Day 1  |  Day 2

8:35 Engineering Molecules to Be Amenable to Aerosol Delivery
David Cipolla, Ph.D., Senior Director, Pharmaceutical Sciences, Aradigm Corporation
Nobody likes needles or the risk that needle stick injuries pose. With issues such as life cycle management and the generic competition facing the biotech industry, novel noninvasive approaches to deliver injectable therapeutics is a competitive advantage. This session discusses technology strategies to enable systemic delivery of proteins via the pulmonary or transdermal routes.

9:05 Parallel Strategies for Protein Production and Analysis
Scott Lesley, Ph.D., Director of Protein Science, Institute of the Novartis Research Foundation
Optimization of protein properties is an iterative process of alteration, expression, purification, and characterization. Despite advances in predictive capabilities, this practice is still primarily an empirical one that suffers from processing constraints. We have developed and successfully applied instrumentation and methods for parallel processing of targets and their derivatives. This throughput, combined with strategic decision points, is a key aspect of the production of protein for drug discovery and biotherapeutic projects.

9:35 In Silico Modeling for Guiding Therapeutic Antibody Design
Robert J. Bauer, Ph.D., Senior Director, Pharmacokinetics, Pharmacodynamics, and Bioinformatics, XOMA (US)
In silico PK/PD modeling for guiding therapeutic antibody design allows one to quantitatively assess the likely impact of product design on the clinical dosing regimen required for therapy. Early in the development program, information may be obtained from the literature or from previous knowledge and incorporated into the model, such as the non-specific clearance profile of antibodies, the turn-over rate, half-life, and distribution of the target protein and its activating natural ligand, affinity between target protein and natural ligand, and the relationship between the activated target protein level and clinical activity. Simulations may then be performed demonstrating the degree of clinical efficacy for a given dosing regimen and affinity of antibody for its target, allowing one to make assessments of greatest affinity required between target and antibody, cost of goods, and likelihood of clinical and commercial success.

10:05 Coffee Break in the Exhibit Hall

11:05 Expressing & Engineering IgGs in Saccharomyces cerevisiae
K. Dane Wittrup, Ph.D., The J.R. Mares Professor of Chemical Engineering and Bioengineering, Chemical Engineering, Massachusetts Institute of Technology
Saccharomyces cerevisiae can be used as an expression host for the secretion of whole IgG antibodies. We have engineered a secretory leader peptide that enables secretion of 1-20 mg/L whole IgG in shake flask cultures, and these antibodies are useful for immunofluorescent cell labeling, Western blots, and soluble immunoassays. This yeast expression system is a rapid means of obtaining useful quantities of IgG for reagent and preclinical purposes.

11:35 Challenges in Formulating Biologics to Address Issues in Stability and Aggregation
Tudor Arvinte, Ph.D., Professor, Pharmaceutics & Biopharmaceutics, University of Geneva; Chairman and Chief Executive Officer, Therapeomic Inc.
This talk will present protein case studies and newly developed analytical methods to analyze protein aggregation in formulations in conditions as near as possible to those in which the drug is applied in vivo. These "tailor-made" analytical methods should be adapted to the necessities of the formulation rather than to the needs of the analytical techniques. The methods should also be able to detect small differences against a complex background and, if necessary, provide information on the protein properties in heterogeneous formulations such as aggregated slow release formulations, or proteins adsorbed onto adjuvants in vaccines.

12:05pm Luncheon Workshop (Sponsorship Available) or Lunch on Your Own

1:05 Break

CHALLENGES TO PROTEIN DELIVERY

1:25 Chairperson’s Remarks
Volker Schellenberger, Ph.D., Vice President, Drug Discovery, Amunix, Inc.

1:30 Pulmonary Delivery of Domain Antibodies
Amrik Basran, Ph.D., Director, BP CEDD, Domantis Limited
The first dAb products are now in the clinic and a broad pipeline of additional late stage preclinical assets are following close behind. This talk describes the preclinical proof of concept of a novel class of drugs, that is, pulmonary delivered dAbs. Pulmonary delivered dAbs offer unique advantages compared to conventional mAb based therapies. We show superior efficacy in a murine model for chronic obstructive pulmonary disease using a low dose of pulmonary delivered dAb against the TNF receptor 1, thereby demonstrating the utility of dAbs for treatment of pulmonary disease.

