ペプチドと抗体のファージディスプレイ

4月29日 (火)

8:00 am - 5:15 pm レジストレーション開始

二重標的化抗体のエンジニアリング
ENGINEERING DUAL TARGETING ANTIBODIES

8:25 am Chairperson's Remarks
Sachdev Sidhu, Ph.D., Senior Scientist, Protein Engineering, Genentech Inc.

8:30 Synthetic Antibodies
Germaine Fuh, Ph.D., Scientist, Protein Engineering, Genentech Inc. 
Synthetic antibodies have been isolated from phage libraries with designed diversity. The utility and molecular mechanism of the exampled synthetic antibodies crossing species of low homology will be discussed. The versatility of antibody binding surface will be highlighted.

9:00 Engineering Stable Bispecific Antibodies via Combinatorics from a Human Library 
Robert Mabry, Ph.D., Senior Scientist, Protein Engineering and Antibody Discovery, Zymogenetics 
Bispecific antibodies (bsAbs) present an attractive approach to combine the additive and potentially synergistic effects of monotherapeutics. One complication in engineering bsAbs is molecule construction with retention of affinity and stability comparable to the parent antibody. Here we present a combinatorial strategy employing shuf-fling techniques to isolate a variety of antibody formats conducive to bsAbs using a single human phage display library.

9:30 Ligand-Directed Vascular Targeting and Molecular Imaging
Renata Pasqualini, Ph.D., Helen Buchanan & Stanley Seeger Professor of Medicine and Cancer Biology, The University of Texas, M. D. Anderson Cancer Center 
Our group has originally developed two broad vascular targeting biotechnology platforms to uncover and exploit ligand-receptor interactions in the context of human disease: combinatorial selection of peptide libraries in patients and hybridoma-free generation of monoclonal antibodies. Essentially, by using these two complementary technologies, we have been probing the molecular diversity (for example, of the vascular endothelium or of the humoral immune system) to find unique cell surface addresses--endothelial and otherwise--for delivery to selective cell types or cell populations, vasculature of tissues and/or organ systems. There are many potential, as yet unrecognized, protein-protein interactions that may lead to applications such as targeted drug delivery, vascular-mediated tissue repair or acute hemorrhagic control of non-surgical bleeding. Such set of ligand-receptor interactions can encompass applications in different organ-specific vascular beds in health and diseased conditions. The aggregate data we have generated thus far indicates that a new ligand-directed pharmacology and its ramifications is now unequivocally at hand.

10:00 Coffee Break in the Exhibit Hall 

親和性成熟
AFFINITY MATURATION

10:40 Chairperson's Remarks
Aaron K. Sato, Ph.D., Senior Director, OncoMed Pharmaceuticals, Inc.

10:45 Selection of Horseradish Peroxidase Variants with Enhanced Enantioselectivity by Yeast Surface Display
Dasa Lipovsec, Ph.D., Director of Protein Engineering, Codon Devices, Inc.
Two variant libraries of horseradish peroxidase were constructed using either error-prone PCR throughout the gene or saturation mutagenesis directed at five positions near the active site. The libraries were displayed on yeast cell wall, which the enzyme was allowed to modify using a fluorescently labeled substrate. In vitro selection from the active site–directed library resulted in variants with up to eight-fold change in enantioselectivity, including its reversal, towards L/D tyrosinol. This work illustrates the utility of yeast surface display for in vitro evolution of enzymatic activity, especially for enzymes with multiple disulfide bonds.

11:15 Implementation of Phage Escape Libraries in the Study of Viral Evolution and High-Throughput Drug Screening
Tobin J. Dickerson, Ph.D., Assistant Professor of Chemistry, Scripps Research Institute
The evolutionary competition between viral mutation and the immune system has been contested for millions of years. We have recently developed a technology termed phage escape libraries that recreates this competition in vitro using bacteriophage-displayed proteins and allow rapid analysis of molecules that antagonize protein-ligand binding. Ultimately, simple sequencing of viral mutants and the corresponding antagonist biomolecules details the trajectory of viral escape. Furthermore, not only does this technology allow for the in vitro study of viral evolution, but in an alter-native format, provides a powerful methodology for high-throughput screening with resolution at the single molecule level. This lecture will discuss the implementation of phage escape libraries in an immunological context as well as the development of robust screening procedures for the discovery of novel antagonists of protein-protein interactions.

