2017 Archived Content

Cambridge Healthtech Institute’s Ninth Annual

Immunogenicity Prediction & Control

Regulatory Perspectives, Risk Factors, and Management

October 25-26, 2017 | The Westin Alexandria | Washington, DC


This conference is designed to help the investigator understand the causes of immunogenicity, work out how to predict it, and to design products that are safe and efficacious in the clinic. It will address regulatory and industry perspectives on immunogenicity risk assessment and address risk management for products that impact on the immune response. We will examine factors that contribute to immunogenicity, and tools for immunogenicity risk prediction. In addition, we present experiences with engineering out immunogenicity, and progress in deimmunization and tolerance induction.

Final Agenda

WEDNESDAY, October 25

12:45 pm Conference Registration


1:25 Chairperson's Opening Remarks

Vibha Jawa, Ph.D., Director, Biologics and Vaccines Bioanalytics, Merck and Co., Inc.

Joao_Pedras-Vasconcelos1:30 KEYNOTE: FDA Regulatory Perspectives on Immunogenicity Risk Assessment from Phase I IND to BLA and Beyond

Joao Pedras-Vasconcelos, Ph.D., Biotech Quality and Immunogenicity Reviewer, Biotechnology Products, FDA/CDER

The cost to the biotechnology industry of developing a biologic from early stage all the way to licensing is very high, and many factors can impinge upon approval, particularly the occurrence of immune responses against the biologic. Immunogenicity can impact product efficacy and safety depending on patient-related and product-related factors. This presentation will provide an updated overview of the FDA regulatory perspective to immunogenicity risk management for innovator and biosimilar biologics including risk assessment and mitigation, and anti-drug antibody detection during the various stages of product development.

2:00 Challenges and Considerations Assessing Preclinical Immunogenicity Risk of Combination Checkpoint Inhibitors

Jochem_GokemeijerJochem Gokemeijer, Ph.D., Associate Director, Molecular Discovery Technology, Bristol-Myers Squibb

Immune checkpoint inhibitors for oncology immune therapy have made impressive inroads for difficult to treat cancers. One approach to further increase the efficacy and response rates of these novel therapies is combination therapy of multiple checkpoint inhibitors or other targeted drugs. Because these therapies rely on manipulating the immune system, they pose a set of immunogenicity challenges clinically as well as preclinically.

2:30 The Complexities and Complications of Characterizing and Predicting Anaphylaxis

Becky_SchweighardtBecky Schweighardt, Ph.D., Senior Director, Immunogenicity Assessment, Biomarin Pharmaceutical, Inc.

Historically, the term anaphylaxis was reserved for IgE-mediated hypersensitivity events and anaphylactoid was used to describe similar clinical events that were non-IgE mediated. However, some non-IgE hypersensitivity events are now being caught under the broad term of anaphylaxis, complicating the processes of determining immunological mechanism and discerning which patients are at higher risk. This presentation will focus on deciphering the immunological mechanism of anaphylaxis and the implications on patient management.

3:00 The Prediction of Immunogenicity of PCSK9 MABs and Analysis of ABIRISK Data 

Anne De Groot, Ph.D., CEO/CSO, EpiVax

New biologics face many research and development hurdles through the pipeline, not the least of which is the potential for unwanted immune response. This presentation will compare prevailing methods to evaluate immunogenicity risk and review recent Abirisk data. We will explore prediction of effector and regulatory T cell epitopes (Tregitopes) in silico, ranking of biologic candidates by T cell epitope content and humanness, in vitro validation studies, and potential sources of discordance across methodologies.

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing


4:10 Determining Potential Risk of Immunogenicity of Process-Related High Molecular Weight Species in in vitro and in vivo Model Systems

Marisa K. Joubert, Ph.D., Principal Scientist, Process Development, Amgen, Inc.

4:40 Factors That Stimulate Innate Immunity and Contribute to Immunogenicity Risk

Daniela_VerthelyiDaniela Verthelyi, Ph.D., Chief, Immunology Lab, Therapeutic Proteins, FDA/CDER

In this talk, we will describe in vivo studies in primates performed to link the levels of innate immune response modulating impurities (IIRMIs) with immunogenicity risk. We will also describe a new approach to detect IIRMI based, not on the identification of individual impurities, but on the activation of innate immune pathways. This multiple cell based assay may be useful when screening products for the presence of unidentified IIRMIs and may inform the immunogenicity risk assessments, particularly in the context of comparability and biosimilarity exercises. Lastly, we will present case studies that illustrate the results.

5:10 Monitoring of Immunogenicity for a Therapeutic Protein after Manufacturing Changes

Laura_Salazar-FontanaLaura I. Salazar-Fontana, Ph.D., Associate Director, Biomarkers and Clinical Bioanalysis, Translational Medicine and Early Development, Sanofi

The quality by design (QbD) concept continues to emphasize the relevance of a knowledge-based decision making and a risk-based approach to find critical product quality attributes (CQA) and critical process parameters to warrant the desired product quality through its lifecycle. The impact of these CQAs on clinical immunogenicity is still inconclusive; however, it is predicted that favorable physicochemical properties can minimize the risk for immunogenicity as suggested by studies conducted in early and late drug development.

