2013 Archived Content

Immunogenicity Risk Assessment and Mitigation 

Investigators are continuing to study the causes of immunogenicity such as particular amino acid sequences, peptides and epitopes, and the propensity to aggregate, and are developing models and tools for risk prediction. Meanwhile innovative approaches are being devised to reduce immunogenicity and/or induce tolerance. This conference will provide case studies on identification of risk factors and on how investigators translate their findings into a risk assessment strategy to enable them to decide whether to take a product into clinical studies in patients and beyond, and on means of reducing potential immunogenicity.

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Tuesday, November 12

2:00 pm Chairperson’s Opening Remarks

Jack RaghebJack Ragheb, Ph.D., Principal Investigator, Therapeutic Proteins, FDA/CDER





2:05 Understanding and Controlling Anti-Drug Antibody Responses to Enzyme Replacement Therapy; a Proposed Mechanism for Immune Tolerance Induction

Alexandra Joseph, Ph.D., Associate Scientific Director, Investigative Clinical Immunology, Clinical Laboratory Sciences Department, DSAR, Sanofi


Identification of Risk Factors 

2:35 Evaluation of Immunogenicity Risk of Biotherapeutics Targeting Dendritic Cell Receptors

Li Xue, Ph.D., Principal Scientist, PDM Immunogenicity Sciences, Pfizer, Inc.

Reliable immunogenicity risk assessment and mitigation is built upon accurate evaluation of immunogenicity risk factors that are associated with biotherapeutics. Several methods for risk assessment were developed and/or applied to investigate the immunogenicity risk of targeting dendritic cell receptors. The risk contribution to our understanding of the underlying causes of immunogenicity will be discussed.

3:05 A Pharmacogenetic Approach to Immunogenicity: Implications for Overcoming Attrition Owing to Development of Anti-Drug Antibodies during Clinical Trials Using Factor VIIa as a Model

Zuben E. SaunaZuben E. Sauna, Principal Investigator, Hematology, FD/CDER

An algorithm based on an individual patient’s genotype and MHC-II repertoire can be used to assess patient-specific immunogenic responses to therapeutic-proteins. To demonstrate the utility of this approach we will evaluate the immunogenicity-risk of neo-epitopes generated in two bio-engineered Factor VIIa products. The development of these products was recently discontinued due to the development of ADAs. The implications of identifying at risk patients and drug development based on pharmacogenetics will be discussed.

ProImmune3:35 Tools and Technologies for Comprehensive Immunogenicity Risk Management

BrianaBetzBriana Betz, Ph.D., Immunology Sales Specialist, ProImmune, Inc.

ProImmune has developed a comprehensive suite of in vitro assays that characterize DC, T cell, B cell and innate immune responses.  Antigen presentation assays using mass spectrometry, dendritic cell - T cell assays and physical HLA-peptide binding assay can be combined to provide a broad picture of protein antigenicity.  Data from these assays can help inform improved drug design and lead selection through a clearer understanding of the mechanisms that drive immune responses.

 3:50 Refreshment Break in the Exhibit Hall with Poster Viewing 

Aggregate-Induced Immunogenicity/Benefits of Mouse Models 

4:30 Investigation of Immunogenicity Induced by Aggregates Using Immune-Tolerant Mice

Vera BrinksVera Brinks, Ph.D., Postdoctoral Researcher, Utrecht University, Utrecht Institute for Pharmaceutical Sciences; Currently Visiting Scientist, Therapeutic Proteins, FDA

Aggregation is a major risk factor for immunogenicity of therapeutic proteins. Nonetheless, the mechanisms by which aggregates induce the formation of antidrug antibodies are unknown. Here, I will present several studies on the characterization of aggregate-driven immunogenicity, focusing on its initiation and subsequent immunological processes including timing of CD4+ T-cell help, formation of germinal centers, and effect of immune modulating drugs on antibody levels. These studies are performed in immune tolerant mice.

5:00 Humanized Mouse Models for Nonclinical Immunogenicity Assessment of Novel Protein Therapeutics

Birgit Reipert, Ph.D., Director, R&D Immunology, Baxter BioScience

Current activities focus on the design of protein therapeutics with molecular and/or chemical modifications to improve the pharmacokinetic properties of these proteins. However, any of these modifications bears the risk of creating neoepitopes that could stimulate T-cells and/or B-cells. We developed new animal models for assessing the immunogenicity of such modified proteins during preclinical development. First results as well as advantages and limitations of these new models will be discussed.


Relevance of Animal Models for Predicting the Immunogenicity of Therapeutic Proteins

Moderated by: Jack Ragheb, Ph.D., Principal Investigator, Therapeutic Proteins, FDA/CDER

  • Pros and cons of humanized mice and transgenic mice
  • Time, investment and skill in getting mouse models up and running
  • How to work out the appropriate dose
  • Applications and recent progress with biotherapeutics: e.g. recombinant cytokines, gene therapy
  • Are relative immune responses (e.g. 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?

6:00 End of Day One of Immunogenicity Risk Assessmentand Mitigation 

6:00 Registration for SC4 

6:30 – 9:00 Dinner SC4: Immunogenicity Risk Assessment and Regulatory Strategy* 

Instructors to include: Laurie Graham, Product Quality Reviewer, Division of Monoclonal Antibodies FDA/CDER  

Robin Thorpe, Ph.D., FRCPath, Head, Biotherapeutics Group, National Institute for Biological Standards and Control 

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*Separate Registration Required

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