Immunogenicity Summit

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The impact of Immunogenicity on efficacy is costing the industry vast amounts every year and denying patients much needed treatment. Moreover the danger of adverse reactions is ever present. Assessment of immunogenicity continues to be hampered by complications such as target interference, interfering drug and pre-existing antibody, while setting of cut points and interpretation of data is complicated. Cambridge Healthtech Institute's Sixth Annual Immunogenicity Assessment & Clinical Relevance conference will enable investigators to work out a risk assessment immunogenicity strategy for their product that satisfies themselves and the regulatory authorities that their product is safe and efficacious. 

Monday, November 17

7:30 am Registration and Morning Coffee

8:30 Chairperson’s Opening Remarks

Steven J. Swanson, Ph.D., Executive Director, Medical Sciences, Clinical Immunology, Amgen, Inc.


8:35 Cut Points and Confirmatory Assays: A Case Study of Pre-Existing Reactivity, ADCs and Statistics

JimMcNallyJim McNally, Ph.D., Senior Principal Scientist, Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.

Determination of cutpoints for screening and confirmatory assays is a straightforward process for normal, drug-naïve individuals with no baseline reactivity for the drug. However, with increasing frequency, pre-existing reactivity is observed in anti-drug antibody assays and these individuals complicate the process of setting the cutpoint. A case study will be presented where a large percentage of normal individuals exhibited pre-existing reactivity and describes the methods to determine an appropriate cutpoint.

9:05 Overcoming Challenges with Target Interference in ADA Assays: A Case Study in Multimeric Targets

RezaMozzafariReza Mozaffari, Investigator, Clinical Immunology, GlaxoSmithKline

Multimeric targets present in clinical samples can cause interference in bridging assay formats used for anti-drug antibody (ADA) detection. This interference may potentially generate a false positive result which could impact the immunogenicity assessment of the compound. I will present our experiences and the different approaches we have used to minimize interference of this nature.

9:35 Minimizing Interference from Fc-Fc Interactions in Bridging Immunogenicity Assays for IgG4 Monoclonal Antibody Therapeutics

MichaelPartridgeMichael Partridge, Ph.D., Staff Scientist, Bioanalytical Sciences, Regeneron Pharmaceuticals, Inc.

Human IgG4 antibodies are known to interact with other IgG4s via their Fc. In bridging immunogenicity assays, IgG4 Fc-Fc contacts generate increasing signal over time for the negative control, reducing assay sensitivity and complicating confirmation cut point determination. Increasing background signal over time is especially problematic for automated analysis, as reagents are prepared in advance and used over several hours during a run. This presentation will discuss these interactions and the impact they have on immunogenicity assays for IgG4 drugs.

10:05 Overcoming the Challenges of Immunogenicity and Cell Based Neutralizing Antibody Assays for Biosimilar Drug Development 

Kathyrn_BioAgilytixKathryn Lindley, M.S., Director, Bioanalytical Operations, BioAgilytix Labs

Successful development of biosimilar drugs requires demonstration of biosimilarity to the originator drug. Immunogenicity assays require extensive method development and validation to support preclinical and clinical comparative studies, and overcoming the challenges of developing cell based assays to detect neutralizing antibodies is critical for success. The challenges of development and validation of qualitative immunogenicity (ADA) screening assays, and neutralization (Nab) assays for biosimilar drug development will be presented.

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


11:15 Drug Interference and Other Challenges with the Development of Neutralizing Antibody Assays

Renuka C. Pillutla, Ph.D., Director, Bioanalytical Sciences – Biologics, Bristol Myers Squibb

The presence of drug product in serum can reduce or block the detection of anti-drug product neutralizing antibodies (NAbs). Examples of the effect of drug interference on the detection of clinically relevant NAbs will be presented. In addition, the evaluation of new methods and approaches to remove NAb assay drug interference will be presented.

11:45 Improving Drug Tolerance in a Clinical Neutralizing Antibody Assay by Solid-Phase Extraction with Acid Dissociation

GiselaPerausNovartisGisela Peraus, Ph.D., Lab Head, Pharmacology, Novartis Biologics

Neutralizing antibody assays are inherently prone to interference from circulating drug in-vivo. This is a particular concern with therapeutic monoclonal antibodies due to long half-lives. To improve drug tolerance for the determination of human neutralizing antibodies in a competitive ligand-binding assay, Solid-Phase Extraction with Acid Dissociation (SPEAD) was implemented, which significantly increased the amount of tolerated drug in the assay.