5:40 Dinner Short Course Registration

Recommended Dinner Short Courses*

*Separate registration required,

THURSDAY, October 26

7:30 am Morning Coffee


7:55 Chairperson's Opening Remarks

Becky Schweighardt, Ph.D., Director, Immunogenicity Assessment, Biomarin Pharmaceutical, Inc.

8:00 Approaches to Evaluate Immunogenicity Risk of Immune Modulatory Therapies

Vibha_JawaVibha Jawa, Ph.D., Director, Biologics and Vaccines Bioanalytics, Merck and Co., Inc.

With the advent of biologics that can target human immune cells, the contribution to immunogenicity can be due to the sequence and related attributes as well as modulation of immune cells due to target engagement. This talk will discuss potential methods of managing immunogenicity risk and dissecting sequence vs. target related immune modulation.

8:30 Case Study on Immunogenicity Systems Modelling for Adalimumab

Xiaoying_ChenXiaoying Chen, Ph.D., Senior Manager, Early Oncology Development & Clinical Research, Pfizer, Inc.

A systems pharmacology approach was applied to tackle the challenge of predicting clinical immunogenicity for therapeutic proteins, by recapitulating key biological mechanisms using a mechanistic, multi-scale mathematical model. The model is able to simulate immune responses based on experimental inputs, including protein-specific antigenic properties (e.g., T cell epitopes affinity) and host-specific immunological characteristics (e.g., HLA genotype). A case study of simulating human population immune responses against adalimumab will be provided.

9:00 An Integrated Approach to Managing Immunogenicity Risk and Drug Immune Modulation

Jim_CookJim Cook, Immunology Sales Specialist, Sales, ProImmune Inc

Immunogenicity is one of the most complex issues to address in drug design and development. Integrated platforms such as, Mass Spectrometry antigen presentation assays; DC-T and T cell proliferation assays for biologic lead selection/optimization; HLA-peptide binding assays to characterize individual epitopes and undiluted whole blood cytokine storm assays, can be used to mitigate immunogenicity risk and characterize immune responses directed toward biologics.

9:30 Problem Solving Roundtable Discussions

Practical Application of Immunogenicity Preclinical Risk Assessment

Moderator: Joao Pedras-Vasconcelos, Ph.D., Biotech Quality and Immunogenicity Reviewer, Biotechnology Products, CDER-FDA

  • Relevant risk factors
  • Potential of emerging antibody products for greater immunogenicity
  • Features of the risk analysis and risk mitigation plan
  • Risk assessment at different stages of development
  • How to translate the identified risk into a testing strategy
  • Management in the clinic of products with low and high risk of immunogenicity
  • Experiences with reporting findings to the regulatory authorities

Current and Emerging Predictive Tools: Selecting Candidates and Predicting Clinical Outcome

Moderator: Vibha Jawa, Ph.D., Director, Biologics and Vaccines Bioanalytics, Merck and Co. Inc.

  • Working in discovery – combining in silico and in vitro approaches
  • Applying tools in a matrix environment
  • Preparing for clinical success: Selecting the right tools for the question posed
  • Progress on the road to predicting clinical outcomes

Risk of Immunogenicity of Product-related Attributes, Process-related Impurities, and Leachables/Extractables

Moderator: Marisa K. Joubert, Ph.D., Principal Scientist, Process Development, Amgen, Inc.

  • Product-related attributes that cause the greatest concern for immunogenicity
  • Do level of attribute, dosing regimen, and patient population mitigate this risk?
  • Stringent requirements for process-related impurities and process reagents
  • Evidence that leachables/extractables (i.e. silicone oil) act as an adjuvant
  • Should product specifications be more biologically based?

Progress Towards Inducing Immunological Tolerance to Biotherapeutics

Moderator: Ronit Mazor, Ph.D., Post-Doctoral Fellow, Molecular Biology, National Cancer Institute

  • Tolerance mechanisms and different approaches for tolerance induction
  • Immunodominant T-cell epitopes and how these may be used as targets for tolerance induction
  • Methods for identification and removal of T cell epitopes and evidence for its impact on reducing immunogenicity
  • Tools to use with protein engineering to design non immunogenic biotherapeutics
  • Applicability to enzyme-deficiency disorders, allergies, autoimmune disease and protein drugs in general

Understanding Monkey HLA and Peptide Presentation

Moderator: Priya Sriraman, Ph.D., Principal Investigator Non-Clinical Development, Celgene Corp

  • What is its similarity to humans?
  • To what extent can monkey immunogenicity results help understanding of immunogenicity in man?
  • To what extent could they guide deimmunization efforts?
  • Does characterization of a monkey immune response help us understand when it might (and might not) predict immunogenicity in man?
  • Can monkey be used as a model for tolerance induction studies?


