Part One: Immunogenicity Assessment and Clinical Relevance - Immunogenicity Summit

7:30 am Registration & Morning Coffee

UPDATE ON WHITE PAPERS & CURRENT CONCERNS

8:30 Chairperson’s Opening Remarks

Valerie Quarmby, Ph.D., Principal Scientist & Director, BioAnalytical Technologies & Strategies, Genentech, Inc.

UPDATE ON APPROACHES TO IMMUNOGENICITY ASSAYS

9:05 Strategy for Dealing with Drug Interference

Michele Fiscella, Ph.D., Associate Director, Clinical Immunology, Human Genome Sciences

We have developed a protein therapeutic that combines the efficacy of interferon alfa with the half-life of serum albumin. The novelty of the product combined with the certainty of unmatched interference generated many challenges. The approach to assess overall immunogenicity and the development of an assay with acceptable sensitivity will be discussed.

9:35 Experiences with Fluorometric and Electrochemiluminescence Based Blocking/Neutralizing Assays during the Clinical Development of a Biotherapeutic

Jaya Goyal, Ph.D., Principal Investigator, Clinical Science and Technology, Biogen Idec, Inc.

This case study highlights that during the course of clinical development; careful consideration of study population, dose levels and anticipated levels of circulating drug is required prior to the selection of assay configuration. Membrane based Delfia® fluorometric assay that provides ease of use may potentially be used for the detection of antibodies in a healthy volunteer study but in studies with autoimmune disease population, cell based ECL assay format that provides better matrix tolerance may be more appropriate.

Sponsored by
 10:05 Immunogenicity Assays: A Single Step in the Right Direction
Nicola Gaskell, Client Manager, Bioanalytical Sciences, Quotient Bioresearch
The challenges of immunogenicity screening assays include definition of suitable cut-points, and furthermore assays which can lack drug tolerance, and shortages of appropriate positive controls. This short presentation will focus on some technical aspects of determining the most suitable platforms for immunogenicity screening, and explores the application of homogenous (or semi-homogenous) immunogenicity assays for high throughput screening. 

10:35 Networking Coffee Break, Poster and Exhibit Viewing

11:15 Detection of Neutralizing Activity Using Cell-Based RNA Expression Assay

Margot O’Toole, Ph.D., Director, Translational Medicine, Pfizer, Inc.

Ex vivo treatment of human and monkey blood with recombinant human IL-21 (rhuIL21) induced IL2RA gene expression, and this response was inhibited in the presence of anti-human IL21R antibody. We evaluated correlations between the pharmacodynamic (PD) activity of, and anti-product antibody responses to, two anti-human IL21R antagonistic antibodies. Reflecting in vivo PD activity, the ex vivo rhIL21-dependent response was inhibited in blood from monkeys dosed IV with anti-IL21R, and inhibition correlated with pharmacokinetics. In monkeys that developed neutralizing ADA, however, anti-IL21R had no effect on their ex vivo response to rhIL21, providing a reliable cell based assay for neutralizing activity. 

INTERPRETING THE DATA

11:45 Inducing Tolerance to Statisticians: Cutpoint Determination Made Easier with Statistics

Donald Bennett, Ph.D., Director, Biostatistics, Biogen Idec, Inc.

This presentation will demonstrate the advantage of tolerating statistician’s requests when defining a cutpoint for an immunogenicity assay. We will compare statistical methods of cutpoint determination with immunogenicity data examples to help you evaluate which method to use for your assays. The goal is a better understanding of the statistical options for cutpoint determination, targeting false positive rates, and the data needed to get a good cutpoint estimate. Ultimately a statistically well defined immunogenicity assay cutpoint will save you and your company time and money.

Sponsored by
 12:15 pm Strategies for Identification and Characterization of ADAs Using MSD
David Sloan, Ph.D., Meso Scale Discovery 
The MESO SCALE DISCOVERY® (MSD) platform offers significant advantages for the rapid development and robust implementation of immunogenicity assays in preclinical and clinical settings to detect and characterize antibodies produced in response to biological therapeutics.  High sensitivity, broad dynamic range and tolerance to free drug, along with reduced matrix effects and a simplified workflow renders the platform ideally suited to address the challenges of immunogenicity assays. MSD® also provides solutions for NAb (neutralizing antibody) assays. Nab assays on the MSD platform can range from monitoring changes in receptor phosphorylation status or modulation of intracellular markers, to quantification of secreted proteins such as cytokines, to characterization and measuring cell surface receptors directly on the surface of whole cells. In this talk, strategies for optimization of screening immunogenicity assays will be discussed, and the applicability of the multiplexing capabilities of the MSD platform to isotype ADAs will be presented.

