Antibody Discovery & Pre-Clinical Drug Development

Venue: Wyndham U.S. Grant

Location: San Diego, California, United States

Event Date/Time: Feb 25, 2003 End Date/Time: Feb 26, 2003
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Description

Antibody Discovery & Pre-Clinical Drug Development
February 24 - 28, 2003


Monday, February 24, 2003

2:00 - 5:00 - Exhibitor Set-Up



5:30 - 7:00 - Welcoming Reception



Tuesday, February 25, 2003

7:15 - 8:45 - Registration, Networking, Exhibits & Posters



8:45 - 9:00 - Chairs' Opening Remarks


Speaker
Katherine Bowdish
President
Alexion Antibody Technologies

Venkat Mukku, Ph.D.
Laboratory Head, Analytical Sciences
AMGEN INC

Maurice Zauderer, Ph.D.
President & CEO
Vaccinex Inc

9:00 - 9:30 - A CBER Perspective on the Rapid Development of Antibody Therapeutics
The production and development of antibody therapeutics has reached a level of maturity unlike any other in the biotech arena. As such, the growing pains which accompanied early developmental processes have given way to a more comprehensive understanding of the issues and concerns that need to be addressed at various phases in product development. An overview of some of these areas will be presented.

Speaker
Gerald Feldman
Senior Investigator, Office Of Therapeutics
FDA

9:30 - 10:00 - Pre-Clinical Development of KS-IL2 Immunocytokine for Treatment of EpCAM Positive Tumors
Immunocytokine KS-IL2 consists of the humanized antibody hu KS1/4 fused to IL2. This immunotherapy has three separate effector functions: The Fv antibody portion targets to the cell adhesion molecule EpCAM, which is highly expressed on carcinoma cells. The Fc portion confers ADCC activity and NK mediated tumor target killing. The IL2 portion stimulates and activates NK and T cells at the tumor microenvironment and in draining lymph nodes. Data will be presented on the unique pre-clinical and clinical issues involved in the development of this candidate e.g. methods for cell culture, purification and analysis of the Immunocytokine product and the development of assays for analysis of the product and its effect in pre-clinical and clinical samples.

Speaker
Michael Super, Ph.D.
Director of Immunobiology
LEXIGEN PHARMACEUTICALS CORPORATION

10:00 - 10:30 - Analytical Strategy for a Monoclonal Antibody Technology Platform
Monoclonal antibodies are now fulfilling their potential as human therapeutics. To facilitate the development of monoclonal antibodies toward bolstering Amgen's clinical pipeline, a platform has been developed for monoclonal antibody production, characterization and analysis. The high level of similarity among monoclonal antibodies makes the platform approach feasible. This presentation will describe many of the approaches and strategies used in the characterization and analysis of monoclonal antibodies which are intended to expedite the entry of these products into the clinic.

Speaker
Mike Klein, Ph.D.
Department of Analytic Sciences
AMGEN, INC.

10:30 - 11:15 - Networking, Exhibits, & Posters



11:15 - 11:45 - Pre-Clinical Considerations in the Development of Therapeutic Antibodies
The pre-clinical studies conducted to support the development of therapeutic antibodies (human, humanized etc.) require some special considerations depending on the clinical indication and the biology of the antibody target. Additionally, the nature of the therapeutic antibody (effector function, toxin conjugated etc.) requires special consideration in the area of dosing strategies, assay development and duration of exposure to support clinical studies. Some case studies and important points to consider will be discussed.

Speaker
Abbie Celniker, Ph.D.
Vice President, Biotherapeutics
MILLENNIUM PHARMACEUTICALS

11:45 - 12:15 - Pharmacokinetics and Immunogenicity Issues in the Development of Therapeutic Antibodies
Numerous monoclonal antibodies are now approved as human therapeutics in several therapeutic areas including oncology, inflammation and cardiology. This presentation will provide an overview of some of these antibodies and an assessment of the pre-clinical studies and strategies through Phase 2 used to expedite their development. Issues such as species specificity, immunogenicity and availability of a pharmacodynamic (PD) endpoint and the impact on the design and interpretation of these preclinical studies will be discussed.

Speaker
Sharon Baughman, Ph.D.
Director, Protein PKDM
AMGEN, INC.

12:15 - 1:45 - Luncheon



1:45 - 2:15 - Antibody Aggregation and its Impact on the Development of High Concentration Subcutaneous Formulations
Abstract unavailable at time of printing; please view at www.srinstitute.com/absummit

Speaker
Steve Shire
Senior Scientist and Group Leader, Pharmaceutical Research & Development Department
Genentech, Inc.

