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8:00 am Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
Greg Walsh, Senior Scientist, Technology Development, Genzyme
8:35 KEYNOTE PRESENTATION
Improving Physicochemical Properties of Biopharmaceutical Drug Candidates
 David Litzinger, Ph.D., Director, Pharmaceutical Sciences, Amylin Pharmaceuticals, Inc.
Often drug candidates in discovery and development have undesirable chemical and physical instability. This presentation will focus on options for modifying the drug molecules to improve their physicochemical properties such as chemical stability, solubility, and to lessen their potential for aggregation. Changes that will be discussed include creating analogs, chemical conjugation, and other modifications.
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9:05 Protein Structure Alteration and Aggregation in Liquid Formulations: What Impact on the Drug Product Features and How to Monitor These Issues?
Joel Richard, Ph.D., Senior Director, Head of Drug Product Development, Pharmaceutical Development, Ipsen
State-of-the-art development for therapeutic proteins is presently focusing on liquid formulations, requiring high concentration formulations(> 100 mg/mL). It needs properly assessing and carefully monitoring the compatibility of the protein with the container and the stabilizing excipients, as well as the stability of the protein in the formulation over time. Structure alteration and aggregation are among the most striking issues, the latter triggering immunogenic reactions upon repeated subcutaneous administration. This talk will focus on case studies using the appropriate combination of biophysical methods (fluorescence, thermal analysis, circular dichroism, dynamic light scattering, analytical ultracentrifugation, etc.) to show structural modifications of the protein in the formulations and study the effect of excipients on these modifications. Clinical impact will also be discussed.
9:35 Case Studies of Monoclonal Antibody Aggregation: Lessons Learned from Apparently Stable Molecules
Tia Estey, Ph.D., Scientist II, Protein Pharmaceutical, Development, Biogen-Idec
The presentation will highlight a number of case studies in which unexpected aggregation behavior was observed during the development of monoclonal antibody formulations. Examples of processing and long-term stability challenges will be presented. For each of the case studies, the origins of physical instability as well as formulation and development mitigation strategies will be discussed. The audience will gain a better understanding of some of the drivers behind the aggregation of monoclonal antibodies, how process stresses can contribute to aggregation, how to characterize aggregation in order to get at the root cause, and potential solutions to this problem.
10:05 Coffee Break, Poster and Exhibit Viewing
11:05 Monoclonal Antibody Aggregation Intermediates Visualized by Atomic Force Microscopy
Henryk Mach, Ph.D., Senior Investigator, Bioprocess Analytical and Formulation Sciences, Merck Research Laboratories
In this work we present the use of an atomic force microscopy to examine morphology of monoclonal antibody aggregates. Despite varying in primary structure, most antibodies studied exhibited aggregation intermediates consisting of several monomers. The manner of subsequent condensation of these oligomers appeared to differ between the antibodies.
11:35 Structure-Based Engineering of a Monoclonal Antibody for Improved Solubility
Sam Wu, Ph.D., Senior Research Scientist, Biologics Research, Centocor R&D, Inc.
Three structure-based engineering approaches were employed in antibody solubility: 1) modifying the isoelectric point, 2) decreasing the overall surface hydrophobicity, and 3) re-introduce an N-linked carbohydrate moiety within a complementarity-determining region (CDR) sequence. We have demonstrated that all three approaches led to improved solublility and that adding an N-linked carbohydrate to the CDR was the most effective route for enhancing the solubility of this antibody, in which an aggregation “hot spot” overlapped with residues in contact with the target antigen.
12:05 pm End of Conference
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