National Biotechnology Conference 2009 Preliminary Program - (Page 5) CONFERENCE PROGRAM - MONDAY 1:00 pm - 3:30 pm 1:00 pm - 3:30 pm 3:30 pm - 5:00 pm Free (Specific) and Total Drug-drug Interactions (Generic) Immunoassay in of Therapeutic Proteins Biotherapeutic Development SYMPOSIUM SYMPOSIUM Process Analytical Chemistry for Manufacturing Therapeutic Proteins SYMPOSIUM The determination of circulatory drug levels is an integral part of pharmaceutical development for the assessment of pharmacokinetic, pharmacodynamic and safety profiles of the drugs. For macromolecules and for antibodies in particular, the determinations which give direct (specific or free) measurement relating to the idiotypic (active) region is most desired. However, in the early development stages generation of critical relevant reagents to establish such specific assays are challenging and may not be available. To move the process along in a timely manner, generic assays, also referred to as total assays based on common sections of a monoclonal antibody such as the FC/LC regions or a class of proteins have been explored, developed and used. Currently, there is no guidance on the use of such assays. This symposium will explore the pros and cons of specific and generic assays, give insight into what is being measured by each assay format, what types of conclusions can be drawn from the results from these assays and what stage of drug development are the assays applicable and finally give further recommendations of their use. Moderators Ago Ahene, M.S., Ph.D. Roche Valerie Quarmby, Ph.D. Genentech Therapeutic proteins such as monoclonal antibodies are increasingly being combined with small molecules and/or with other therapeutic proteins. However, little is known about the drug-drug interaction (DDI) risk for such combinations with respect to shared pathways of clearance (PK DDI potential) and/or shared mechanism of action (PD DDI potential). Moreover, based on our current knowledge of DDI with therapeutic proteins and clinical relevance of such interactions, is there a need to place an equal emphasis on assessment PK and PD DDI potential? The need for a broader understanding of clearance mechanisms for proteins for DDI risk assessment; lack of specific guidance for DDIs with large molecules. This symposium will review the current state of knowledge on the potential for DDI with therapeutic proteins and present case studies, focus on quantitative pharmacological methods and strategies to discern DDI potential of therapeutic proteins during clinical development and provide a risk-based approach to assessing potential for DDI. Moderators Sandhya R. Girish, M.Pharm, Ph.D. Genentech Frank-Peter Theil, Pharm.D., Ph.D. Genentech What Does a “Total” Ligand Binding Assay Measure? The Challenges from Target Binding Proteins and Biotransformation Jean Lee, Ph.D. Amgen, Inc. Monoclonal Antibody Clinical Development: A Science-driven Risk-based Approach to Assessing Potential for Clinical DDI Strategy Sandhya R. Girish, Ph.D. Genentech DDI Study Designs and Logistic Constraints in Immunology Setting Honghui Zhou, Ph.D. Centocor, Inc. The physiochemical properties (e.g., tertiary structure and reactivity) of a therapeutic protein are chiefly determined by its amino acid sequence and post-translational modifications (PTM) thereof. Consequently, sequence, PTM and molecular formula-specific peptide mapping in the laboratory has become the most important post-manufacturing analytical method for identity testing and process monitoring. For peptide mapping of monoclonal antibodies (mAbs), disulfide bonds are reduced to separate the heavy and light chains prior to cleavage by exogenous sequence-specific protease(s) and ionization of the resulting peptide products. Next, the mass-to-charge ratio (m/z) of peptide ions are measured by mass spectrometry (MS) and compared to that of ions predicted by in silico cleavage by protease(s). Observation of close matches between the observed and predicted m/z values for these ions enables one to assign amino acid sequences, PTMs (e.g., glycosylation) and molecular formulas to the peptides in question. Likewise, observation of peptides spanning the N- toC-terminus of the mAb (i.e., high sequence coverage) enables one to assign the amino acid sequence, PTMs, and molecular formula to the mAb in question. To support peptide mapping results, liquid chromatography (LC)/MS is employed to determine the mass distribution of the intact mAb and its heavy and light chain reduced forms. While much has been learned from laboratory-based peptide mapping and LC/MS, quality by design (QbD) initiatives and online measurement and control process analytical chemistry (PAT) require novel process analytical chemistry (PAC) devices and algorithms. Moderator William E. Haskins, Ph.D. University of Texas at San Antonio Use of Free (Specific) and Total (Generic) Immunoassay in Biotherapeutic Development Ago Ahene, M.S., Ph.D. Roche DDI-Informative Study Design and Logistic Constraints in Oncology Setting Yu-Nien (Tom) Sun, Ph.D. Amgen, Inc. Case Studies: “Free” vs. “Total” Ligand Binding PK Assays to Support Monoclonal Antibodytherapeutic Development Jihong Yang, Ph.D. Genentech What Can the Biopharmaceutical Industry Learn from the Use of QbD in Small Molecule Production? Mel Koch, Ph.D. University of Washington Regulatory Perspective on Drug-drug Interaction Strategy for Protein Biotherapeutics Jang-Ik Lee, Ph.D., Pharm.D. (Invited) U.S. Food and Drug Administration Characterization of Monoclonal Antibody Glycosylation by CE/MS Lynn Gennaro, Ph.D. Genentech Relevance and Issues of the Measurement of Free/Bound/ Total Drug Martin Ullman, Ph.D. Amgen, Inc. DDI Strategy for Therapeutic Proteins: Case Studies Barbara Brennan, Pharm.D. F. Hoffmann-La Roche Top-down Mass Spectrometry for Rapid Characterization of Variable Regions of Monoclonal Antibodies Zongqi Zhang, Ph.D. Amgen, Inc. Quantification of Free and Total Target Protein by Ligand Binding Assay Hossein Salimi-Moosavi, Ph.D. Amgen, Inc. 2009 AAPS NATIONAL BIOTECHNOLOGY CONFERENCE Process Analytical Chemistry Considerations for Manufacturing Biologics William E. Haskins, Ph.D. University of Texas at San Antonio 5 PRELIMINARY PROGRAM
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