12:15 pm Immunogenicity of Topical Drug Products

Mirela Ionescu, Principal Scientist, Immunology, Charles River Montreal

Immunogenicity testing is a critical step in the development of biotherapeutics. Although topical dermatological products are typically lower in immunogenic potential, in some instances they do have the potential to induce an immunologic response. During this presentation, a case study where an anti-cancer antibody was administered topically in mini-pigs and humans will be discussed. A dose-dependent immunogenic effect was observed in both the preclinical and clinical studies, further confounding the need for early phase immunogenicity assessment of topical drug products and the clinical relevance of performing such assessments.

ThermoFisher Scientific12:45 Luncheon Presentation: ImmunoCAP ADA Bridging Assay – A New ADA Assay with High Inter-Laboratory Precision Based on a IVD Platform

Camilla Eriksson, Senior Scientist, New Technology Development, Thermo Fisher Scientific

Anti-drug antibodies (ADAs) to therapeutic proteins could interfere with efficacy of treatment, and need to be monitored during clinical development. A case study will be presented where an automated and high performance specific ImmunoCAP ADA Bridging assay was used to detect ADAs to infliximab in a global multicenter study. Characterization of the assay demonstrates high sensitivity, drug tolerance and inter-laboratory precision, which enable robust transfer between laboratories and the use in multicenter studies.

1:45 Session Break


2:15 Chairperson’s Remarks

JimMcNallyJim McNally, Ph.D., Senior Principal Scientist, Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.

2:20 Development and Characterization of a Non-Cell-Based Assay to Assess the Presence of Neutralizing Antibodies to Interferon-Beta in Clinical Samples

IsabelleCludtsIsabelle Cludts, Ph.D., Biotherapeutics, National Institute for Biological Standards and Control (MHRA, UK)

Different cell-based assay formats are available for detection of neutralizing anti-IFN-β antibodies. To overcome the limitations of these assays, a non-cell-based assay has been developed, utilizing an ECL detection platform. Neutralizing antibody titers in clinical samples from multiple sclerosis patients treated with IFN-β were determined and compared with those obtained using cell-based assays. The non-cell-based assay is less sensitive, however a good correlation between the two approaches was observed.

2:50 Immunogenicity Assessment Strategies and Assay Development for Enzyme Replacement Therapies

Stephen DeWall, Ph.D., Investigator, Clinical Immunology, GlaxoSmithKline

Enzyme replacement therapies (ERTs) have been successfully used to treat a number of rare, inherited diseases that are caused by deficiencies in specific metabolic enzymes. Although ERTs are typically highly immunogenic, they remain one of the most effective treatments for these disorders. Anti-ERT antibodies can potentially affect the safety and/or efficacy of these therapies, so monitoring patients for an immune response is vitally important. This presentation will cover immunogenicity testing strategies and assay development for ERTs.

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

4:00 Re-Assessment of Immunogenicity Risk Based on Clinical Data: Case Study of a Humanized IgG1 Monoclonal Therapeutic with a Knob-and-Hole Structure

MauricioMaiaMauricio Maia, Ph.D., Bioanalytical Sciences, Genentech, Inc.

Initial clinical immunogenicity evaluation plans are often based upon an immunogenicity risk assessment that includes a myriad of molecule and patient factors, but prior to attaining clinical experience. Clinical data can and should modify this assessment. This presentation will describe a case study of a structurally novel biotherapeutic whose risk-based assessment was changed following analysis of clinical immunogenicity data derived from early-stage trials.

4:30 Problem Solving Roundtable Discussions

Regulatory Expectations Regarding Immunogenicity Assessment

Laurie Graham, Ph.D., Product Quality Reviewer, Division of Monoclonal Antibodies FDA/CDER

Steven J. Swanson, Ph.D., Executive Director, Medical Sciences, Clinical Immunology, Amgen, Inc.

  • How and when to approach the regulators: Benefits of discussion with the regulators
  • How much assessment is necessary? How much is too much? What is the essential strategy?
  • Proper validation and characterization of assays
  • Neutralizing antibody assays: When should they be carried out and why?
  • Ligand binding assays. Can they be used instead of cell-based assays?
  • Pitfalls to avoid

Challenges in Developing Neutralizing Antibody (Nab) Assays

Moderator: Renuka C. Pillutla, Ph.D., Director, Bioanalytical Sciences – Biologics, Bristol Myers Squibb

  • Factors for selection of cell-based Nab vs. non-cell-based Nab assays
  • New technologies
  • How you deal with poor drug tolerance, lack of sensitivity and matrix interference
  • Challenges for Nab validation
  • Interpretation of the results and implications for risk assessment

Dealing with Pre-Existing Positive ADA Activity in Study Patients

Moderator: Jim McNally, Ph.D., Senior Principal Scientist, Biotherapeutics Research, Pfizer, Inc.

