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Strategies and Techniques for

IMMUNOGENICITY TESTING

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Meeting Immunogenicity Challenges While Maintaining FDA and Regulatory Expectations

March 8-9, 2007 · La Jolla Marriott · San Diego, CA

LEARN FROM INDUSTRY EXPERTS!

Novel Cell-based Avenues in Evaluating the Immunogenicity Potential of Therapeutic Antibodies

HOFFMAN LA-ROCHE

HUMAN GENOME SCIENCES

Compare and Contrast White Paper Screening Cut Point Calculations for Immunogenicity Assays

7 INDUSTRY CASE STUDIES

INCLUSIVE WORKSHOP

How To Solve Matrix Interference and Other Immunology Challenges

WYETH

Developing a Novel Statistical Approach for Setting a Cut Point for a Confirmatory Assay

PDL BIOPHARMA

BIOMARIN PHARMACEUTICALS

Evaluating Immunogenicity Data in the Context of Clinical Safety and Efficacy

Methods for Pre-Screening Protein Therapeutics for Potential Clinical Immunogenicity

EPIVAX

EX-FDA

A Regulatory Perspective on the Use of Comparability Protocols for Expedited Approval and Implementation of Manufacturing Changes

PHARMANET

Monitoring CD4+ T Cell Responses with Class II Tetramers

BENORAYA

.....AND MANY MORE

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Organized By: SWE Enterprises · P.O. Box 23202 · Tampa, Florida 33623 Telephone: 813-655-7788 · Fax: 413-480-9953 · Website: www.sweinc.biz

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Immunogenicity Challenges While Maintaining FDA and Regulatory Expectations

DAY ONE THURSDAY, MARCH 8, 2007

7:45 REGISTRATION AND BREAKFAST

CASE STUDY 1:00 METHODS FOR PRE-SCREENING PROTEIN THERAPEUTICS FOR POTENTIAL CLINICAL IMMUNOGENICITY: REVIEW OF AVAILABLE TOOLS AND TECHNIQUES, AND DEVELOPING A STANDARD FOR COMPARISON Annie De Groot MD, Associate Professor, Brown Medical School, CEO EPIVAX

8:45

CHAIRPERSON'S WELCOME AND OPENING REMARKS IN-DEPTH WORKSHOP

9:00

HOW TO SOLVE MATRIX INTERFERENCE AND OTHER IMMUNOLOGY CHALLENGES Michel Awaad, Ph.D., is Associate Director WYETH

Matrix interference could be defined as a substance(s) in serum/plasma that can through their interaction with assay component affect, either positively or negatively, the signal generated in an assay, such that results produced could be inaccurate. Reactivity of many of the substances that cause matrix interference are specific, through irrelevant to the product being tested. Examples of matrix interference may include: · Reactivity of serum/plasma components (lgG/lgM) with carbohydrates of analyte · Reactivity of serum/plasma component with the analyte (soluble receptor, binding protein, anti-cytokine Abs) as a result of normal physiological response · Reactivity of serum/plasma component (lgG/lgM) with "Impurities" in the product Matrix interference can be reduced by simple solutions, e.g. increasing dilution factor or ionic strength. Such solutions, however, may reduce sensitivity of the assay and may not completely reduce interference in samples for some individuals. Identifying the source of the interference may allow its removal and the development of more sensitive assays that works with all individuals.

The screening of biological compounds for T cell immunogenicity plays an important role in the safety and efficacy of protein therapeutics. There is a considerable amount of interest in this area of research and it is important to provide scientist with the necessary information about the tools and options that are available to reliably assess their compound. Educating researchers as to which of these tools is the most effective and appropriate for their needs will help to improve the development of safer protein therapeutics. The goal of this session is to begin to develop a consensus on the role of cellular immunity (T helper cells and T regulatory cells) in the development of anti-drug antibodies and immune-related adverse events such as aplastic anemia following the administration of erythropoietin. In addition, methods for predicting and confirming T cell immunogenicity (in silico, in vitro and in vivo) will be compared and contrasted. New theories about immunogenicity and standards for the determination of immunogenicity will be discussed. An attempt will be made to clarify "what is known" about the contribution of cellular immune response to protein therapeutics (drawing from what is known about protein immunogens such as vaccines) and 'what is not known" including such topics as the role of T regulatory cells and cytotoxic T cells. CASE STUDY 2:00 DEVELOPING A NOVEL STATISTICAL APPROACH FOR SETTING A CUT POINT FOR A CONFIRMATORY ASSAY Ingrid Caras, Ph.D., Senior Director, Pre-clinical and Clinical Development Sciences PDL BIOPHARMA INC.

About the workshop leader: Michel Awaad, Ph.D., is Associate Director of DSM at Wyeth. He holds a Ph.D. in Parasitology, did his postdoctoral studies in Cancer Immunology and Immunotherapy, and worked in Transplantation Immunology. Dr. Awwad has worked in one instance to boost the immune responses to destroy tumors while in others, worked to destroy the immune response to allow the survival of transplanted organs into NHP, xenotransplantation. Over 65% of his efforts have been in preclinical development.