2:15 - 2:45 - A "Template" for Therapeutic Antibody Development Program from Preclinical through Phase II Clinical Trials?
Antibodies have demonstrated as successful therapeutics in oncology, inflammation, graft rejection and cardiovascular disease areas. With rapid advances in genomics and proteomics and the potential for new targets, antibodies will emerge as a major class of therapeutics. To take advantage of these advances and gain competitive edge, efficient utilization of available technologies and adoption of product development strategies are important. This talk will give an overview of platform technologies and timelines for the development of therapeutic monoclonal antibodies from pre-clinical stage through Phase II clinical trials.


Speaker
Venkat Mukku, Ph.D.
Laboratory Head, Analytical Sciences
AMGEN INC

2:45 - 3:15 - Networking, Exhibits, & Posters



3:15 - 3:25 - Chairs' Opening Remarks


Speaker
Katherine Bowdish
President
Alexion Antibody Technologies

Maurice Zauderer, Ph.D.
President & CEO
Vaccinex Inc

3:25 - 3:55 - Using On-Rate Amplification Sites (ON-RAMPS) to Increase the Association Rate of an Antibody for its Antigen
Traditional approaches for increasing the affinity of protein-protein complexes focus on constructing highly complementary binding surfaces. Recent theoretical simulations and experimental results suggest that electrostatic steering forces can be manipulated to increase association rates while leaving dissociation rates unchanged, thus increasing affinity. Here we demonstrate that significant changes in the association rate of an antibody fragment and its cognate antigen can be achieved through application of a few simple rules to identify potential on-rate amplification sites (ON-RAMPS).

Speaker
Jonathan S. Marvin, PH.D.
Postdoctoral Fellow
GENENTECH, INC.

3:55 - 4:25 - Novel Recombinant Bispecific Molecules for Immunotherapy of Blood Malignancies
Bispecific antibodies (BsAb) can redirect effector cells towards therapeutic targets. We bispecific diabodies (BsDb) with the dual specificity to human CD19 on non-Hodgkin's lymphoma cells, and either to CD3 or CD16 on human T cells and NK cells, respectively. Combination of CD19 x CD3 and CD19 x CD16 BsDbs retargeting different populations of human effector cells clearly demonstrated synergistic anti-tumor effect. To further improve the therapeutic potential of BsAb, we have constructed a tetravalent CD19xCD3 tandem diabody (Tandab). Compared to the heterodimeric BsDb, the Tandab exhibited a higher apparent affinity for both CD19+ and CD3+cells and longer blood retention when injected into mice. Treatment of SCID mice bearing an established Burkitt's lymphoma with human PBLs, Tandab and anti-CD28 MAb resulted in the complete elimination of tumors in all animals within ten days. Besides,CD19 x CD3 Tandab alone induced vigorous autologous Tcell activation and killing of malignant cells in peripheral blood
cultures from patients with chronic lymphocytic leukemia (CLL). These data demonstrate that the Tandab might be a promising tool for the immunotherapy of human leukemias and lymphomas.


Speaker
Sergey M. Kipriyanov, Ph.D.
Head of Antibody Engineering
AFFIMED THERAPEUTICS AG

4:25 - 4:55 - Selection of Fully Human Monoclonal Antibodies from Immunoglobulin cDNA Libraries Expressed in Mammalian Cells
We have developed a novel method for selection of bivalent, fully functional human antibodies from immunoglobulin cDNA libraries constructed in vaccinia virus. Selection of high affinity antibodies is facilitated by assembly of very large and diverse libraries through combinatorial association of immunoglobulin heavy and light chains. The functionality of antibodies synthesized and assembled in mammalian cells is very high. Immunoglobulin chains fold and are assembled under physiological conditions and undergo full post-translational modifications including glycosylation. As a result, the titer of functional antibodies can be much higher than for libraries expressed in bacterial cells. In addition, selection of antibodies efficiently expressed in mammalian cells may lead to manufacturing efficiencies relative to antibodies selected in bacteria. In relation to antibody selection in normal or Ig transgenic mice, this library-based technology offers a means of avoiding limitations in the antibody repertoire due to tolerance to murine homologs of important human proteins. Finally, since fully functional, bivalent antibodies can be produced in either membrane associated or secreted forms, this technology also has the potential to permit direct functional screening of specific antibodies in high throughput assays for a specific stimulatory or inhibitory activity.