11:45 Solutions Showcase (Sponsorship Available)

12:15 pm Luncheon Workshop (Sponsorship Available) or Lunch on Your Own

1:15 Break

ケーススタディ: 臨床におけるファージディスプレイによる組み換え抗体
CASE STUDIES: RECOMBINANT ANTIBODIES IN THE CLINIC DERIVED FROM PHAGE DISPLAY
(Shared session with Recombinant Antibodies)

2:00 Chairperson's Remarks
Lutz Jermutus, Ph.D., Director of Research - Technology, MedImmune Ltd. 

2:05 Respiratory Antibody Portfolio Case Study: anti-IL-13, anti-GMCSFR, anti-IL5R, anti-IL-9
Roland Kolbeck, Ph.D., Director, Inflammation & Head, Respiratory Disease, MedImmune, Inc.
Asthma is an inflammatory disorder of the airways associated with airway remodeling, mucus hypersecretion and reversible airway obstruction. Inflammation is characterized by increased numbers of eosinophils, basophils, mast cells and T-helper 2 cells that are a rich source of eicosanoids such as leukotriens and prostaglandins, as well as cytokines such as IL-4, IL-5, IL-9, IL-13 and GM-CSF, each of which orchestrates different aspects of asthma pathology. We have designed specific monoclonal antibodies that have been optimized and engineered in ways that allow for the efficient interference with IL-13, IL-9, GMCSFR and IL5R signaling pathways. The relative contribution of either pathway to asthma pathology and the optimization of inhibitory monoclonal antibodies for clinical development will be discussed in detail.

2:50 Dll4 and Notch1 Antagonist Antibodies Inhibit Tumor Growth by Deregulating Angiogenesis
Yan Wu, Ph.D., Senior Scientist, Antibody Engineering, Genentech Inc.
Dll4 (ligand) and Notch1 (receptor) are key molecules for angiogenesis. Activation or over expression of Notch1 is also implicated in many cancers. Blocking Dll4 or Notch1 with specific phage antibodies renders endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 or Notch1 inhibited tumor growth in several tumor models.

3:20 DVD-Ig: a Novel Bispecific Antibody Technology
Chengbin Wu, Ph.D., Senior Scientist, Biologics, Abbott Bioresearch Center
Human diseases are often complex and involve multiple disease mediators, therefore drugs that block multiple targets simultaneously will likely yield enhanced therapeutic efficacy. We have developed a novel bispecific antibody technology termed dual-variable domain Ig (DVD-Ig) that can be engineered from any two monoclonal antibodies for targeting two antigens. This new class of molecules can be efficiently produced from mammalian cells and exhibits drug-like properties. Our studies of a DVD-Ig agent in a preclinical animal model demonstrate a strong potential for its therapeutic application in human diseases. 

3:50 Refreshment Break in the Exhibit Hall

4:15 Case Study: Antibodies as Protease Inhibitors
Laetitia Devy, Ph.D., Principal Scientist, Dyax SA
Antibodies provide the potential for a new generation of protease inhibitors with high levels of potency and selectivity. Combining our human antibody phage display library with automated selection and screening strategies, we have isolated inhibitors of a range of metallo- and serine proteases. We will illustrate this success using DX-2300 and DX-2400. DX-2300 potently inhibits tissue kallikrein 1 (Ki=39 pM) and has demonstrated activity in preclinical models of airway inflammation. DX-2300 has been shown to block kinin generation by tissue kallikrein in vivo and therefore, may be efficacious in various inflammatory diseases. DX-2400 selectively inhibits MMP-14 (Ki=0.8nM), a membrane bound metalloproteinase and has been shown to inhibit tumor progression in different tumor models (MDA-MB-231, MDA-MB-435, BT-474 and PC3). DX-2400 also significantly decreases the incidence of metastases and inhibits tumor angiogenesis. These antibodies represent innovative approaches for the inhibition of key protease regulators of inflammation and cancer.

4:45 Development of a Portfolio of Therapeutic Antibodies for Oncology Combining Xenomouse and Display Technologies 
David Blakey, Ph.D., Senior Principal Scientist, Cancer Discovery, AstraZeneca
Astrazeneca has developed a portfolio of antibody-based therapeutics in oncology through its collaboration with Abgenix/Amgen and acquisitions of CAT and Medimmune. Antibodies to some of the target in this portfolio e.g. CD20, ErbB2, MCP1 will be described focusing on differentiation from competitor molecules. The advantages of combining transgenic mouse technology and display technology to yield optimal lead antibodies will be discussed.

5:15 pm End of Phage Display of Antibodies and Peptides Conference