Clinical data from confirmatory assays, designed to confirm the presence or absence of anti-Drug antibodies in a sample, are often ambiguous and difficult to interpret. This session will focus on how to set a meaningful cut point for confirming positivity. A novel approach employing the student's t-test will be presented and the session will detail how different approaches to the cut point problem impact data from a real clinical trial.

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You will learn about: · Problems and issues frequently encountered when running confirmatory assays on clinical samples · How to set a meaningful and non-random cut point for a confirmatory assay 2:45 AFTERNOON BREAK · 7TH INNING STRETCH

· · · ·

An update on class II tetramer technology The uses of class II tetramers in identifying T cell epitopes The uses of class II tetramers in monitoring CD4+ responses How HLA polymorphisms influences T cell responses INTERACTIVE PANEL DISCUSSION INCLUDING ALL DAY ONE SPEAKERS

5:15

Best Practices for Immunogenicity Testing ANALYZING AND INCORPORATING THE IMMUNOGENICITY DATA INTO THE OVERALL CLINICAL DATA AND CLINICAL DEVELOPMENT CASE STUDY 3:00 EVALUATING IMMUNOGENICITY DATA IN THE CONTEXT OF CLINICAL SAFETY AND EFFICACY: NAGLAZYME CASE STUDY Joleen White, Ph.D.Scientist, BioAnalytical Sciences BIOMARIN PHARMACEUTICAL

7:45

· Discuss Current Trends and Developments · Complying with FDA and Other Regulatory Requirements · Questions and Answers 5:30 END OF DAY ONE

DAY TWO FRIDAY, MARCH 9, 2007

BREAKFAST

The evaluation of immunogenicity is an essential component of the evaluation of biopharmaceutical safety and efficacy. Once the data is collected, the results need to be placed back into the context of the overall clinical program. The focus of this session would be to present some possible approaches for this analysis: · Review the risk-based approach to evaluating immunogenicity · Review additional data pharmacodynamic commonly collected during clinical trials that could be affected by immune response · Present methods that can be employed to determine whether the clinical results are affected by the presence of an immune response · Present a case study with Phase 2 and Phase 3 clinical data from total antibody and neutralizing antibody addressing: · · · · Correlations with safety measures Correlations with primary study endpoints Correlations with surrogate biomarkers Correlations with pharmacokinetic parameters

8:45

CHAIRPERSON'S OPENING REMARKS

CASE STUDY 9:00 COMPARISON OF NEUTRALIZING ANTIBODY ASSAYS FOR RECEPTOR BINDING AND ACTIVITY OF THE ENZYME REPLACEMENT THERAPEUTIC NAGLAZYME Erik Foehr, Ph.D., Associate Director, Pharmacology and Toxicology BIOMARIN PHARMACEUTICAL INC.

Naglazyme (recombinant human N-Acetyl-galactosamine 4-sulfatase) is an enzyme replacement therapeutic for the treatment of Mucopolysacharidosis VI (MPSVI). MPSVI is a lysosomal storage disorder characterized by accumulation of glycosaminoglycans (GAGs). The progressive disorder results in multiple organ and tissue involvement resulting in severe disability. Neutralizing antibodies that inhibit receptor binding and/or enzyme activity could decrease the therapeutic efficacy. This session will: · Present ways to incorporate cell-free neutralizing antibody assays that are based on the drug mechanism of action

4:00

MONITORING CD4+ T CELL RESPONSES WITH CLASS II TETRAMERS William Kwok, Member, Benaroya Research Institute VIRGINIA MASON

· Describe the assay characteristics and present clinical · Evaluate neutralizing antibodies assays in the context of FDA post-marketing commitments · Present technical challenges that have broad impact on immunogenicity testing

This session will describe the uses of class II tetramers in identifying CD4+ T cell epitopes and monitoring of CD4+ responses. The following topics will be addressed:

