10:00am-1:00pm
(SC1) PHAGE & YEAST LIBRARIES & SCREENING
Instructors:
Jamie Kathleen Scott, M.D., Ph.D., Professor and Canada Research Chair in Molecular Immunity, Department of Molecular Biology & Biochemistry and Faculty of Health Sciences, Simon Fraser University
Andrew M. Bradbury, M.B. B.S., Ph.D., Staff Scientist, Biosciences, Los Alamos National Laboratory
This workshop is meant to bring the scientist up to speed on the display technologies covered by the main conference. The workshop will provide an overview of:
- Phage display and construction of phage-displayed peptide, scFv and Fab libraries
- Yeast display and construction of yeast-displayed scFv and Fab libraries
- Screening technologies that are compatible with phage- vs. yeast-display libraries
10:00-11:00am
Jamie Kathleen Scott, M.D., Ph.D., Professor and Canada Research Chair in Molecular Immunity, Department of Molecular Biology & Biochemistry and Faculty of Health Sciences, Simon Fraser University
11:00-12:00pm
Andrew M. Bradbury, M.B. B.S., Ph.D., Staff Scientist, Biosciences, Los Alamos National Laboratory
12:00-1:00pm
Andrew M. Bradbury, M.B. B.S., Ph.D., Staff Scientist, Biosciences, Los Alamos National Laboratory
2:00-5:00pm
(SC5) ANTIBODY DRUG CONJUGATES
Moderator:
Pamela A. Trail, Ph.D., Vice President, Oncology, MedImmune, Inc.
- Linker technology and drug characteristics
- Site-specific antibody modifications
- Use of alternative scaffolds for delivery
- Recent clinical proof of concept data
2:00 Introduction and Opening Comments
Pamela A. Trail, Ph.D., Vice President, Oncology, MedImmune, Inc.
2:15 Antibody-Drug Conjugates: Technology Advances in Linkers and Cytotoxic Agents
Ravi V.J. Chari, Ph.D., Exective Director, Chemistry & Biochemistry, ImmunoGen, Inc.
Multiple antibody-drug conjugates (ADCs) made with ImmunoGen’s tubulin interacting maytansinoid cell killing agents are undergoing clinical evaluation. ImmunoGen has developed approaches to tailor the design of each maytansinoid conjugate to achieve the best performance for the specific cancer target. My talk will discuss ImmunoGen’s technology and also highlight advances in linker design and new effector molecules for use in ADCs.
3:00 Cysteine Engineered Antibodies for Site-Specific Antibody-Drug Conjugates
Changshou Gao, Ph.D., Principal Scientist, Antibody Discovery & Protein Engineering, MedImmune
Significant progress has been made most recently in using recombinant strategies to generate antibody-drug conjugates with predetermined sites and stoichiometries for drug attachment. Here, I discuss our recent effort in cysteine engineered antibodies with reactive thiol groups for site-specific labeling in order to improve conjugation efficiency and product homogeneity.
Changshou Gao, Nazzareno Dimasi, and Herren Wu
3:45 Refreshment Break
4:00 Antibody-Drug Conjugates Targeting the Tumor Neo-Vasculature
Dario Neri, Ph.D., Professor, Chemistry & Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich
In collaboration with Philogen (www.philogen.com), my laboratory has developed seven antibody derivatives which are currently being investigated in Phase I and Phase II clinical trials.
In this lecture, I will present preclinical data on antibody-drug conjugates, which selectively target the tumor neo-vasculature with residence times of weeks and which release potent drugs at the site of disease without the need for antibody internalization.
4:30 Safety Assessment of Antibody Drug Conjugates
Kirsten Achilles Poon, Senior Toxicology Research Associate, Development Sciences Safety Assessment, Genentech, Inc.
Antibody drug conjugates (ADCs), or immunoconjugates, are hybrid molecules usually comprised of monoclonal antibodies conjugated with potent cytotoxins that are being developed for the treatment of a variety of cancers. Since ADCs contain both biologic and small molecule components, standard approaches for pre-clinical safety evaluation for either component may not be
appropriate or adequate and regulatory expectations are not well defined. This presentation will highlight safety assessment challenges, development strategies and case examples of the toxicology associated with certain ADCs.
5:00 Close of Short Course
2:00-5:00pm
(SC7) PHAGE DISPLAY FOR VACCINE DEVELOPMENT
Moderator:
Aaron K. Sato, Ph.D., Senior Director, OncoMed Pharmaceuticals, Inc.
