We are interested in establishing alliances to develop and access:

• 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
• 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
  • Alternative methodologies to analytical reagent generation, characterization and modification
    • Methods & reagents for high specificity ligand binding and affinity capture LCMS
• Disposition of Antibody-Drug Conjugates
  • Cellular and systemic fate of the conjugate and components
  • Quantification and prediction of pharmacokinetics
  • Biodistribution of large molecules (drug and target) at whole organ and cellular level
    • Catabolism of large molecules (drug and target) at tissue level
• 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
• 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
• 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
• 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
• 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
• 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