Day 1 | Day 2 | Day 3
Tuesday, OCTOBER 27
8:30am Chairperson’s Remarks
Michael G. Tovey, Laboratory of Viral Oncology, Institute Andre Lwoff, CNRS
8:35 Current Regulatory Expectations for the Incorporation of Immunogenicity Assessments in Pre-clinical Studies
Joy Cavagnaro, Ph.D., D.A.B.T., R.A.C., President, Access BIO, LC
Immunogenicity testing has become “an industry” fueled by both real and perceived regulatory expectations. It is well understood that human proteins will likely be immunogenic in animals and thus the presence of antibodies in animals will generally not be predictive for humans. The information obtained, however, can be useful in identifying potential consequences of an immune response, assessing relative immunogenicity and, more importantly, is essential for interpretation of pre-clinical safety data. This presentation will provide an overview of current regulatory expectations and introduce some of the challenges in the design, scope and translatability of pre-clinical immunogenicity assessments for clinical and regulatory decision making.
9:05 Featured Presentation
Commonly Encountered Issues and Challenges in Pre-clinical Immunogenicity Assessments: Overview of the Biosafe White Paper, Consequences, and Specific Examples for Application
Bonnie Rup, Ph.D., Assistant Vice President, Protein Bioanalytics, Drug Safety and Metabolism, Wyeth Research
There has been significant confusion about the purpose of nonclinical immunogenicity assessments and their relevance to human immunogenicity. A white paper published in 2009 addresses the requirements and impact of immunogenicity testing on the toxicity profile. This presentation will overview the key points presented in that paper and present examples of the common issues and challenges that occur during pre-clinical immunogenicity assessments as well as when/when not relevant to human immunogenicity. The recommendations of the white paper will be presented in the context of specific examples of common issues encountered and strategies for overcoming them.
9:35 Sponsored Presentation (Opportunity available, please
contact Ilana Quigley, iquigley@healthtech.com)
9:55 Practical Application of Immunogenicity Pre-clinical Risk Assessment
Nadja S. Prang-Richard, Ph.D., M.B.A., Program Director, Monoclonal Antibodies, LFB S.A.
Immunogenicity risk assessment has become an important element in state-of-the-art biopharmaceutical development. To mitigate the risk related to the potential immunogenicity of a biological, an analysis of risk factors should be performed on a case-by-case basis resulting in a tailor-made immunogenicity assessment strategy prior to entering clinical trials. This presentation will discuss the predictive value of in silico methods, and in vitro and in vivo pre-clinical assessment from a regulatory perspective and will provide examples from “lessons learned” by the pharmaceutical industry.
10:25 Networking Coffee Break, Poster and Exhibit Viewing
11:00 KEYNOTE
Clinical Impact of Anti-Drug Antibodies
Meena Subramanyam, Ph.D., Senior Director, Clinical Science & Technology, Biogen Idec, Inc.
Development of anti-drug antibodies (ADA) to protein therapeutics results in a wide range of clinical sequelae. An effect on pharmacokinetics and pharmacodynamics is more commonly seen. Less frequently, there can be loss of efficacy due to neutralization of drug. In some instances, development of ADA may also result in generalized immune effects, such as anaphylaxis, serum sickness, hypersensitivity, etc. In rare cases, immunogenicity of a biotherapeutic can lead to neutralization of the endogenous human protein, resulting in fatal outcomes. Assessment of the nature of the risk, and development of appropriate analytical methods to understand the risk are two key elements in developing an immunogenicity evaluation strategy. This talk will provide an overview of the immunogenicity experience with therapeutics approved for clinical use.
11:30 Clinical Immunogenicity Assessment of an Adnectin Evaluated from a PK and PD Perspective
Jochem Gokemeijer, Principal Scientist, Pharmacology, Adnexus Therapeutics, a Bristol-Myers Squibb R&D Company
Adnectins are a novel, proprietary of targeted biologics that are derived from human fibronectin, which is a well-characterized, highly-expressed plasma protein. Adnectin-based products offer potential advantages compared to traditional protein therapeutics, including speed of discovery, ease of manufacturing, and the ability to create an array of multi-functional targeted biologics. This presentation will review the risk based assessment of immunogenicity in patients treated with CT-322, a VEGFR-2 inhibiting Adnectin and the evaluation of clinical relevancy of anti drug antibodies
12:00 Managing Allergenicity Risks in Clinical Development of 
Biopharmaceutical Drugs
Jörgen Dahlström, Ph.D., Scientific Specialist, Clinical Allergy, Phadia
The clinical benefits of measuring IgE antibodies to biologicals. Further, the value of quantification of antibody responses to biologicals in clinical situations will be covered.
12:20 Luncheon Presentation (Opportunity available, please contact Ilana Quigley, iquigley@healthtech.com)
1:30 pm Chairperson’s Remarks
Meena Subramanyam, Ph.D., Senior Director, Clinical Sciences & Technology, Biogen Idec, Inc.
1:35 Featured Presentation
Development of Cell-based Assays for Neutralizing Antibodies for Routine Clinical Immunogenicity Studies
Michael G. Tovey, Ph.D., Director, Research, Laboratory of Viral Oncology, Institute Andre Lwoff, CNRS
Regulatory authorities require the use of cell-based assays for the detection of NAbs since some antibodies can neutralize drug activity without inhibiting binding, and consequently would not be detected using competitive ligand binding assays. A novel cell-based platform technology has been developed that allows both drug levels and anti-drug NAbs to be quantified in a single serum sample using an identical readout for different drugs, luciferase induction, in division arrested, frozen, genetically engineered cells. This fully automated technology allows direct comparison of immunogenicity data for patients treated with different drugs.