12:45 Luncheon Presentation or Lunch on Your Own (Opportunity available, please contact Ilana Quigley, Iquigley@healthtech.com) 

CASE STUDIES: PRE-CLINICAL IMMUNOGENICITY ASSESSMENT

2:15 Chairperson’s Remarks

Michele Fiscella, Ph.D., Associate Director, Clinical Immunology, Human Genome Sciences

FEATURED PRESENTATION
2:20 Studies in Immunotoxicology in Animals

Deborah Finco, Ph.D., Senior Principal Scientist, Immunotoxicology, Pfizer, Inc.

Administration of human monoclonal therapeutic antibodies administered to species commonly used in toxicology studies generally elicits an anti-drug antibody (ADA) response in some animals. The generation of ADA may impact drug exposure and/or result in other immune mediated toxicological findings. This case study present a unique hepatic toxicity associated with intravenous administration of a human monoclonal antibody to rats in a 13-week study. Similar findings were not observed in the subcutaneous arm of the rat study or in the IV or SC arms of a cynomolgus monkey study. The findings and possible mechanistic reason(s) for the findings will be discussed.

2:50 Risk Assessment and Monitoring of Antibody Responses to Biopharmaceuticals: BioMarin Case Studies

Eric D. Foehr, Ph.D., Director, Bioanalytical R&D, Biomarin Pharmaceuticals, Inc.

The following topics will be covered and discussed: evaluating immunogenicity in animal models of enzyme replacement therapeutics; review of a successful tolerance regimen in a canine model; the role of pre-existing antibodies in immune response to enzyme therapeutics; case studies of the impact of immunogenicity on safety, PK, and PD.

3:20 Optimizing a Suite of PK-PD-IG Assays for Assessment of Immunogenicity Illustrated by Case Studies

Sebastian Spindeldreher, Ph.D., Deputy Head, Bioanalytics, Novartis Biologics

Immunogenicity to a monoclonal antibody (mAb) often affects clearance of the mAb itself and/or binding to the target ligand. In addition, analytical methods which characterize either drug exposure or target binding are often affected by the presence of anti-drug antibodies and/or mAb-ligand complexes. Consequently, additional information regarding immunogenicity and the ability to neutralize target binding can be obtained from an understanding of the assay characteristics for both PK and PD assays. An integrated approach which combines information from a suite of appropriate PK-PD and IG assays can obviate the need for assays designed to characterize the neutralizing ability of anti-drug antibodies.

3:50 Networking Refreshment Break, Poster and Exhibit Viewing
 

MOVING FROM PRE-CLINICAL TO CLINICAL

FEATURED PRESENTATION
4:30 Informative Immunogenicity Assessment Strategies for Clinical Trials

Valerie Quarmby, Ph.D., Principal Scientist & Director, BioAnalytical Technologies & Strategies, Genentech, Inc.

In order to assess the immunogenic potential of biotherapeutics, appropriate methods must be developed for the detection and characterization of ATA responses. These methods must then be deployed in a systematic manner in well designed clinical studies, so that clinical events can be correlated with laboratory test results. This talk will discuss methods and strategies that are used in the acquisition of immunogenicity data from clinical trials. The talk will also review case studies showing the importance of interpreting ATA results in the context of safety, efficacy, pharmacokinetic and pharmacodynamic aspects of protein therapeutics.

5:00 Interpretation of Pre-Clinical Immunogenicity Results and How they Correlate with the Clinical Outcome

Kay-Gunnar Stubenrauch, Ph.D., Senior Scientist, Pharma Research, Bioanalytics, Roche Diagnostics

The immunogenicity of novel biologics is frequently screened for by use of a bridging ELISA. However, the ELISA is considered to be limited in the detection of low-affinity or IgG4 subtype anti-drug antibodies (ADAs). This case study will report on the experience with a clinical safety event-driven immunogenicity testing strategy for a novel biologic in comparison to conventional two-tiered immunogenicity testing. The correlation of ELISA-based ADA screening results with the incidence of clinical ADA events will be discussed in the light of the consistency of the results of the bioanalytical testing battery. The relevance of a safety event-driven testing strategy to reduce the risk of false-negative ELISA results will be examined.

5:30 Break-Out Sessions

Break out sessions are interactive moderated discussions on topics of interest to investigators in the field of Immunogenicity. Problems are discussed and solutions are shared.

