Determining Target Occupancy using LC-MS: Advantages and Application to a Preclinical Drug Discovery Paradigm

Drug Discovery and Development, Laboratory Technology, Life Sciences, Pharmaceutical, Preclinical,
  • Thursday, June 28, 2012

There is an increasing need for integrated target/physiology based preclinical drug discovery approaches that allow for conclusive evidence of target engagement and subsequent effects on in vivo efficacy and toxicology. One approach has been to use target site occupancy assays to understand the optimal dosing regimen to achieve a desired therapeutic effect and minimize side effects. Traditionally, these target site occupancy assays have relied on the use of radioisotoically labeled tracers, detected by positron emission tomography (PET), single photon emission computer tomography (SPECT) or liquid scintillation spectroscopy, to drive the analysis of structure-activity-relationship within a drug-discovery effort. Although this approach has proven to be very useful and can provide conclusive evidence of target engagement, it can often be very expensive and not allow for the degree of throughput that is often required in early preclinical discovery efforts.

An alternative to PET/SPECT for detection and quantification of radiolabeled tracer ligands has been to use liquid chromatography combined with mass spectrometry (LC/MS), which offers a variety of advantages, such as the ability to monitor multiple tracer ligands in the same animal—allowing for simultaneous quantification of target occupancy at multiple targets in the same subject. Also, since novel tracer discovery can often be an iterative and lengthy process, the use of LC-MS can dramatically increase throughput for tracer screening by eliminating the requirement of adding a radiolabel to every potential tracer candidate for PET/SPECT detection or liquid spectral scintillation counting.

Covance has expertise in using LC-MS to design and conduct preclinical in vivo target occupancy assays that provide a quantitative measure of the interaction of a test article or drug candidate with its intended target, be it a receptor, ion channel, transporter, enzyme or other target. Covance not only has the ability to use the “cold”-based tracer molecules to rapidly confirm target engagement, but can also help to correlate target occupancy to behavioral efficacy and safety of test molecules. Covance currently has a large and growing list of in vivo occupancy assays–mostly assessing central targets. They are also capable of conducting tracer discovery studies to validate novel tracers at both central and peripheral targets. Moreover, they have experience applying the LC-MS-based target occupancy approach to both normal (e.g., brain) and pathological (e.g., tumor xenograft) tissues.

This webinar will discuss the Covance LC-MS based in vivo target occupancy capabilities and discuss the advantages of using this approach in a preclinical drug discovery arena.



Patrick L. Love, B.S., Staff Scientist and Supervisor, Receptor Occupancy/In Vivo Pharmacology, Discovery and Translational Services, Covance

Patrick Love leads the receptor occupancy laboratory within the In Vivo Pharmacology Department at the Covance facility in Greenfield, Indiana. Mr. Love has 13 years of drug development experience including roles as an Associate Senior Biologist with Eli Lilly & Company within the Discovery Neuroscience and In Vivo Pharmacology Departments. In his current role, Mr. Love provides consultation to clients on experimental strategies, data analysis and results interpretation for in vivo and ex vivo receptor target occupancy assays.

Areas of expertise include: development and optimization of target tracers for targeting, monitoring, and/or treating CNS disease, the use of LC-MS/MS-based in vivo receptor occupancy/binding assays to assess binding of putative drug molecules at central and/or peripheral G protein coupled receptors, neurotransmitter transporters, enzymes and ligand-gated ion channels, the use in vivo receptor occupancy/binding assays to determine correlations between pre-clinical behavioral efficacy and/or therapeutic efficacy in humans.

Prior to leading the receptor occupancy laboratory at Covance, Mr. Love worked as an Associate Senior Biologist with Eli Lilly and Company where his primary focus was development of various models of learning/memory, psychosis, pain and anxiety. A central part of this role was to help various discovery efforts understand correlations between the behavioral efficacy/safety data and target engagement.

Additional responsibilities have included: HPLC-Mass Spectroscopy for small molecule bioanalysis, development of many LC-MS based in vivo receptor occupancy assays at single or multiple targets, development of CNS biomarker assays to determine target engagement and subsequent downstream pharmacodynamic effects of drug molecules.

Message Presenter

Sally Old, Ph.D., Site Leader, Alnwick, Covance

Dr. Sally Old is the Site Leader at the Alnwick facility. She is responsible for all scientific operations and facilities and has overall accountability for the site. Prior to becoming Site Leader, she had overall responsibility for project activities and non-clinical toxicology studies conducted at Alnwick. She represents the Company on several external committees and working parties. During her 22 years within pharmaceutical research, Dr. Old has developed experience of many aspects of Drug Development, both strategically and scientifically, with a particular emphasis on Regulatory Toxicology. Dr. Old has excellent people skills and extensive leadership experience, leading increasingly larger teams over the past 15 years, at a local and international level.

Dr. Old joined Covance Laboratories in 2010 as part of the transfer of the ex-sanofi sites of Alnwick and Porcheville.

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John Batchelor, M.Sc., Head of Toxicology, Alnwick, Covance

John Batchelor is the Project Licence Holder and Head of Toxicology at Alnwick. He has 25 years experience of non-clinical safety assessment in pharmaceutical R&D, including 12 years as a Study Director and Drug Safety Evaluation Project Team Member (Toxicology and Safety Pharmacology). He was previously the laboratory manager for clinical pathology at Alnwick and has several publications in toxicology journals relating to this area of expertise. In addition to serving as chairman of the Association for Comparative Clinical Pathology for several years, he represented the UK on the joint international task force for harmonisation of clinical pathology testing on non-clinical toxicity studies.

Since completing a phased transfer into general toxicology in 2001, Mr. Batchelor has studied for and been awarded an MSc in Applied Toxicology (with distinction) and has continued to develop experience in strategic and scientific aspects of drug development. As a project team member, Mr. Batchelor had responsibility for molecules from several different therapeutic areas including CNS, covering all stages of development (from entry into development up to phase III), dossier (CTA) preparation and meetings with regulatory agencies. Additional responsibilities have also included; co-ordination of non-clinical development plans (Toxicology, Safety Pharmacology, MPK and PDS activities) to support first in human studies, and in-licensing (due diligence) activities.

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Who Should Attend?

Drug development scientists and decision makers with a focus on early development/discovery phase

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Covance, with headquarters in Princeton, New Jersey, is one of the world’s largest and most comprehensive drug development services companies, with annual revenues greater than $2 billion and more than 11,000 employees in more than 60 countries. Covance has the people, processes, client service, and global resource capabilities to respond to biotechnology and pharmaceutical clients’ toughest drug development challenges.

Covance Discovery and Translational Services more effectively and efficiently bridges research gaps by providing integrated solutions throughout preclinical and clinical phases of development. Only Covance drives innovative pipeline development by integrating custom immunology services with early non-clinical safety, efficacy and Discovery services, Biomarkers, Genomics and antibody products.

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