Speaker
Maurice Zauderer, Ph.D.
President & CEO
Vaccinex Inc

5:00 - 6:30 - Networking Reception



Wednesday, February 26, 2003

7:30 - 8:45 - Networking & Exhibits



8:45 - 9:15 - The Power of Complex Libraries and Display Technologies
Barriers to entry and partnership in human and humanized antibody therapeutics are primarily focused on intellectual property issues. Alexion Antibody Technologies has solutions that transcend these barriers including novel approaches to building and screening large, highly diverse, combinatorial human and immune source antibody libraries and their use as a successful discovery tool for identification of therapeutically relevant antigen/antibody interactions. Newly relevant examples of the power and speed of these display technologies will be provided. This suite of technologies is immediately available for partnership opportunities.

Speaker
Katherine Bowdish
President
Alexion Antibody Technologies

9:15 - 9:45 - MSCRAMM Protein Antibodies-A New Treatment Pradigm
Staphylococci are major human pathogens that cause a spectrum of clinical conditions that range from surgical site and catheter-related infections to pneumonia, endocarditis, ana sepsis. Due to the conitnued increase in the numbers of community-acquired and nosocomial methicillin resistant S. aureus infections (MRSA), a need for novel alternative therapies exists. Microbial adhesion is recognized as the first crucial step in a series of events that leads to infections in human. Staphylococci express MSCRAMM proteins, a family of cell surface adhesins, that facilitate adherence and colonization by attaching to extracellular matrix components of host tissues or serum conditioned implanted biomaterials. Using state of the art genomic and proteomic tools, we have indentified a number of human antibodies that target these MSCRAMM proteins. The MSCRAMM protein antibodies prevent stahylococci from attaching or recolonizing host tissues or implanted medical devices, as well as promote clearance by the immune system. We currently have three programs focused on the developing MSCRAMM protein human antibodies for the prevention and treatment of staphylococcal infections. Veronate, a human polyclonal immunoglobulin containing elevated levels of antibodies to both S. aureus and coagulase-negative staphylococci MSCRAMM proteins, is being developed for the prevention of infections in very low birth weight infants. Veronate is currently in a Phase II clinical trial. AurexisTM, the esecond product in the pipeline is a humanized monoclonal antibody that specifically recognizes clumping factors (ClfA), a MSCRAMM protein expressed by almost all strains of S.aureus. Aurexis will begin Phase I clinical trials in Q1 2003. Finally we are developing a nosocomial vaccine that will prevent both S.aureus and coagulase-negative staphylococci infections. Data supporting all three approaches will be the topic of discussion

Speaker
Joseph Patti, Ph.D.
CSO & VP Preclinical Development
INHIBITEX INC

9:45 - 10:15 - Antibody-Drug Conjugates: Conferring Therapeutic Potency to Anti-Tumor Antibodies
Unfortunately, many monoclonal antibodies that possess favorable affinity and target specificity toward tumors cells provide insufficient efficacy on their own for the successful treatment of cancer. Arming these anti-tumor antibodies with potent cytotoxic agents is proving to be a successful approach to the development of specific cancer therapeutics.


Speaker
Robert J. Lutz, Ph.D.
Senior Director, TAP Research
IMMUNOGEN

10:15 - 11:00 - Networking & Exhibits



11:00 - 11:30 - Bacterial Cell-based Selection Systems for Antibody Engineering
We will describe the development of enzyme sensors that can be activated or inactivated by target molecules and protein-protein interactions, and the use of these sensors in cell-based systems for epitope-guided selection, humanization, and affinity maturation of therapeutic antibodies.

Speaker
Robert Balint, Ph.D.
Chief Scientific Officer
KaloBios, Inc.

11:30 - 12:00 - The Immunome, Target Discovery & Antibody Development
Viventia Biotech's three complementary technology platforms will be described: Hybridomics(tm) is Viventia's unique human immune system-driven discovery approach that leverages the intrinsic antibody response to cancer. ImmunoMine(tm) is a state of the art high-throughput screening process that Viventia has developed to rapidly characterize anti-cancer monoclonal antibodies. Armed Antibodies(tm) provides a rational vehicle to leverage the innate binding properties of our antibodies as payload carriers to deliver potent cytotoxic agents directly to cancer cells.

Speaker
Nick Glover
Vice President, Corporate Development
Viventia Biotech Inc.

