2015 Archived Content

Immunogenicity Assessment and Clinical Relevance

CHI's Seventh Annual Immunogenicity Assessment and Clinical Relevance conference, part of the Immunogenicity and Bioassay Summit 2015, presents regulatory expectations and advice, and industry experiences on all the key challenges for innovators and biosimilars: interpretation and reporting of data including confirmatory assays and cutpoints, preclinical studies and risk assessment, dealing with pre-existing antibody, managing target interference, and setting up appropriate ADA assays including neutralizing antibody assays. Clinical case studies on anti-TNF, a formulation of Herceptin, and a receptor for autoimmune disease will be presented.

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7:30 am Registration and Morning Coffee

8:30 Chairperson’s Opening Remarks

Bonita Rup, Ph.D., Biotechnology Consultant, Bonnie Rup Consulting LLC

8:35 A Harmonized Approach to Interpretation and Reporting of Clinical Immunogenicity Data

QuarmbyValerie Quarmby, Ph.D., Staff Scientist, BioAnalytical Sciences, Genentech, Inc.

A recent “White Paper” (Shankar et al 2014 AAPSJ) has provided a common set of terms and definitions to describe clinical immunogenicity data. The paper also provides a harmonized approach to the interpretation of immunogenicity results in the context of pharmacokinetics, efficacy, and safety. Industry-wide use of these recommendations will enable the clinical relevance of immunogenicity to be assessed consistently.


9:05 How Product Quality Attributes of Biotherapeutics Affect Immunogenicity: A Regulatory Perspective

William HallettWilliam Hallett, Ph.D., Product Quality & Immunogenicity Reviewer, CDER/OPQ/OBP FDA

Several quality attributes of biopharmaceuticals can significantly impact its immunogenic potential. Critical quality attributes of biopharmaceuticals that affect immunogenicity include molecular structure, glycosylation, aggregates, subvisible particulates, mechanism of action, etc. Manufacturing changes made during product life cycle, e.g. scale up, fermentation, raw materials, formulation, dosage form, etc. may affect a product’s immunogenic potential. This presentation discusses the regulatory perspective on product quality management and its effect on immunogenicity.

9:35 Regulatory Perspectives on Setting up the Clinical Immunogenicity Study for a Biosimilar

Susan KirshnerSusan Kirshner, Ph.D., Associate Chief, Laboratory of Immunology, Therapeutic Proteins, Biotechnology, CDER/FDA


10:05 Multiplexing Immunogenicity Assays with the MSD U-PLEX® Platform

Moller_LaureLaure Moller, Ph.D., Director, Scientific Support North America, Meso Scale Discovery

There is an increasing demand to test for the presence of anti-drug antibodies (ADA) in multiple immunogenicity assays. Examples include determining which epitope of a drug is recognized by ADA in test samples, or which co-administered therapeutic is eliciting an immune response. Multiplexing also enables the development of assays that can simultaneously test samples for the presence of both ADA and potential interfering factors such as free drug or rheumatoid factor. Traditionally, immunogenicity assays have been performed as individual assays. Using MSD’s MULTI-ARRAY® technology, the U-PLEX® platform enables conversion of individual immunogenicity assays into a multiplex assay while maintaining the sensitivity and drug tolerance of the individual assay format. The U-PLEX system provides a simple, flexible method to multiplex assays using the same reagents used in individual bridging immunogenicity assays, and requires no specialized equipment. Multiplexing is an effective method for both increasing assay throughput and reducing the amount of sample required for testing.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

11:15 Lessons Learnt from the European Experience Regarding Biosimilars and Immunogenicity

Paul ChamberlainPaul Chamberlain, NDA Advisory Board

The experience gained during the 10-year period following the implementation of the EU biosimilars pathway indicates that a suitably cautious approach was applied, insofar as no immunogenicity-related issues have emerged for the approved applications of the different biosimilar products. In some cases, product quality-related issues were identified in the pre-authorization setting as being potential relevant for heightened risk of immunogenicity and were duly taken into account for the biosimilarity decision.

11:45 Experiences with Immunogenicity Assessment in Biosimilar Trails with a Monoclonal Antibody

Niklas_CzelothNiklas Czeloth, Ph.D., Head, Biosciences, Biosimilars, Boehringer Ingelheim

Immunogenicity assessment of biosimilar products is an important aspect of the overall development process while the experience with monoclonal antibody biosimilars still remains limited. The presentation will share experiences in setting up immunogenicity assays for a biosimilar product and will discuss on relevance of differences observed for the same product in two independent trials using healthy volunteers. 