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FDA PERSPECTIVE ON COMPARABILITY PROTOCOLS 10:00 A REGULATORY PERSPECTIVE ON THE USE OF COMPARABILITY PROTOCOLS FOR EX-FDA EXPEDITED APPROVAL AND IMPLEMENTATION OF MANUFACTURING CHANGES Duu-Gong Wu, Ph.D., PharmaNet, Inc, former Reviewer, Chemistry Team Leader, and Deputy Division of New Chemistry II, Officer of New Drug Chemistry (ONDC) on CDER, FDA Due to unique molecular characteristics, comparability assessment of biotechnological/biological products after manufacturing changes often requires more than simple physicochemical and biological tests and a long regulatory approval process through prior approval supplements. As a part of new regulatory initiatives, FDA has published two guidance documents for the use of comparability protocols to facilitate approvals and implementation of manufacturing changes by manufacturers. In some cases, with a pre-approved comparability protocol, the changes can be implemented through downgraded submissions such as Changes-Being-Effected (CBE) supplements or Annual Reports. The presentation will focus on regulatory perspectives and practical applications of comparability protocols, including: · Scope of comparability protocols for manufacturing changes · Feasibility and utility of comparability protocols · How to design comparability protocols for anticipated manufacturing changes · Experience in submissions and reviews of comparability protocols 11:00 MID-MORNING BREAK CASE STUDY 11:15 NOVEL CELL-BASED AVENUES IN EVALUATING THE IMMUNOGENICITY POTENTIAL OF THERAPEUTIC ANTIBODIES Harald Kropshofer, PhD. Head & Global Coordinator, Immunosafety of Biotherapeutics HOFFMAN LA ROCHE The vast majority of high-affinity and IgG-mediated immunogenicity responses against therapeutic antibodies rely on activation of CD4+ T helper cells. For their activation they need to recognise short sequence stretches within the heavy or light chain of the respective antibody molecule, denoted as "T cell epitopes". Besides in silico algorithms, in vitro assays based on human antigen presenting cells are available to identify T cell epitopes. Moreover, human T cell activation assays have

entered the field: they are suitable to rank antibody lead candidates with respect to their differential potential to stimulate T cells and, thereby, trigger immunogenicity. Implementation of these cell-based tools into the pre-clinical development plan may provide an opportunity to control and reduce the number of immunogenicity-induced adverse events of next generation monoclonal antibodies. This presentation will provide knowledge on: · How to judge sequence-based immunogenicity hot spots within therapeutic antibodies · How good in silico tools can only be for predicting immunogenicity · How advanced human cell-based in vitro tools are for pre- clinical assessment of immunogenicity · How to compare peptide scanning versus whole proteinbased approaches · How the target molecule of therapeutic antibodies may codetermine their immunogenicity 12:15 LUNCHEON CASE STUDY 1:15 COMPARE AND CONTRAST WHITE PAPER SCREENING CUT POINT CALCULATIONS FOR IMMUNOGENICITY ASSAYS Martin Kane, M.S., Senior Manager, Process Statistics, Department of Biostatistics HUMAN GENOME SCIENCES, INC

This session will compare and contrast the three statistical methods for determining the screening cut point as outlined in the Immunoassay Validation White Paper. We will examine: · Fixed, Floating, and Dynamic ­ Do any of these methods sound familiar to you? · Comparison using simulation to demonstrate the benefits of each method · Case Study for Human Genome Sciences CASE STUDY 2:00 DETECTION OF IgE ANTIBODIES SPECIFIC TO THE ENZYME REPLACEMENT THERAPEUTIC NAGLAZYME ­ A REVERSED ELISA FORMAT Bin Zhao, Scientist II, BioAnalytical Research & Development BIOMARIN PHARMACEUTICAL INC.

Naglazyme is an enzyme replacement therapeutic for the treatment of MPS VI. Due to its nature as a recombinant protein,

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immunogenicity specific to this therapeutic is a concern. As part of our Post-Marketing Commitment to the FDA, we developed and validated a Naglazyme-specific IgE antibody assay. Detection of drug specific IgE is often limited due to the presence of IgG at a higher concentration. To circumvent this we will discuss the development of a new reversed ELISA format to detect Naglazyme-specific IgE. We will examine: · Discuss the immunogenicity assay systems currently requested by regulatory authorities · Describe IgE assay characteristics and present clinical sample test results · Present the technical challenges that have broad impact on immunogenicity testing · Evaluate an approach to develop isotype specific assays when drug-specific isotypes are not available for use as controls

2:45 3:00

AFTERNOON BREAK THE PREDICITIVE UTILITY OF TECHNOLOGIES FOR PROFILING THE IMMUNOGENICITY OF THERAPEUTIC PROTEINS DURING PRECLINICAL DEVELOPMENT Matthew Baker ,Chief Scientific Officer ANTITOPE LTD

Data will be presented demonstrating enhancements in the in vitro detection of T cell epitopes within therapeutic antibodies. This enhanced method has been applied to screen lead therapeutic proteins during preclinical development, and provides an assessment for the relative risk of immunogenicity. Furthermore, data will be presented in which a refinement of this process has been applied to enable the selection of fully human sequence segments that are devoid of T cell epitopes. These non-immunogenic fully human sequence segments are used to generate novel humanized therapeutic antibodies. This presentation will include: · Outline of the benefits of in silico, in vitro and in vivo methods for assessing immunogenicity · How assessment of the relative risk for immunogenicity can be used to select lead therapeutic proteins during early pre-clinical development · How 'immunogenicity testing' assays can be integrated with exisiting and new protein engineering technologies 4:00 CLOSE OF CONFERENCE

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STRATEGIES AND TECHNIQUES FOR IMMUNOGENICITY TESTING March 8-9, 2007 La Jolla Marriott · San Diego, CA

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