2:05 Generation of Anti-idiotype Antibodies as Reagents for the Development of Immunogenicity Assays
Claire Dobson, Ph.D., Head, Display Technology - Neuroscience & CVGI, Lead Generation, MedImmune, Inc.
The pre-clinical and clinical development of therapeutic antibodies requires assays that measure the potential immune response to the candidate drug. Anti-idiotype antibodies with high affinity and specificity for the candidate drug are ideal reagents for the development of such assays. We describe methods for generating anti-idiotype antibodies using either phage display or hybridoma technology. This has been combined with high-throughput screening utilizing parallel HTRF assays to identify anti-idiotype antibodies with the required specificity and function.
2:35 Challenges with Development of Anti-Therapeutic Antibody Assays to Detect Antibodies of IgE Subtype
Sally Fischer, Ph.D., Senior Scientist and Group Leader, Bioanalytical Research and Development (BARD), Genentech, Inc.
Therapeutic proteins may elicit immune responses ranging from detectable but not clinically significant, to having significant impact on efficacy and/or safety. Type 1 or immediate type hypersensitivity reactions are IgE mediated. Development of anti-therapeutic antibody assays to detect antibodies of the IgE subtype is technically very challenging. This is due to availability of appropriate positive controls and low circulating levels (ng/ml) of IgE. This talk will outline the challenges associated with development of such methods in general and will also discuss a Xolair case study.
3:05 Cutpoint Assessments for Immunogenicity Validation: Comparison, Considerations, and Challenges
Michele Gunsior, Ph.D., Principal Investigator, Covance
One of the most important parameters evaluated in validation of an immunogenicity method is the cutpoint, which allows for the designation of samples as putatively positive or negative. The clinical impact of false-negative samples can range from little effect to devastating consequences. Recent white papers have called for a more statistical approach to cutpoint determination, including normality assessments and possible mathematical transformations. Several case studies will be presented discussing the particular approach employed with comparisons to other possible methods, and impact on relative percent positive or negative rates.
3:25 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 Development and Validation of Drug Specific IgE Antibody Assays for use in Clinical Trials
Erik D. Foehr, Ph.D., Director, BioAnalytical Research and Development, BioMarin Pharmaceuticals, Inc.
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 drug specific IgE. The presentation will also describe IgE assay characteristics and present clinical sample test results. Technical challenges that have a broad impact on immunogenicity testing will be presented. We evaluate approaches to develop isotype specific assays when drug-specific isotypes are not available for use as controls.
4:30 Evolution of Immunogenicity Assays over the Life-cycle of a Clinical Program
Albert Torri, Ph.D., Senior Director, Pre-clinical Development, Regeneron Pharmaceuticals, Inc.
The methods used to evaluate drug immunogenicity often evolve as a drug moves through clinical development. Assay methodologies may change reflecting new technologies and lessons learned from past experiences. In addition, regulatory expectations often become higher over time and data presented to the agency may elicit concerns about the current assay, requiring that new methods be developed and validated. In this presentation we will present two case studies and discuss how new technologies and past experience impacts current assays development efforts.
5:00 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.
Table 1
Relevance of Animal Models for Predicting the Immunogenicity of Therapeutic Proteins
Moderator: Joy Cavagnaro, Ph.D., D.A.B.T., R.A.C., President, Access BIO, LC
Are relative immune responses (aggregated vs. non-aggregated human protein in a mouse) a valid measure? How might known differences in the human and mouse adaptive and innate immune systems impact the results? What, if any, is the role of adjuvants in such studies?
Table 2
Immunogenicity Testing during Clinical Trials
Moderator: Meena Subramanyam, Ph.D., Senior Director, Clinical Science & Technology, Biogen Idec, Inc.
Table 3
Monoclonal Antibodies: Level of Immunogenicity-related Risk Relative to other Product Types
Moderator: Paul Chamberlain, NDA Advisory Board
What are the pertinent risk factors? How should we interpret bioanalytical signals relative to clinical significance? How adequately can the residual clinical risk be managed?
Table 4
What Can and Cannot be Learned from Pre-clinical Studies and How to Carry out a Meaningful Risk Assessment
Moderator: Nadja S. Prang-Richard, Ph.D., M.B.A., Program Director, Monoclonal Antibodies, LFB S.A.
What are the limitations of current approaches? Are there better alternatives to animal testing? What are the benefits of surrogate systems? What is the best way of bringing together pre-clinical, in silico, and cell-based assay data for risk assessment? Should clinical programs be stopped on the basis of pre-clinical or in silico data? Sharing experience in presenting an immunogenicity risk assessment to the health authorities Current status and future trends in immunogenicity pre-clinical programs
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6:00 End of Day Two of Immunogenicity Assessment and Clinical Relevance
For more information, please contact:
Nicole Lyscom, Ph.D.
Conference Producer
Cambridge Healthtech Institute (CHI)
Phone: +44-1483-826359
E-mail: nlyscom@healthtech.com
For sponsorship information, please contact:
Ilana Quigley
Manager, Business Development
Cambridge Healthtech Institute (CHI)
Phone: +1-781-978-5457
Cell: +1-857-636-2334
Email: iquigley@healthtech.com