We are interested in establishing alliances to develop and access:
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Translational research – large and small molecule efforts
- Translational modeling and simulation approaches, systems pharmacology/PK-PD, integrated with quantitative biomeasures; deeper knowledge of targets and pathways; and increased confidence in target and drug selection
- Systems models of specific areas of toxicity, e.g., cardiovascular toxicity and application of PKPD to safety biomarker technologies increasing confidence in safety
- Understanding and de-risking the influence of hepatic and renal uptake and clearance on toxicology in these organs – focus on disorders of bile production and bile acid transport
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Quantitative Bioanalytics, Biomarkers, Biomeasures, and Immunogenicity (ADA) Assays
- Novel LC-MS/MS large molecule bioanalysis and automation techniques
- Stable isotope labelled pulse chase studies with LC-MS/MS for measurement of target turnover
- Flow cytometry, cellular imaging techniques (Amnis) for biomarkers and biomeasures , and highly multiparametric single cell analysis using mass cytometry (CyTOF)
- Development of a universal platform for cell-based neutralizing antibody assays
- Biocomparability: identification of critical attributes influencing PK and disposition
- Targeted and untargeted metabolomics and fluxomics
- Biotherapeutics bioanalytical capabilities across various modalities
- Next-generation of advanced intelligent high-throughput automation platforms for bioanalysis
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Alternative methodologies to analytical reagent generation, characterization and modification
- Methods & reagents for high specificity ligand binding and affinity capture LCMS
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Disposition of Antibody-Drug Conjugates
- Cellular and systemic fate of the conjugate and components
- Quantification and prediction of pharmacokinetics
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Biodistribution of large molecules (drug and target) at whole organ and cellular level
- Catabolism of large molecules (drug and target) at tissue level
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Disposition and delivery of therapies – large and small molecule efforts
- Novel commercially viable delivery technologies (oral and non-oral)
- Predictive tools and technologies targeting oral absorption and disposition of peptides
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Targeting, prediction and modeling of transporter-mediated disposition and DDIs – small molecules
- Quantitation and scaling of transporters for input into physiological PK models of tissue penetration and clearance
- Determination of intracellular unbound concentrations of transported drugs
- Prediction and quantification of human transport mediated (e.g., biliary) clearance
- Novel approaches to achieving selective tissue distribution
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Immunogenicity prediction – large molecules
- In silico immune epitope prediction
- In vitro drug-specific immune response (e.g., PBL stimulation; whole protein & epitope mapping; DC-T cell assays, Bcell response assays)
- Ex vivo immune response and immune tolerance biomarkers
- Models for predicting immunogenicity impact of product and treatment-related risk factors
- ADA Clinical relevance predictors to include: ADA affinity measures and prediction of adverse events, e.g., infusion reactions
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Physiologically relevant in vitro assays
- Methods for expanding cell numbers or stabilizing phenotypes of directly isolated primary cells (particularly from patients)
- Robust, reliable in vitro differentiation protocols from human pluripotent stem cells for difficult to obtain cell types
- Non-natural amino acid substitutions in target proteins to create novel screening readouts
- Advances in human genome editing technologies for greater speed and efficiency and reduction of off-target effects
- Advances in High Content Analysis cell based assays
- Endogenous gene reporter and genetically encoded biosensor models in human primary cells and stem cells
- Detection of tagged-protein at physiologically relevant concentrations in human cell based assays
- Visualization of drug interaction with targeted- protein within the cellular environment
- Quantification of cellular environment changes by biosensors
- Advances in 3D culture systems and high content analysis for metabolism, safety, distribution and pharmacology
- Visualization of drug interaction with targeted-protein within the cellular environment
- Quantification of cellular environment changes by biosensors
- Advances in high content analysis in 3D culture system
- Novel expression approaches for functional expression of difficult gene families e.g., solute transporters
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In vitro Phenotypic Screening:
- o Novel deconvolution advances for in vitro phenotypic screening
- o Prediction of in vitro cellular phenotypic changes due to patient-derived single point mutation and genetic defects
- o Quantification of electro-physiologic measurement in plate cell based assays
- o Advances in single cell mass cytometry technology for phenotypic screening
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Optimizing Human ADME Properties and PK Prediction Capabilities
- Novel technologies to enhance SAR for ADME properties utilizing chemical library, high- throughput in vitro assays coupled to LC-MS detection and computational models
- Full complement of drug metabolism assays, including biotransformation and induction capabilities
- Ability to conduct a suite of nonclinical studies to develop robust human PK prediction for routine and less common elimination pathways (AO, UGT, GST etc.,)
- Integration in vitro and in silico PK data and mechanisms into PB-PK models to predict human plasma-time profiles for small and large molecules
- Selection and deselection of monoclonal antibody drug candidates based on PK properties that are predictive of human PK by using a characterized human FcRn transgenic mouse model and allometric scaling
- o Prediction of routine and complex DDI involving CYPs and transporters