12:00 - 1:30 - Luncheon



1:30 - 2:00 - Isolation of Human Fnlll Domain-Based Antibody Mimics Using an In Vitro Protein Display Technique
We are developing the tenth type III repeat of human fibronectin (¹ºFnIII) as an antibody mimic for therapeutic applications. The structural and biophysical characteristics of ¹ºFnIII, as well as its ease of expression in E. coli, make this immunoglobulin-like domain an attractive scaffold for the development of specific affinity reagents. We are using an in vitro protein display technique (mRNA display) where by proteins are covalently attached to their encoding mRNA via puromycin moiety to select for affinity reagents from a ¹ºFnIII-based mRNA display library (>10¹² members) containing randomized amino acid sequences in three solvent-exposed loops which are structurally analogous to antibody CDRs. Because the link between the protein and its genotype is covalent, the protein moiety can be selected for under stringent conditions and its genetic material amplified by PCR. We have used mRNA display to select for ¹ºFnIII antibody mimics that bind specifically to their targets in the low nano-to-picomolar range. Here we provide examples of fibronectin antibody mimics that inhibit the interaction between their target and itsnatural ligand, and that bind to their target when it is expressed on the cell surface.

Speaker
Tom Cujec
Senior Research Scientist
PHYLOS INC

2:00 - 2:30 - Leveraging Tissue-Specific Progenitor Cells as the Input for an Integrated Discovery Platform for Monoclonal Antibody-Based Target Identification and Validation
Raven biotechnologies, inc., has developed a drug discovery platform that simultaneously identifies a cell surface target and generates a monoclonal antibody directed to that target. The input into this process is a panel of proprietary, tissue specific progenitor cells that by their very nature contain unique subsets of cell surface receptors that are involved in tissue differentiation and renewal. High throughput hybridoma generation and tissue-based screening protocols form the basis of a simplified and focused proteomic discovery (the antigen) and therapeutic generation (the monoclonal antibody) process. Application of this program to the identification of cell surface targets on tumor cells has generated a panel of antibodies directed to known cell surface targets (such as HER2/neu, Ep-CAM, EGFR, CEA, etc.) as well as new and novel targets that are being pursued to evaluate their clinical applications.

Speaker
Gordon A. Vehar, Ph.D.
Vice President, Research and Development
RAVEN BIOTECHNOLOGIES, INC.

2:30 - 3:00 - In vitro Optimization of Therapeutic Human Antibodies
Therapeutic human antibodies candidates are currently isolated using a variety of approaches including transgenic animals and phage display. These antibody "hits" are often developed into clinical candidates with minimal or no in vitro optimization. Our premise is that though these antibodies may be sufficient, they may not represent the antibodies with the best manufacturing and clinical profiles. In this context, we advance the concept of implementing a "lead optimization" process aimed at generating and selecting the best possible therapeutic candidates. We will describe Diversa's approach to directed evolution of human therapeutic antibodies and how it can be successfully integrated in a cost- and time-effective manner into an antibody lead generation process. In brief, we employ a mammalian expression system to produce full IgG molecules of each antibody variant. Using a high throughput transfection format, in combination with a functional Luminex bead assay, we can rapidly identify those variants with improved binding characteristics. In our model system, we demonstrate the identification of antibody variants that show significant enhancement in the binding affinity of an antibody to its antigen.

Speaker
Bruce Kimmel, Ph.D.
Director, Protein Therapeutics
Diversa Corporation

3:00 - 3:30 - Antibody Optimization by AISIMTM Technology
Abmaxis Inc, based in Mountain View, California, has developed a powerful technology platform for antibody discovery and optimization. AISIM(tm) (Abmaxis In Silico IMmunization) combines proprietary computational algorithms (AISIM-Discover(tm)) with biological selection (AISIM-Select(tm)) for antibody optimization. AISIM-Discover(tm) can identify important variants at critical sites for functional antibody candidates while containing the antibody library size for easy experimental targeting. AISIM-Select(tm) is a highly streamlined experimental system that enables efficient construction of designed libraries, using AISIM-Construct(tm), and biological selection of functionally expressed antibodies, using AISIM-Display(tm) These features enable AISIM(tm) to optimize antibodies with unprecedented speed and accuracy at significantly reduced cost. Specific examples are used to demonstrate the capabilities of the AISIM(tm) technology in optimizing antibodies: (1) Framework humanization with significantly enhanced binding affinity, (2) CDR optimization for affinity maturation, and (3) optimization for expression, folding and stability of candidate antibodies.

Speaker
Peter Luo, Ph.D.
President/CTO
Abmaxis, Inc.

3:30 - 3:35 - Conference Concludes

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