12:15 pm Sponsored Presentations (Opportunities Available)

12:45 LUNCHEON PRESENTATION: Challenges Associated with the Immunogenicity Assessment of Pegylated Products

Marie-Soleil Christine-Piché, Ph.D., Scientific Director, Immunology, Charles River Montreal
End User to be Announced

1:45 Session Break


2:15 Chairperson’s Remarks

Theo RispensTheo Rispens, Ph.D., Senior Scientist, Immunopathology, Sanquin


2:20 Strategies for Immunogenicity Risk Assessment

Bonita Rup, Ph.D., Biotechnology Consultant, Bonnie Rup Consulting LLC

Immunogenicity risk assessments typically consider an established set of risk factors relating to the product and recipient population, and treatment regimens. As the number of biopharmaceuticals under development increase, competitive and regulatory risk should also be considered. To assure the value of these assessments, it is important to continuously re-examine the “generally accepted” risk factors, particularly to better understand how they interact and determine how to improve their reliability. This presentation will overview the current practices of risk assessment and mitigation and discuss potential options for continuous improvement.

2:50 Case Studies in Non-Clinical Immunogenicity Testing with Fit for Purpose Assays: Isotype Control Assays for Overcoming Target Interference

Michael PartridgeMichael Partridge, Ph.D., Staff Scientist, Bioanalytical Sciences, Regeneron, Inc.

The industry standard for ADA detection, the bridging immunoassay, requires the production of specific reagents and may be susceptible to target interference. We evaluated fit for purpose assays in non-clinical studies as alternatives for ADA detection. These methods included bridging assays that detect ADA generated to the constant regions of mAb drugs as well as ELISAs. This presentation will discuss the advantages and limitations of these approaches in several non-clinical studies.

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 Choosing an Appropriate ADA Assay for Preclinical Studies: Comparison of Different ADA Assays in NHP Case Studies

Jianyong (Jerry) Wang, Ph.D., Scientist, Biochemical and Cellular Pharmacology, Genentech, Inc.

Sensitive and fast ADA testing methods play important roles in preclinical studies. Different plate-based ADA assays were compared in multiple NHP studies involving bispecific antibodies, IgG1 and IgG4 mAbs. The attractive features and limitations of each method, and critical factors on assay development will be discussed to provide a general guidance for selecting an appropriate ADA assay for preclinical studies.

4:30 Problem Solving Roundtable Discussions

These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

Table1: Meeting Regulatory Expectations

Moderator: William Hallett, Ph.D., Product Quality & Immunogenicity Reviewer, CDER/OPQ/OBP FDA

Table 2: Challenges in Developing Neutralizing Antibody (Nab) Assays

Moderator: Yuling Wu, Ph.D., Principal Scientist, Translational Sciences, MedImmune

Table 3: Overcoming Target Interference in ADA assays

Moderator: Jim McNally, Ph.D., Associate Director, PDM Immunogenicity Expert, EMD Serono

Table 5: Critical Issues in ADA Assay Validation

Moderator: Amy Loercher, Ph.D., Manager, Clinical Immunology, GSK

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day One of Immunogenicity Assessment & Clinical Relevance

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7:30 am Registration and Morning Coffee

8:00 am Chairperson’s Remarks

Jim McNallyJim McNally, Ph.D., Associate Director, PDM Immunogenicity Expert, EMD Serono



8:05 Replacing Legacy ADA Assays with New and Better Methods to Support Routine Patient Care

Yongchang QiuYongchang Qiu, Ph.D., Senior Director, Head, Bioanalytical and Biomarker Development, Research & Nonclinical Development, Shire

Legacy ADA testing used to support early clinical trials are often limited by technologies and guidance available at that time and can be very complex with many methods. As a result, these assays have presented many challenges, such as slow turn-around time and high cost, for ADA testing to support routine patient care. Here we present our effort on development of new and better assays to replace legacy methods and address “data continuity” issues before and after method switch.


