Immunogenicity: Regulatory and Clinical Case Studies

Managing and predicting immune response from biological therapies can be challenging to the drug development scientist, especially as new constructs and immunotherapy approaches continue to be discovered. The regulatory approaches to ensuring safety of new products needs to take into account what has been learned in the clinic to date. This meeting will review case studies of clinical candidates in order to learn the most clinically relevant information for immunogenicity, and also share insights from regulators on winning approaches for ensuring safety of biologic drugs.


7:00 am Registration and Morning Coffee


8:30 Chairperson’s Remarks

Narendra Chirmule, Ph.D., Senior Vice President, Biocon Research Labs


Harold Dickensheets, FDA


9:10 Update on EU Regulatory Environment for Immunogenicity Assessment of Therapeutic Proteins

Paul Chamberlain, NDA Advisory Board

The EU regulatory environment for assessment of immunogenicity-related risks for therapeutic proteins continues to evolve, broadly in parallel to that in USA, but with some differences in detail. This presentation will summarize: 1) Main changes introduced by September 2015 draft revision of main EU immunogenicity guideline, including feedback from stakeholder discussion. 2) Learnings for recent product reviews.

9:40 Immunogenicity of Biologics and Biosimilars: Clinical Impact of Aggregates, Glycosylation and Other Post-Translational Modificiations

Nilanjan Sengupta, Ph.D., Biocon Research Labs

Assessment of clinical immunogenicity is a critical step in establishing biosimilarity. We will present our experience in development, validation and implementation of the immunogenicity assessment strategy for Biologics and Biosimilars. The presentation will discuss the unique challenges involved immunogenicity assessment, which in the final step towards demonstrating the similarity to the reference licensed product, with “totality of evidence”.

10:10 Coffee Break


10:45 Chairperson’s Remarks

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

10:50 Humanized Mice as a Tool to Measure Immunogenicity

Michael Brehm, Ph.D., Professor, Program in Molecular Medicine, University of Massachusetts Medical School

The development of severely immunodeficient IL2rgnull mice that support engraftment of functional human immune systems has enabled the in vivo study of human immunity. This presentation will include a general overview of these humanized mouse models, describing currently available strains, the protocols to generate humanized mice, the strengths of each system and a discussion of the application of these models to study immunogenicity.

11:20 Immunogenicity Assessment In Toxicology Studies

Mark Milton, Ph.D., Executive Director, DMPK-Biologics PKPD, Novartis Institutes for Biomedical Research Inc.

Analysis of samples for the presence of anti-drug antibodies in Toxicology studies is a common practice. However, there is no standard for the interpretation of these data. This presentation will describe the different ways in which the data can be interpreted and will discuss the value of generating such data.

11:50 Clinical Implications of Immunogenicity of TNF Inhibitors

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

Many patients treated with adalimumab or infliximab develop anti-drug antibodies (ADA) to these TNF inhibitors. However, there remains controversy about the clinical consequences of ADA formation, which is in part due to different assay methodologies and testing strategies. This presentation will address the characteristics of ADA responses to TNF inhibitors and the relationship between drug concentration, ADA, and clinical outcome.

12:20 pm Late Breaking Presentation

BIOVIA12:50 Luncheon Presentation I: In silico Approaches for Early Assessment of Immunogenicity

Ralph Eckenberg, Integrative Therapeutics, Dassault Systems

Unexpected adverse events are reasons of drug development failures that contribute to the attrition rate in pharmaceutical industry. A possible cause specifically associated to Biotherapeutics (peptides/proteins) is immunogenicity: the ability of some biotherapeutics to trigger immune responses that conduct to the generation of antibodies specifically directed against the drug. This immune response can possibly reduce the treatment efficacy and provoke adverse effects. Predicting immunogenicity is proving difficult because of the complexity of the underlying biological processes. We present here an informatics application based on modeling and simulation approaches that can help the pharmaceutical R&D to prioritize promising drugs with respect to the immunogenicity risk.

1:20 Luncheon Presentation II (Sponsorship Opportunity Available) 

1:50 Session Break

2:20 Problem-Solving Breakout Discussions

Immunogenicity Assessment of Biosimilars

Paul Chamberlain, NDA Advisory Board

  • What are the regulatory priorities?
  • What is the relative importance of intrinsic versus extrinsic factors as potential sources of difference?
  • How does this influence the clinical evaluation of immunogenicity?
  • Does the measurement of relative ADA response require additional control(s) to minimize impact of bioanalytical bias?

Clinical Relevance

Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

  • Are increasingly sensitive assays effecting how immunogenicity is determined?
  • ADA response on PK and PD in the context of clinical relevance
  • What is the balance between assay sensitivity and a clinically meaningful response?

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


4:00 Chairperson’s Remarks

4:10 The Promise of Cancer Immunotherapy: An Overview of Recent Advances and Jounce’s Approach to Delivering the Right Therapy to the Right Patient

Deborah_LawDeborah Law, D. Phil. CSO Jounce Therapeutics, Inc.

As immunotherapies become an increasingly important component of cancer treatment the challenge will be to identify ways to provide the best therapy(s) to the individual. This presentation will provide an overview of current cancer immunotherapies as well as highlight some of the challenges ahead including selection of optimal combinations, moving outside of T cell-directed approaches, and will highlight how Jounce Therapeutics is using its Translational Science Platform as an approach to develop and deliver the right therapy to the right patient.