10:30 Coffee Break in the Exhibit Hall with Poster Viewing

Amy_Rosenberg11:10 FEATURED PRESENTATION: The Role of the Immune System in Complex Diseases: Strategies for Improved Outcomes

Amy S. Rosenberg, M.D., Division Director, Office of Biotechnology Products, FDA/CDER

In this presentation, I shall examine biotherapeutics that impact on the immune response, particularly those involved in the breaking and induction of tolerance such as checkpoint inhibitors and Treg promoting factors. Immune tolerance is also crucial in the context of immunogenicity of life saving therapeutic proteins, for example enzyme replacement therapy. The FDA has numerous tools to accelerate development of novel multi-strategy approaches for complex diseases which elucidate the criteria necessary for entry into pathways for expedited drug development including Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review.

11:40 Strategies to Reduce Immunogenicity of Recombinant Immunotoxins

Ronit_MazorRonit Mazor, Ph.D., Post-Doctoral Fellow, Molecular Biology, National Cancer Institute

Recombinant Immunotoxins (RITs) are a genetically engineered therapeutic proteins that were developed in our lab to treat cancer. Because they contain a bacterial toxin that kills the cancer cells, RITs are very immunogenic to cancer patients with a normal immune system; 100% of patients made high ADA titers, which prevented retreatment and greatly lowered efficacy. This talk will describe the multiple approaches used in our lab to reduce the inherent immunogenicity of RITs. These include linear and confirmation B cell epitope mapping, experimental and algorithm based T cell epitope mapping, combination with immune suppressive agents and recently, combination with methotrexate or nanoparticle encapsulated rapamycin to induce specific immune tolerance.

12:10 pm Predicting and Managing Unwanted Immune Responses to Biologics

Mark_FoggMark Fogg, Group Leader, Immunology, Abzena

  • Understanding how therapeutic antibodies and proteins can induce an immune response in patients leading to the development of anti-drug antibodies (ADAs)
  • Accurate and sensitive ways to assess the potential immunogenicity of proteins and antibodies ex vivo by measuring CD4+ T cell responses
  • Methods for managing and reducing potential immunogenicity

12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:10 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing


1:50 Chairperson's Remarks

Laura I. Salazar-Fontana, Ph.D., Associate Director, Biomarkers and Clinical Bioanalysis, Translational Medicine and Early Development, Sanofi

1:55 Modulating the Immunogenicity of Blood Coagulation Protein Factor VIII

Kathleen_PrattKathleen P. Pratt, Ph.D., Associate Professor, Medicine, Uniformed Services, University of the Health Sciences

Development of antibodies that interfere with factor VIII (FVIII) pro-coagulant activity (“inhibitors”) can seriously complicate the treatment of hemophilia A. Our laboratory is mapping immunodominant T-cell and B-cell epitopes in FVIII and generating sequence-modified proteins having reduced immunogenicity. I will present our strategies for designing less immunogenic FVIII proteins that retain biological activity and for examining various factors that influence the immunogenicity of this therapeutic protein drug.

2:25 Domain/Epitope Mapping to Guide Engineering-Out Immunogenicity of Bispecific Antibodies

Priya_SriramanPriya Sriraman, Ph.D., Principal Investigator, Non-Clinical Development, Celgene Corp.

Bispecific or multispecific biotherapeutics are often engineered by incorporating multiple protein domains. Experimental approaches to map the domain and epitope that is the primary trigger of a humoral response will be presented. Such data can help focus engineering efforts in producing de-immunized therapeutics or avoid immunogenicity in the next generation of molecules.

2:55 Tolerance-Inducing Programs for Enzyme Replacement Therapies

Ankit K. Desai, M.B.B.S., Postdoctoral Associate, Genetics and Genomics Center, Department of Pediatrics, Duke University

Cross-Reactive Immunological Material (CRIM)-negative (CN) and a subset of CRIM-positive (CP) Infantile Pompe disease (IPD) mount an immune response against enzyme replacement therapy (ERT) resulting in clinical decline. Prophylactic immune tolerance induction (ITI) has prevented immune responses in CN and CP patients treated with ERT. We will present data on the safety and efficacy of ITI approaches for CP and CN IPD receiving ERT.

3:25 Clinical Development of SEL-212: Use of Tolerogenic Nanoparticles to Mitigate Immunogenicity against an Enzyme Therapy to Treat Severe Gout

Takashi-Kei_KishimotoKei Kishimoto, Ph.D., CSO, Selecta Biosciences

We have recently engineered nanoparticles to provide a tolerogenic signal to antigen-presenting cells to induce antigen-specific immune tolerance. Preclinical data demonstrate the ability of these nanoparticles to mitigate immunogenicity against a broad array of biologic therapies. Here we will present a case study on the clinical development of SEL-212, a combination product consisting of a pegylated uricase enzyme and tolerogenic nanoparticles for the treatment of gout.

3:55 Close of Immunogenicity Prediction and Control