- Peptide Mimotopes: Discovery of small peptides that can mimic vaccine antigens
- Vaccine Antigen Epitope Mapping: Use of phage display to discover dominant antigen epitopes
- Phage Based Vaccines: Use of peptides on phage vs. peptides alone for vaccination
2:00pm Introduction
Aaron K. Sato, Ph.D., Senior Director, OncoMed Pharmaceuticals, Inc.
2:15 Cancer Vaccines with Mimotopes of Tumor-Associated Carbohydrate Antigens
Danuta Kozbor, Ph.D., Associate Professor of Immunology and Microbiology, Department of Immunology, Roswell Park Cancer Institute
A major challenge for inducing antitumor immune responses with native or modified tumor/self-Ags in tumor-bearing hosts relates to achieving efficient uptake and processing by dendritic cells (DCs) to activate immune effector cells and offset the suppressive environment established by the tumor in a tumor-bearing host. We analyzed the ability of therapeutic DC vaccines expressing a CD166 cross-reactive mimotope of the GD2 ganglioside to selectively expand adoptively transferred, tumor-specific T cells in NXS2 neuroblastoma tumor-bearing syngeneic mice. Prior to the adoptive cell transfer (ACT) and DC vaccination, the tumor-bearing mice were lymphodepleted by nonmyeloablative total body irradiation (TBI) or a myeloablative regimen that required bone marrow transplantation. The 47-LDA mimotope, isolated from a phage display peptide library with anti-GD2 mAb 14G2a, was presented to DCs either as a linear polypeptide in conjunction with universal T helper epitopes or as a fusion protein with the murine IgG2a Fc fragment (47-LDA-Fc2a) to deliver the antigenic cassette to the activating Fcgamma receptors (FcRs). We demonstrated that immunization of adoptively transferred T cells in tumor-bearing mice with the 47-LDA mimotope expressed in the context of the activating Fc fusion protein induced higher levels of antitumor immune responses and protection than the 47-LDA polypeptide-DC vaccine. The antitumor efficacy of the therapeutic 47-LDA-Fc2a-DC vaccine was comparable to that achieved by a virotherapy-associated cancer vaccine using a recombinant oncolytic vaccinia virus (rOVV) expressing the 47-LDA-Fc2a fusion protein. The latter treatment, however, did not require TBI or ACT and resulted in induction of antitumor immune responses in the setting of established tolerance, paving the way for testing novel anticancer treatment strategies.
3:00 Refreshment Break
3:30 Broadly Neutralizing Antibodies Against HIV-1, AIDS Vaccines and Phage Display
Dimiter S. Dimitrov, Ph.D., Senior Investigator, Protein Interaction Group, National Cancer Institute, NIH
We and others have used phage display and other methodologies for identification of HIV-1-specific human monoclonal antibodies some of which exhibit potent and broad neutralizing activity (bnAbs). However, attempts to elicit bnAbs by using structures containing their epitopes as vaccine immunogens have not been successful. We found that germline-like antibodies corresponding to known bnAbs do not bind HIV-1 envelope glycoproteins and have proposed a conceptually new approach for their elicitation based on two or more immunogens (primary and secondary) that can help guiding the immune system through complex maturation pathways. In progress are experiments to identify such immunogens by using phage display and other methodologies.
4:15 Filamentous Bacteriophage as a Novel Therapeutic Tool for Alzheimer’s Disease Treatment: Active Immunization Against Alzheimer’s
Beka Solomon, Ph.D., Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University
Antibodies towards the N-terminal region of beta-amyloid peptide (AβP) bind to beta-amyloid (Aβ) fibrils, leading to their disaggregation. We developed an immunization procedure using filamentous phages displaying the only four amino acids EFRH encompassing amino acids 3-6 of the 42 residues of AβP, found to be the main regulatory site for Aβ formation. Phages displaying EFRH epitope are effective in eliciting humoral response against AβP which, in turn, relieves amyloid burden in brains of amyloid precursor protein transgenic mice, improving their ability to perform cognitive tasks. In order to overcome the low permeability of the blood brain barrier for targeting 'anti-aggregating' monoclonal antibodies (mAbs) to Aβ plaques in the brain, we applied antibody engineering methods to minimize size of mAbs while maintaining their biological activity. Single-chain antibodies displayed on the surface of filamentous phage showed ability to enter the central nervous system (CNS). The genetically engineered filamentous bacteriophage proved to be efficient, nontoxic viral delivery vector to the brain, offering an obvious advantage over other mammalian vectors. The feasibility of these novel strategies for production and targeting of anti-aggregating antibodies against Aβ plaques to disease affected regions in the CNS may have clinical potential for treatment of Alzheimer's disease.
5:00pm Close of Short Course
*Separate Registration Required
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