4:50 Antibody as Drugs: Then, Now and Tomorrow

Paul_CarterPaul J. Carter, Ph.D., Senior Director and Staff Scientist, Antibody Engineering, Genentech

Antibodies have grown into a clinically and commercially important drug class with more than >45 antibodies marketed for imaging or therapy in the USA and/or Europe and with ~$63 billion in worldwide sales in 2013.  This presentation will highlight progress in developing antibody drugs and consider opportunities for future innovation.  

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

6:45 End of Day


8:00 am Morning Coffee


8:25 Chairperson’s Remarks

Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

8:30 Statistical Considerations in Design of Multi-Tiered Methods to Detect and Confirm the Presence of ADAs in Clinical Studies

Harry Yang, Ph.D., Senior Director R&D, 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, 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 optimal cut point.

9:00 Linear epitope mapping, binding strength, and neutralization of interferon-beta using patient-derived monoclonal antibodies: Results from ABIRISK

Florian Deisenhammer, Ph.D., Clinical Department of Neurology, Innsbruck Medical University

One of the goals of the ABIRISK project ( is to isolate monoclonal anti-drug antibodies (mADA) for use as positive controls in binding and neutralization assays. We isolated 5 different mADA which showed very high affinity binding to IFNb with kinetics constants in the picomolar range. The nature of the binding sites will be explored by linear epitope mapping in order to identify critical sites for neutralization. This work will help understanding the complexity of drug neutralization and guide how to properly use mADA as positive controls in neutralization assays.

9:30 Measures of a Clinically Relevant Immune Response: Weighing between the Sensitivity and Impactful Response

Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

The immunoassays currently employed for the immunogenicity assessment are highly sensitive and can detect low signals of anti- therapeutic immune responses. However, the impact of such responses on exposure and efficacy requires further evaluation. The relevance of ADA impact on PK depends on the study design and impact on PD. The onset and magnitude of the ADA response on PK and PD will also be discussed in the context of clinical relevance.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Awards


10:50 De-Immunizing Immunotoxins

Ira Pastan, M.D., Co-Chief, Molecular Biology, National Cancer Institute, National Institutes of Health

Many non-human proteins have beneficial therapeutic properties, but cannot be administered repeatedly to humans, because of their immunogenicity. We have developed an immunotoxin targeting mesothelin-expressing malignancies (SS1P) that contains a portion of Pseudomonas exotoxin A. The protein has shown activity against mesothelioma in human and we have been improving its usefulness by identifying and removing T cell and B cell epitopes.

11:20 Impact of Target Interference in PK and ADA Assays and Potential Mitigation Strategies

Manoj Rajadhyaska, Ph.D., Director, Bioanalytical Sciences, Regeneron Pharmaceuticals Inc.

Ligand binding assays are susceptible to interfering target molecules that can distort assay results by generating false positive or negative signals or blocking desired assay interactions. If not properly characterized and mitigated, these artefactual results can impact the result interpretation. With the help of some case studies, the mechanistic aspects of the variety of ways by which target interference can occur will be discussed with potential mitigation strategies for each case.

11:50 PANEL DISCUSSION: Determining a Clinical Relevant Response

Moderator: Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

This panel will discuss:

-What determines a clinically relevant response?

-Are assays too sensitive?

-The relevance of ADA impact on PK

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own

1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing

Clinical Case Studies

2:00 Chairperson’s Remarks

Michel Awwad, Ph.D., former Director, Pharmacokinetics & Dynamics & Metabolism, Merrimack Pharmaceuticals

2:05 NEW: Immunogenicity Assessment Strategies and Clinical Relevance for Multi-Domain Biotherapeutics

Yanchen Zhou, Ph.D., Scientist, Medical Sciences, Clinical Immunology, Amgen Inc.

A product related impurity was identified in the material used in clinical study. To assess the potential ability of patients to develop an immune response to the impurity and impact on immunogenicity of the therapeutic two bridging ELISA were developed and validated. Samples from treated subjects were evaluated in both assays. This presentation will discuss the results of the immunogenicity assessment to the impurity and observed immunogenicity rate of the antibody therapeutic.

2:35 Immunogenicity: Why and How

Michel Awwad, Ph.D., former Director, Pharmacokinetics & Dynamics & Metabolism, Merrimack Pharmaceuticals

Biologics are increasingly being used as therapeutic products for treatment of many different diseases ranging from neurological to cancer and other immunological diseases. Understanding, predicting, measuring and attempting to avoid the immune response to these biologics is critical to develop efficacious drugs.

3:05 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


4:25 Positive Effects in Reducing Immunogenicity Target Interference

Erik Meyer, Ph.D., Senior Scientist, GlaxoSmithKline

During Phase II clinical studies, a high incidence of immunogenicity did not correlate with decreased PK profiles or loss of drug efficacy. Drug target analysis revealed its accumulation during treatment, with target interference possibly impacting immunogenicity analysis. Subsequent immunogenicity assay modifications reduced the ADA positive rate and supported clinical observations for additional clinical studies.

4:55 ERT Immunogenicity and Experimental Immune Tolerance Induction: Results of a BioMarin Sponsored Advisory

Brian Long, Ph.D., Senior Scientist, Immunology Assessment, BioMarin

Enzyme replacement therapies (ERT) for the treatment of lysosomal storage diseases (LSD) have demonstrated great success in attenuating the disease phenotype for many rare and debilitating disorders. We convened an advisory board of treating physicians and key opinion leaders where we reviewed the current data regarding immunogenicity with ERTs and contemporary immune tolerance inducing regimens; the results of which are presented.

5:25 End of Immunogenicity: Regulatory and Clinical Case Studies

5:30 Registration for Dinner Short Courses

Recommended Dinner Short Course*

SC9: Overcoming the Challenges of Immunogenicity Assessment

*Separate registration required