6:30 Networking Reception in the Exhibit Hall

7:30 End of Day One of Immunogenicity Assessment and Clinical Relevance

MOVING FROM PRE-CLINICAL TO CLINICAL

7:30-8:15 am Sponsored Breakfast Presentations Available (Please contact Ilana Quigley, iquigley@healthtech.com)

8:30 am Chairperson’s Remarks

Margot O’Toole, Ph.D., Director, Translational Medicine, Pfizer, Inc.

8:35 Immunogenicity Monitoring of Nanobodies®: Translation of Pre-Clinical Data into Clinical Development

Josefin-Beate (Josi) Holz, Ph.D., Chief Medical Officer, Drug Development, Ablynx NV

Ablynx develops antibody-derived therapeutic Nanobodies for the use in patients affected by diseases such as cardiovascular, bone and in-flammation. Currently there are 4 llama-derived Nanobodies in clinical development and data will be presented on assessment of pre-clinical and clinical immunogenic potential and translation of immunogenicity assays from bench to bedside. The talk will address challenges of im-munogenicity assay development, preclinical versus clinical outcome, and risk assessment.

9:05  Assessment of Immunogenicity and Relevance to Clinical Observations

Matthew Baker, Ph.D., Chief Scientific Officer, R&D, Antitope Ltd.

New technologies are evolving aimed at pre-clinical prediction of immunogenicity in patients with the main focus being on detection of CD4+ T cell epitopes and analysis of immunogenicity in animal models. Validation of these pre-clinical technologies has either been through comparison of the MHC restriction or T cell responses in the laboratory vs. the clinic, or through comparison of immunogenicity in the laboratory vs. the clinic. Data from laboratory studies will be shown in order to determine the relevance of various preclinical technologies to clinical observations of immunogenicity including studies with in silico, ex vivo and animal model technologies.

CLINICAL CASE STUDIES

9:35  Measurement and Clinical Impact of IgE Anti-Drug Antibodies

Arno Kromminga, Ph.D., CEO, Immunology, IPM BIOTECH

There has been an increasing concern about the possibility and risk of IgE mediated type I hyper-reactivities, particularly due to novel host sys-tems such as plants or yeast. In addition, the route of administration may increase the risk of IgE ADA formation. The detection of IgE ADA is technically challenging due to the (un)-availability of appropriate positive controls and low circulating levels (ng/ml) of IgE.

Sponsored by
10:05 Validation of a Neutralizing Antibody (NAB) Elisa Based on Enzymatic Protein Functional Activity in Human Serum
Dominique Gouty, Ph.D., Scientific Director, Intertek-ALTA Immunochemistry
The clinical effect of patient immune responses to therapeutic proteins has ranged from no effect at all to extremely harmful effects to patient health depending on the therapeutic drug.  For some therapeutics, such as replacement proteins, validation of a neutralization assay may be required at the clinical stage.  In this presentation, we will describe the validation of an ELISA-based assay of serum enzymatic protein functional activity that has been adapted to detect the presence of NAB.  We will highlight the unique challenges of setting an IC50 cutpoint, determining the stability, linearity, and sensitivity for this assay.

Sponsored by
10:20 Clinically Relevant Immunogenicity Testing of Biologicals – Hypersensitivity Risks and IgE Measurement
Jörgen Dahlström, Ph.D., Scientific Director, Immune Response Diagnostics, Phadia, Sweden
The dramatic increase in the use of recombinant monoclonal antibodies and other biopharmaceuticals in the treatment of cancers and autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis has resulted in increased reporting of hypersensitivity reactions including anaphylaxis. This talk will cover the clinical benefits of measuring IgE antibodies to biologicals. Further, the value of quantification of antibody responses to biologicals in clinical situations will be discussed.

10:40 Networking Coffee Break, Poster and Exhibit Viewing

11:10 Speaker to be Announced

11:40  Immune Responses to Vector and Transgene Product in AAV-Mediated Gene Therapy

Katherine A. High, M.D., Investigator, Howard Hughes Medical Institute; William H. Bennett Professor of Pediatrics, University of Pennsylvania School of Medicine; Director, Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia

Recombinant adeno-associated viral vectors (AAV) have been successfully used in gene transfer for genetic disease. However, studies in healthy donors have shown antigen-specific memory CD8+ T cells to AAV capsid in a substantial portion of the human population. A clear understanding of capsid antigen processing and presentation, and of T cell responses to AAV, will be key to optimal application of the vector. In addition, immune responses to the transgene product itself may limit the success of gene transfer in the setting of genetic disease. Risk factors for these immune responses will also be discussed.

12:10 pm  Luncheon Presentation or Lunch on Your Own   (Opportunity available, please contact Ilana Quigley,   iquigley@healthtech.com)

Combined Session