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Though Therapeutic Antibodies have achieved phenomenal success, many challenges stand waiting to be addressed. This meeting will explore some of the successes while reviewing the inherent obstacles that can block progression into the clinic with an eye for ferreting out the optimal protocols and highlighting the best technologies that support development.
The focus for the meeting is the momentous task of designing a soluble and glycosylated therapeutic antibody that can be delivered efficaciously and penetrate into the tissue or tumor.
Experts from around the world will come together in a relaxed, congenial atmosphere to discuss today’s accomplishments and tomorrow’s breakthroughs in the development of Therapeutic Antibodies.
Please join these life science leaders for this indepth discussion of innovative approaches to overcoming the hurdles of developing biologics.
Monday, January 11
7:30 am - 8:45 am Registration and Morning Coffee
8:45 Chairperson’s Opening Remarks
Shikha Varma-O’Brien, Ph.D., Director, LS Modeling & Simulations, Accelrys
9:00 OPENING KEYNOTE PRESENTATION
Development, Maintenance and Life Cycle Management of Critical Reagents for Ligand Binding Assays
Denise M. O’Hara, Ph.D., Associate Director, PDM, Pfizer (formerly Wyeth)
The selectivity and sensitivity of ligand binding assays (LBA) is dependent on the choice of reagents. Development of biotherapeutics relies on the use of these LBA from early discovery through to commercialization and sometimes beyond. The successful maintenance and use of LBAs involves well characterized and quality critical reagents. This talk will discuss the life cycle management of reagents from their development, maintenance and use and include case studies.
9:50 Challenges of Using Ligand Binding Assays to Support Therapeutic Antibody Development
Joseph C. Marini, Ph.D., Associate Director of Pharmacokinetic Bioanalysis, Biologics Clinical Pharmacology, Centocor Research and Development, Inc., A Johnson and Johnson Company
Therapeutic antibodies have been exploited in the pharmaceutical industry because of their target selectivity, favorable pharmacokinetic profile and large safety margin. The unique disposition of therapeutic antibodies is evaluated in non-clinical and clinical studies using PK/PD modeling. Ligand binding assays (LBAs) are employed to generate the data used to evaluate the pharmacological profile of therapeutic mAbs, specifically pharmacokinetic analysis, pharmacodynamic effect and immunogenicity assessments. Due to the dependence on biological reagents, LBAs are inherently challenged by matrix interference, specificity and variability. This presentation will discuss the use of LBAs in drug development and technologies that are being explored to support therapeutic antibody development in the 21st century.
10:20 Networking Coffee Break
10:45 Engineered Antibody Domains Against Cancer and Viruses
Dimiter Dimitrov, Ph.D., Senior Investigator, Protein Interaction Group, National Cancer Institute, National Institutes of Health (NIH)
Engineered single antibody domains are small (sizes about 12-14 kDa i.e. about 10-fold smaller than the size of a typical full-size antibody) and can access targets and epitopes that are not accessible by larger molecules. We have constructed two large (size 2x1010) VH-based libraries of high diversity from which several high affinity domain antibodies against HIV and cancer-related proteins were identified and characterized with potential use as therapeutics. We have also engineered human antibody constant domains (CH2) as scaffolds which are highly stable, soluble, and express at high levels. Based on these new scaffolds several libraries have been constructed, and binders were selected and characterized. Further engineering to confer additional functions (nanoantibodies) is in progress.
11:15 Targeting T Cells or Stem Cells with Chemically Heteroconjugated Bispecific Antibodies
Lawrence G. Lum, M.D., D.Sc., Professor of Medicine; Professor of Immunology and Microbiology; Scientific Director of Immunotherapy and BMT, Barbara Ann Karmanos Cancer Institute
A simple approach using heterconjugation of already approved monoclonal antibodies to produce bispecific antibodies can be used to target effector immune cells or stem cells to tumors or target organs to effect repair. A number of clinical protocols have been developed for clinical applications. These include anti-CD3 x anti-Her2/neu for breast and prostate cancer, anti-CD3 x anti-CD20 for lymphomas or multiple myeloma, anti-CD3 x anti-EGFR for pancreatic, lung, and colon cancer, and anti-CD45 x anti-myosin light chain for targeting myocardia infarctions. Both preclinical and clinical studies will be presented.
11:45 Building a Diverse Portfolio of Immunotoxins for the Therapeutic Treatment of Solid Tumors
Jeannick Cizeau, Ph.D., Director, Research, Viventia Biotechnologies
It is well known that cancer patients can elicit an immune response to their tumor. IDAP (Immune Driven Antibody Platform) is a series of specific technologies that exploits the patient’s anti-tumor response to identify those antibodies specific for membrane-associated tumor targets. This unique screening approach, which does not require upfront knowledge of the target, yields specific antibodies with minimal normal tissue reactivity. These unique, cancer-related antibodies can be engineered as recombinant fusion proteins containing a cytotoxic payload (immunotoxin) as well as be used to isolate novel tumor-associated targets. Two case studies will be presented.
