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7:45am Continental Breakfast in the Exhibit Hall
8:30 Chairperson’s Remarks
Igor A. Kaltashov, Ph.D., Associate Professor, Department of Chemistry, University of Massachusetts, Amherst
8:35 Affinity, Avidity and Assay Limits - What is My Assay Measuring?
Eric Day, M.B.A., Scientist II, Biogen Idec, Inc.
Affinity is a measure of the binding strength between ligand and receptor. It has a precise mathematical definition and with the appropriate tools can be measured directly or indirectly. As such, affinity provides a rigorous parameter to monitor the development of protein therapeutic candidates, for example in antibody humanization. Avidity arises when measuring multivalent or multicomponent binding events. It is not, however, precisely mathematically defined. It is a parameter that depends not only on the intrinsic affinity of the interaction of interest but also on the system in which the interaction is measured. In complex systems, the avidity and affinity components of the observed binding cannot be separated. The limits of an assay are quickly reached in highly avid systems, such that the measurement no longer reflects the strength of an interaction but becomes a simple titration of the number of binding sites available. Examples of monovalent, multivalent and multicomponent receptor-ligand binding systems will be used to demonstrate the information that can and cannot be obtained from a particular assay design. Common techniques such as SPR (Biacore), FACS and ELISA will be discussed.
9:05 Design of Experiments: Case Studies from a Bioanalytical Lab
Franklin Spriggs, Ph.D., Scientist, PDM, Pfizer Global R&D Groton Labs
This presentation and discussion will provide a general introduction to DOE, briefly examine the different kinds of designs available, and finally review a few cases demonstrating the utility and limitations of DOE in a bioanalytical method development.
9:35 Utility of the Gyros Gyrolab in Research and DMPK – An Automated Ligand Binding Assay Platform
Kevin Brady, Ph.D., Senior Principal Scientist, Pharmacokinetics, Dynamics, and Metabolism Division, Pfizer Global R&D
10:05 Coffee Break, Poster and Exhibit Viewing
11:05 Free vs. Total Ligand Binding Assays: Points to Consider in Drug Development
Jihong Yang, Ph.D., Scientist, Bioanalytical Research & Development, Genentech, Inc.
Pharmacokinetic (PK) assays have long been used as an indispensible method to quantify recombinant biotherapeutic IgG exposure in vivo. Need for a “Free” or “Total” PK assay depends on many factors. This talk will give case studies on both “free” and “total” PK assays and the impact on the PK analysis.
11:35 Free and Total Immunoassays for Monoclonal Antibodies to Soluble Targets and Target as Biomarker
Lindsay King, Ph.D., Senior Principal Scientist, PDM Regulated Biotherapeutics, Pfizer, Inc.
Biotherapeutic monoclonal antibodies to soluble targets have the potential to exist in vivo in three forms because each antibody molecule has two binding sites; unbound (free), partially bound and totally bound to target. Soluble targets can also exist in unbound from (free) and bound form, both to drug and to endogenous proteins. Thus, it is important during assay development to understand what forms of analyte exist and would need to be measured to support a specific program. There are a number of different immunoassays formats available but defining what form of analyte any given assay measures also requires experimental data to describe the degree of interference that each analyte exerts on the quantification of the other. Specific total or free assays can be very challenging to develop and the use of multiple assays when one is sufficient can be costly and may not provide useful additional information. However, selection of the wrong assay may result in the generation of PK or PD data that underestimates or overestimates the concentration of the form of drug/target the assay was intended to measure. This talk will discuss assay development of free and total monoclonal drug and soluble target assays in the context of a number of case studies.
12:05pm Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own
1:25 Chairperson’s Remarks
Robin Barbour, Director, Antibody Technology, Elan Pharmaceuticals
1:30 The Mesothelin-CA125/MUC16 Interaction
Mitchell Ho, Ph.D., Head, Antibody Therapy Unit, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health (NIH)
Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. We identified a region at the N-terminal of cell surface mesothelin required and sufficient for its binding to CA125. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.
2:00 Hyaluronan: The Glue that Holds a Tumor Together
Curtis Thompson, Ph.D., Director, Pharmacology, Halozyme Therapeutics, Inc.
Halozyme Therapeutics is developing a novel enzyme therapeutic (PEGPH20) in Phase I clinical trials. The enzyme degrades hyaluronan, the principal ligand for CD44, a tumor stem cell marker. By disrupting the tumor matrix, PEGPH20 depletes both matrix and growth factor support of progressing malignancies.
2:30 Networking Refreshment Break
3:00 Immunogenicity: Regulatory and Technical Overview with Case Studies of Assay Challenges
Eric Wakshull, Ph.D., Senior Scientist & Group Leader, Bioanalytical Research & Development Department, Genentech, Inc.
The assessment of anti-protein therapeutic immunogenic responses is an essential component of drug safety evaluation during both the preclinical and clinical development phases. This presentation will briefly describe the regulatory landscape regarding immunogenicity assessment, touching briefly on the various white papers and regulatory guidances now available. An introduction to the methodological approaches commonly used to measure anti-protein therapeutic antibodies will be provided and some cases studies on the most common assay interference issues and their possible solutions will also be discussed.
3:30 Determination of the Mechanism of Action of an Antibody using Orthogonal Approaches
Victor H. Obungu, Ph.D., Senior Research Scientist, Biotechnology Discovery Research, Eli Lilly and Company
A neutralizing anti FasL antibody for potential therapeutic applications was generated. In order to determine its mechanism of action, several complimentary approaches were used to determine its epitope. These studies revealed the epitope and gave an understanding of the mechanism of neutralizing activity for this antibody.
4:00 The Impact of Shed Target Antigen on the Quantitation of Therapeutic mAb and its Pharmacokinetics Implication
Bing Kuang, Ph.D., Principal Scientist, Pharmacokinetics, Pharmacodynamics, and Metabolism, Pfizer, Inc.
Many therapeutic monoclonal antibodies are designed to target membrane-bound cell surface targets. The membrane-bound proteins, however, may shed their extracellular domain through limited proteolysis. The shed or circulating target antigen in serum would compete with binding of the therapeutic mAb and affect its pharmacokinetic evaluation. Quantifying and distinguish the levels of free and bound form of mAb is therefore important to the characterization of the pharmacokinetics and pharmacodynamics of therapeutic antibody.
4:30 End of Conference
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