Day 1 | Day 2 | Day 3
MONDAY, OCTOBER 26
1:00pm – 2:00 pm Registration for Conference A
2:00 Chairperson’s Opening Remarks
Bonnie Rup, Senior Director, Bioanalytical R&D, Drug Safety and Metabolism, Wyeth Research
2:05 Opening Presentation: Regulatory Guidance and Recent White Papers
Gopi Shankar, Ph.D., Director, Clinical Pharmacology Sciences, Centocor R&D, Inc.
The immunogenicity of therapeutic proteins can affect their safety and efficacy profile. Monitoring of immunogenicity is therefore required during all phases of biotherapeutic drug development, and its characterization represents a key component of regulatory filings. In this context, highlights of current regulatory recommendations and expectations, and industry whitepapers on methods and strategy will be presented.
2:35 Crossroads in Immunogenicity Assays: Where Tolerance and Interference Meet
Michele Fiscella, Ph.D., Associate Director, Clinical Immunology Department, Human Genome Sciences
The development of better clinical assays is a constant effort during the development of any program. More sensitive and drug tolerant immunogenicity assays developed for late-stage clinical studies often supersede less sophisticated assays employed during pre-clinical development and early phase clinical studies. This may lead to characterization of higher incidence of drug-induced immune responses. New assay platforms and/or design can also produce misleading results depending on the drug target. A case study will be presented to show how reducing interference from the circulating drug may generate interference from the target.
3:05 Confirmatory Assays, Cut Points, Statistical Analysis and Clinical Interpretation
Dong Geng, Ph.D., Principal Scientist, Bioanalytical Sciences, Bristol-Myers Squibb Co.
A three-tiered strategy involving screening, confirmation and neutralization assays is widely used for immunogenicity analysis. The confirmation assay uses competitive inhibition to identify the true immunogenicity positive samples and eliminate the false positives from the screening assay. However, defining the cut point is a challenge. The conventional approach can lead to inaccurate results. A specificity confirmation cut point is recommended in the white paper of immunogenicity assay validation. This method calculates the confirmation cut point through statistical assessment of the assay system variance using a panel of negative samples. The differences in confirming anti-drug antibody positive responses using specificity cut point, t-test and arbitrary cut point are examined and discussed in a clinical case study.
3:35 Networking Refreshment Break, Poster and Exhibit Viewing
4:10 Comparison of Cell-Based and Competitive Ligand-Binding Assay Formats to Characterize Neutralizing Antibody Responses
Bonnie Wu, Ph.D., Senior Research Scientist, Clinical Pharmacology Sciences, Centocor Research & Development, Inc.
Anti-drug antibody (ADA) responses to therapeutic protein drugs often involve the generation of neutralizing antibodies (NAb), which can impact the drug’s safety and efficacy profile. Therefore, it is important to assess whether treatment-emergent ADAs can neutralize drug activity. Cell-based assays are typically used for the characterization of NAbs in clinical samples; however, non-cell based competitive ligand-binding assays are another viable option. The latter are particularly attractive because they are generally less prone to the practical and technical limitations. Two case studies will be presented that directly compare the cell-based and competitive ligand binding assay formats for the detection of neutralizing antibodies to therapeutic monoclonal antibodies.
4:40 Sponsored Presentation (Opportunity available, please
contact Ilana Quigley, iquigley@healthtech.com)
5:00 Development and Validation of Anti-drug Antibody Assays for an Antibody Fragment Conjugated to Pseudomonas Exotoxin A
Meina Liang, Ph.D., Associate Director, PKPD & Bioanalysis, MedImmune, Inc.
CAT-8015 is a recombinant immunotoxin comprised of VH and VL chains of mouse anti-CD22 monoclonal antibody and a cytotoxic fragment of Pseudomonas Exotoxin A (PE38). We will report on the development and validation of a bridging immunoassay using electrochemiluminescent (ECL) technology and of a cell-based cytotoxicity assay that can detect antibodies to both the anti-CD22 antibody fragment and PE38 portions of CAT-8015. These assays can be utilized for characterization of anti-drug antibodies in CAT-8015 treated patients or monkeys and the identification of immune responses in these patients that could potentially affect pharmacokinetics and/or efficacy of the drug.
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.
Table 1
Dealing with Unexpected Pre-existing Positive ADA Activity in Study Patients
Moderator: Boris Gorovits, Ph.D., Director, Bioanalytical R&D, Wyeth
Relations between validation-based prediction of reactivity in naive samples (e.g. naive normal human samples) vs. reactivity in pre-dose samples collected from study patients. Focused on potential plan of action, interaction with clinical groups, etc. Should patients be monitored regularly for the presence of ADA or should ADA be assessed only after changes in PK or clinical parameters Challenges of assessing ADA in the presence of high levels of circulating drug Is the determination of ADA “titer” necessary
Table 2
The Cut Point Analysis for the Neutralizing Antibody Assay
Moderator: Dong Geng Ph.D., Principal Scientist, Bioanalytical Sciences, Bristol-Myers Squibb Co.
Table 3
Benefits and Risks of the Competitive Ligand Biding Assays for Neutralizing Antibodies
Moderator: Bonnie Wu, Ph.D., Senior Research Scientist, Clinical Pharmacology Sciences, Centocor Research & Development, Inc.
When can a non-cell based competitive ligand binding assay replace a cell-based bioassay? How close to the MOA should a neutralizing antibody assay be? Does a non-cell based competitive ligand binding assay provide as much information as a cell-based assay? For low risk products, if a sensitive non-cell based assay is already available, is it still mandatory to perform a comparative analysis of the cell-based and non-cell based neutralizing antibody assays to justify the final assay format? Can a sensitive non-cell based competitive ligand binding assay be used throughout the different phases (phases 1, 2 and 3) of a drug program?
Table 4
The Impact of the Dosing Regimen on Drug Immunogenicity
Moderator: Volker Schellenberger, Ph.D., Vice President, Drug Discovery, Amunix, Inc.
Do drug holidays result in increased immunogenicity risk? Are low drug doses more or less immunogenic? Can long half-life and continuous drug exposure reduce the immunogenicity risk?
Table 5
Immunogenicity Lessons from the Literature
Moderator: Fiona A. Harding, Ph.D., Associate Director, New Technologies, Facet Biotech Corp.
Immunoglobulins as vaccines (both IgG constructs as well as idiotype vaccines for B cell lymphomas) Revisiting Jerne’s Network Theory Tolerance and immunity to self Modified self in mouse models
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6:30 Networking Cocktail Reception in the Exhibit Hall (Opportunity available, please contact Ilana Quigley, iquigley@healthtech.com)
7:30 End of Day One 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