2:00 Engineering Human Anti-Viral Monoclonal Antibodies to Have Broad Neutralization Activity Against Multiple Variant Strains
Wayne A. Marasco, M.D., Ph.D., Associate Professor, Department of Cancer Immunology & AIDS, Dana Farber Cancer Institute, Harvard Medical School
Among the barriers to the commercial development of human anti-viral Mab therapeutics is the longstanding concern that antigenic variability of circulating viral strains and the ability of viruses to undergo neutralization escape would limit their utility, particularly with emerging viral pathogens. Using a variety of antibody engineering tools and approaches, we have succeeded in evolving a neutralizing anti-viral Mab from one that has potent, strain specific neutralization activity to one that can block a preferred neutralization escape pathway and neutralize a broad range of viral isolates including viral variants from independent interspecies outbreaks. This approach provides a foundation for the development of broadly neutralizing human anti-viral Mab therapeutics.

2:30 TransPEG Transient PEGylation Technology- Preserving the Original Pharmacology of the Protein
Dirk Vetter, Ph.D., Managing Director, Ascendis Pharma GmbH
Transient or "reversible" PEGylation has been applied to biotherapeutics for several years. Advantages, as compared to conventional permanent PEGylation, are a) sustained release of original drug with uncompromised bioactivity, and b) prodrug approach for maximal renal retention and suppression of receptor-mediated clearance. A short review of the field will be given. A key factor for successful application of the approach is the access to chemical linker systems, reversibly connecting PEG carrier and drug. Relevant parameters in linker selection are tuneability of half-life, storeability and in vitro-in vivo correlation. Different linker families will be presented and case studies will be discussed.

3:00 Networking Refreshment Break

3:30 Tumor Priming to Promote the Delivery and Efficacy of Nanomedicines
Jessie L. S. Au, Pharm.D., Ph.D., Distinguished University Professor, The Ohio State University
Inadequate delivery into solid tumors is a well recognized problem for macromolecules and particulates, such as monoclonal antibodies and gene vectors. The delivery of an agent to cells in solid tumors involves three processes: distribution through the vascular compartment, transport across the microvascular wall or extravasation, and transport within the tumor interstitium. Research on overcoming the barriers for these processes has led to several experimental approaches directed at enhancing the tumor blood flow and/or reducing pressure gradient between microvessels and interstitial fluid pressure, and thereby enhancing the extravasation and intratumoral dispersion of particulates. Through the use of an experimental model that is independent of blood flow or pressure gradient (i.e., 3-dimensional solid tumor histocultures), our laboratory has demonstrated high tumor cell density is a major barrier for intra-tumoral transport. We subsequently identified tumor priming (i.e., pretreatment with a drug efficient in inducing apoptosis) as a tool to improve the tumor-selective delivery and the transport of nanoparticles, resulting in greater efficacy of drug-loaded liposomes.

4:00 Design of Recombinant G-CSF-Transferrin Fusion Proteins for Oral Delivery
Wei-Chiang Shen, Ph.D., Professor, John A. Biles Professor, Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy
A recombinant fusion protein consisting of granulocyte colony-stimulating factor (G-CSF) and transferrin (Tf) has been constructed and expressed. Subcutaneous administration of the fusion protein to BDF1 mice generated a similar increase in neutrophil count to that of commercial human G-CSF. When delivered orally to BDF1 mice, the fusion protein produced a significant increase in neutrophil count while G-CSF had no effect. Inserting appropriate peptide sequences between G-CSF and Tf domains in the fusion protein further improved both in vitro and in vivo myelopoietic effect. Hence, Tf-based recombinant fusion protein technology is a promising approach to achieve oral delivery of protein and peptide drugs.

4:30pm End of the Engineering Protein Therapeutics for Delivery Conference

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