8:35 A Neutralizing Antibody Assay Based on a Reporter of Antibody Dependent Cell-Mediated Cytotoxicity

Yuling WuYuling Wu, Ph.D., Principal Scientist, Translational Sciences, MedImmune

Immunogenicity assessment is an essential component of safety evaluation in biopharmaceutical clinical development. Benralizumab (MEDI-563, anti-IL5Rα mAb) is a humanized afucosylated mAb against IL5Rα with enhanced effector function. It potently induces ADCC (antibody-dependent cell-mediated cytotoxicity) of eosinophils and basophils. To support benrulizumab clinical development, we developed an ADCC cell-based neutralizing antibody (NAb) assay to detect NAbs against benrulizumab in human serum. This study presents the development, optimization and characterization of an ADCC cell-based NAb assay.

9:05 Open Discussion on Dealing with Pre‐Existing Positive ADA Activity in Study Patients

Led by Jim McNally, Ph.D., Associate Director, PDM Immunogenicity Expert, EMD Serono

  • Potential complications with pre-existing antibodies
  • How to distinguish between pre-existing antibodies and potential immune responses to the drug and to determine a meaningful drug-induced response
  • Examples seen in the clinic and their relevance
  • Implications for humanized antibodies and novel humanized antibody products
  • Implications regarding PK/PD safety and efficacy


9:35 Experiences with Confirmatory Assays, False Positives and Negatives, and Cutpoint Determination

Amy LoercherAmy Loercher, Ph.D., Manager, Clinical Immunology, GlaxoSmithKline

This presentation will focus on difficulties that may be encountered with confirmatory assays, false positive and false negative assay signals and various approaches to cutpoint determinations. Case studies will be presented that examine strategies for immunogenicity assessments of biopharmaceuticals for both soluble and membrane-bound cellular targets.

ThermoFisher Scientific10:05 IgE and IgG4 Antibody Response to Biological Drugs

Robert Moverare, Ph.D., Principal Scientist, Immunodiagnostics Division, Thermo Fisher Scientific

The formation of anti-drug antibodies (ADAs) to biological drugs is a well-recognized phenomenon that could lead to serious side effects during treatment or to treatment failure. The present lecture will discuss the scientific and medical potential of measuring IgE and IgG4 antibodies to biological drugs and technical opportunities using the ImmunoCAP® technology developed for the Phadia® Laboratory System.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing


11:10 Immunogenicity Testing in Patients Treated with Anti-TNF: What is the Best Measure of Clinical Response?

Theo RispensTheo Rispens, Ph.D., Senior Scientist, Immunopathology, Sanquin

Anti-drug antibody (ADA) formation to therapeutic monoclonal antibodies such as adalimumab and infliximab (anti-TNF) is associated with lower drug levels and clinical non-response. Controversy exists about the clinical consequences of ADA formation, which partly arises from the use of different assays and testing strategies. This presentation will focus on the relationship between concentrations of the drug (PK), anti-drug antibodies and clinical response, as well as the characteristics of ADA responses to these drugs.

11:40 Immunogenicity and Clinical Relevance Assessment Enabling the Approval of a Subcutaneous Formulation of Herceptin

Rebecca Elliott, MSc, Manager, BioAnalytical Sciences, Genentech, Inc.

The assessment of immunogenicity (antibodies against Herceptin® or recombinant human hyaluronidase) was one of the secondary objectives of a randomized, multi-center, open-label Phase III study. This demonstrated non-inferiority of a fixed-dose subcutaneous formulation of Herceptin® when compared with an intravenous formulation based on pharmacokinetics and efficacy in patients with HER2-positive early breast cancer. Exploratory analyses were performed to investigate any potential correlation of immunogenicity to pharmacokinetics, efficacy, and safety.

12:10 pm Rapid ADA Response against a C5a Receptor Antagonist Impacting PK and PD

Per Holse MygindPer Holse Mygind, Ph.D., Senior Scientist, Immunogenicity Assessment, Novo Nordisk

A first generation antibody therapeutic against the C5a receptor was developed to treat patients with chronic autoimmune diseases. A rapid and significant ADA response was detected in a large number of patients. These discoveries contributed to the development of a second generation antibody against the C5aR receptor. The presentation will provide details on the analytical strategies, assays applied and ADA characterizations, as well as the impact on clinical measures of pharmacokinetics and pharmacodynamics.

12:40 End of Immunogenicity Assessment & Clinical Relevance

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