12:15 pm P200 ScreenTape®: A Complete Automated At-line Analysis System, Ideally Suited to MAb and Protein Production
Adam Inche, Ph.D., Application Scientist, Lab901 Ltd.
We will present the ScreenTape system for rapid, automated and fully integrated SDS-PAGE analysis. The talk will focus on use of the system for at-line monitoring of mAb expression over time, as well as the assessment of antibody quality by a non-reducing analysis directly from a bioreactor. We also present the use of P200 as a tool for the analysis of mAb purification as well as a final quality check of the purified product.
12:30 Luncheon Presentation or Lunch on Your Own
2:00 Chairperson’s Remarks
Dimiter Dimitrov, Ph.D., Senior Investigator, Protein Interaction Group, NCI, NIH
2:05 Why Bad Things Happen to Good Antibodies: Fc Gamma Receptors on Effector Cells Promote Concerted Removal of Monoclonal Antibody-Antigen Complexes from Targeted Cells
Ronald P. Taylor, Ph.D., Professor, Biochemistry and Molecular Genetics, The University of Virginia School of Medicine
More than 25 years ago clinical investigations revealed that infusion of several different immunotherapeutic mAbs directed to tumor cells could lead to loss of targeted epitopes from the cells; the reaction, described in detail for anti-T cell mAb T101 (anti-CD5), was called antigenic modulation, but its underlying mechanism was not delineated. The loss, which we have called “shaving”, appears to be identical to antigenic modulation, and it is clear that this reaction can substantially compromise the efficacy of an immunotherapeutic mAb. We have developed both in vitro model systems and mouse models to investigate the shaving reaction.
2:35 Fab’ PEGylation Strategies
David P. Humphreys, Ph.D., Senior Group Leader, Antibodies, UCB Celltech
3:05 Human IgG1-Fc Rational Design Leads to an Increase in Anti-TLR4 Monoclonal Antibody Potency: Unexpected Help from the Mouse Repertoire
François Rousseau, Ph.D., Head of Antibody Engineering Unit, NovImmune SA
3:35 Modeling the 3-Dimensional Structures of Antibody and their Interaction Interface to Antigen
Shikha Varma-O’Brien, Ph.D., Director, Life Sciences, Accelrys
Given the increased interest in protein therapeutics, significant efforts are put into engineering novel antibody sequences. Modeling antibody 3-dimensional structures and their binding to antigen can provide valuable information in designing antibody sequences. We will present Accelrys' methods in building antibody framework structures, construct and refine the six hypervariable loop regions and predicting the antibody-antigen binding interfaces.
3:50 Networking Refreshment Break
4:15 Improving Antibody Properties by Semi-Rational in silico Engineering: A Realistic Perspective
Philippe Alard, Ph.D., Head of Bioinformatics, AlgoNomics N.V., a Lonza company
Antibody leads generally require optimization of their physical, functional or biological properties. Computer-based methods for affinity maturation and epitope mapping involve heterogeneous data mining, statistical processing, structure analysis, and predictive technology. This presentation focusses on methods for Fv model building, humanization, epitope analysis and affinity enhancement. Two case studies are presented showing increased affinity of antibodies and precise mapping of the antibody-antigen complexes.
4:45 Phage-Displayed scFv Libraries Stabilized with Interdomain Disulfide Bond
An-Suei Yang, Ph.D., Deputy Director & Associated Research Fellow, Genomics Research Center, Academia Sinica, Taiwan
Conventional phage-displayed scFv has multiple conformations due to the mobile interface between the two variable domains. The stability of the scFv and the specificity of scFv-antigen interactions have been significantly enhanced by an inter-domain disulfide bond. But the expression of the disulfide bonded scFv (ds-scFv) on phage surface has been unsuccessful, and hence it has not been practical for directed evolution on the basis of the ds-scFv scaffold with phage display systems. We have established synthetic ds-scFv phage display systems for ds-scFv engineering with phage-based selection and screening, avoiding scFv-antigen interactions resulting from non-native scFv conformations common to conventional scFv.
5:15 Dual Variable Domain (DVD)–Ig Technology: Next Generation Biologics for Targeting Two Disease Mechanisms Simultaneously
Tariq Ghayur, Ph.D., Senior Principal Scientist & Research Fellow, Biologics, Abbott Bioresearch Center
DVD-IgTM molecules are constructed by combining the antigen-binding domains of 2 mAbs as a single agent. These molecules can bind simultaneously to two soluble proteins, to one soluble and one cell surface protein or to two cell surface proteins. Examples of DVD–Igs against different target pairs and technical considerations in making such molecules will be discussed.
5:45 Welcoming Reception in the Exhibit Hall
7:00 Close of Day
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