’s core in vitro immuno-oncology immunophenotyping and cell profiling platform provides a comprehensive range of assays:
FACS and IHC for immuno-oncology agent characterization
Immune cell purification for subset enrichment
Cytokine profiling – Luminex assay, ELISA/ELISPOT to quantify the frequency of cytokine-producing cells
T cell receptor sequencing for biomarker ID and diagnostic development
Cell proliferation assays with isolated immune cells to evaluate your compound’s cytotoxic potential
Optical Imaging Platform
Bioluminescent Human Tumor Xenografts and Syngeneic Models
CrownBio provides clinically relevant optical imaging models enabling in-life visualization of tumor growth and disease progression:
• Delivering efficient and informative efficacy evaluation for different cancer stages, through in vivo
imaging of:
o orthotopic models to mimic primary lesions
o spontaneous metastasis models to evaluate dissemination and disease progression
o experimental metastasis models to replicate late stage disease
o systemic models to replicate hematological disease.
• Imaging of a range of cancer types, including xenografts in immunodeficient mice and syngeneic
models in immunocompetent mice.
• Evaluation of multiple mice simultaneously using the highly sensitive in vivo imaging system IVIS®
Spectrum CT.
• Generation of high quality 2D and 3D quantitative bioluminescence and fluorescence representations
(400–840nm) with fast and low dose CT imaging.
• Available techniques include 3D diffuse tomography, including Fluorescent Imaging Tomography
(FLIT) and Diffuse Luminescence Imaging Tomography (DLIT).
• Bespoke bioluminescent model development available for unique cell lines.
Translational Xenograft Platforms Available for CAR-T Cell Immunotherapy Evaluation, including Patient-Derived Xenografts (PDX) or CD19 targeting with conventional human tumor xenografts
• PDX - 2,500 well-characterized models providing a wide range of CAR-T therapy targets
• Quickly and easily find models overexpressing your antigen of interest from our curated online model
characterization database (HuBase™) and search engine OncoExpress™
• Model expression validation via IHC, confirming antigen expression
• Efficacy testing in highly predictive models, which truly mimic human disease and response
• Completed case studies for solid tumors e.g. targeting GPC3 in lung cancer, and MSLN in pancreatic
cancer.
• Conventional xenograft models for CD19 targeting
• Raji human Burkitt lymphoma cell line derived xenograft model
• CD19 positive
• Highly sensitive to CAR-T CD19 targeting
• Shows validated model survival following CAR-CD19 T cell therapy
• Available immediately for in vivo efficacy studies.
Evaluate Immunotherapeutics with Humanized, Highly Predictive Hematopoietic Stem Cell PDX models
• 2,500 HuPrime® Patient-Derived Xenograft (PDX) models in mice reconstituted with a human
hematopoietic system through engraftment of human cord blood CD34+ cells.
• PDX models preserve the heterogenous pathological and genetic characteristics of the original patient
tumors, providing models highly predictive of patient response.
• Combine our PDX models with humanized CD34+ NSG mice (HuNSG) from The Jackson Laboratory for a range of HSC-PDX evaluations. Our expertise includes:
• Evaluation of combination therapies of an immunotherapy plus a targeted agent where the size and
diversity of our PDX collection ensures relevant models with suitable genetic profiles for testing a wide
range of combinations
• Evaluation of combination immunotherapies where the HSC-PDX platform can be used when there are
not mouse surrogates for both therapies, or when clients require supression of the macrophage
population in the myeloid compartment to sensitize for T cell modulation
• Novel target validation and evaluation
• Population studies in an immune-reconstituted setting allowing us to leverage the HSC donor diversity
found in these models, and to perform translational population studies that mirror the diversity of both the
tumors (made possible due to the model diversity found within our PDX collection) and immune systems
found in the clinic.
Drug Target and Ligand Humanized Models
HuCELL™ Humanized Ligand Model
HuCELL™ platform to evaluate human-specific immuno-oncology agents in vivo, against humanized ligands within a fully functional murine immune system
• Syngeneic mouse tumor models engineered to express humanized ligands
o M38 model available expressing human PD-L1
• Models under development for a range of other I/O targets
• Drug target humanized platform to evaluate human specific biological therapies in vivo
• Can be combined with HuGEMM platform of humanized drug targets (e.g. PD-1)
HuGEMM™ Drug Target Humanized Model
HuGEMM™ platform to evaluate human-specific immuno-oncology agents in vivo, against humanized drug targets within a fully functional murine immune system
• Mice with fully functional murine immune system with murine proteins (the drug target) directly replaced
with their human counterpart e.g. human PD-1, CTLA-4 to replace mouse PD-1, CTLA-4
• Range of validated models available:
o PD-1, CTLA-4, CD137, TIM3, and OX40
o Homozygotes available for PD-L1, LAG3, GITR, CD40, and double knock-ins
• Models under development for a range of other I/O targets
• Drug target humanized platform to evaluate human specific biological therapies in vivo
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