  • 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

Critical Issues in ADA Assay Validation

Moderator: Harry Yang, Ph.D., Senior Director, Translational Sciences, MedImmune, LLC

  • Complications experienced and means of overcoming the difficulties
  • Cut point determination between positive and negative samples for assay validation
  • Determination of sample size for immunoassays
  • Means of interpreting the data

Concerns Regarding Immunogenicity of Multi-Domain Proteins

Moderator: Laura Salazar-Fontana, Ph.D., Former CDER/FDA

  • Complications experienced and means of overcoming the difficulties
  • Cut point determination between positive and negative samples for assay validation
  • Determination of sample size for immunoassays
  • Means of interpreting the data

Focus on Immunogenicity of Biosimilars and Non-Innovator Biologicals

Moderator: Bridget Heelan, MB, Ph.D., Vice President, Consulting, Parexel, (ex-MHRA)

  • Experiences with working with the regulatory authorities
  • Strategies for Biosimilar immunogenicity testing assay formats
  • The most challenging issues
  • Differences in assays for sensitivity, drug-tolerance, positive controls
  • Important features of EU regulatory guidance on Immunogenicity
  • Current update planned for overarching guideline

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

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

Tuesday, November 18

8:30 am Chairperson’s Remarks

Stephen DeWall, Ph.D., Investigator, Clinical Immunology, GlaxoSmithKline


8:35 The Impact of Quality Attributes on Immunogenicity

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

9:05 The Problems in Assessing and Comparing Immunogenicity of Biosimilars with the Reference Product

BridgetHeelanBridget Heelan, M.B., Ph.D., Vice President, Consulting, Parexel, (ex-MHRA)

As biosimilars are not 100% identical to the originator this raises safety and regulatory concerns about relative immunogenicity. Comparing the results of ADA detection rates in the innovator and the biosimilar relies on an appropriate testing strategy. The advantages and limitations of comparing the results derived from a single assay or two separate assay formats will be presented.


9:35 Strategy for Immunogenicity Risk Assessment

SteveSwansonSteven J. Swanson, Ph.D., Executive Director, Medical Sciences, Clinical Immunology, Amgen, Inc.

Immunogenicity assessment continues to be an important component of the development of therapeutic proteins. Establishing an appropriate “risk-based approach” to testing for immunogenicity involves evaluating several factors including: whether the protein therapeutic will be used in a chronic or an acute dosing regimen; if there is an endogenous counterpart for the protein therapeutic, what the likely consequences of a neutralizing immune response would be, and what the predicted immunogenicity of the therapeutic would be. Understanding these factors will greatly assist in developing an appropriate strategy to follow in assessing immunogenicity during clinical trials.

10:05 Detection of Anti Drug Antibodies to a Therapeutic Using a Photonic Ring Immunoassay

MartinGleesonMartin Gleeson, Ph.D., CSO, Genalyte, Inc

Recent data demonstrates the exceptional growth in biologic therapeutics across all phases of development. Often, patients taking infused or injected therapeutics can develop antibodies against the drug (ADAs). These ADAs can cause a decrease in efficacy, increased clearance rate, or adverse events. Genalyte has developed an assay capable of detecting and isotyping ADAs with sensitivity and drug tolerance levels exceeding regulatory guidelines. The assay demonstrated concordance with orthogonal technologies while yielding multiplex isotyping profiles, including IgG4.

10:20 Panel Discussion

10:50 Coffee Break in the Exhibit Hall with Poster Viewing


11:30 Statistical Considerations in Design of Multi-Tiered Methods to Detect and Confirm the Presence of ADAs in Clinical Studies

HarryYangHarry Yang, Ph.D., Senior Director, Translational Sciences, MedImmune, LLC

Biopharmaceuticals have an inherent propensity to elicit immunogenic responses. Key to successful evaluation of immunogenicity is to have well developed and validated assays. This talk will focus on statistical strategies related to ADA assay validation, sample size determination, and cut point estimation in the presence of outliers and skewed distributions. In addition, we will explore ways to combine information from screening and confirmatory assays, so as to derive the optimal cut point.

12:00 pm Impact of Higher Order Complexes on Biomarker Target Quantitation

Surendran Rajendran, Ph.D., Senior Research Investigator II, Bioanalytical Sciences, Biologics, Bristol-Myers Squibb

During bioanalysis, quantitating the target, a biomarker, the drug interfered by an undesired higher order complex formation through multivalent interactions with target and assay reagents. This complex formation follows bell shaped concentration dependence with drug concentration which seems to explain the observed non-linear inverse relationship between immunogenicity and drug exposure. Its formation was confirmed in vitro by light scattering technologies.

12:30 End of Immunogenicity Assessment & Clinical Relevance

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