Cambridge Healthtech Institute’s 10th Annual

Immunogenicity Prediction & Control  

Regulatory Perspectives, Risk Factors, and Management

October 24-25, 2018


The impact of immunogenicity on safety and efficacy, and consequent cost to the industry is well understood. Accordingly, investigators are focusing on factors that contribute to immunogenicity as well as a number of different approaches to predict immunogenicity at the drug discovery stage. There are several major problematic areas such as gene therapy products with viral vectors, and Factor VIII for hemophilia, and efforts are being made to suppress immune responses to these products and to introduce tolerizing and deimmunization approaches.


Final Agenda

Recommended Pre-Conference Short Courses*

October 22, 10:00 AM - 1:00 PM

SC1: Mechanism of Action and Risk-Based Approach for Developing Neutralizing Ab Assays

Instructors: Jim McNally, PhD, Senior Director, Therapeutic Area Lead, Non-Clinical Development, Shire

Weifeng Xu, PhD, Senior Research Investigator, Bioanalytical Science, Bristol-Myers Squibb

October 22, 2:30 - 5:30 PM

SC2: Overcoming Drug Target Interference in ADA Assays

Instructors: Jim McNally, PhD, Senior Director, Therapeutic Area Lead, Non-Clinical Development, Shire

Lilia Macovei, PhD, Senior Scientist, BioMedicine Design, Pfizer, Inc.

October 22, 6:15 - 9:15 PM

SC3: Validation of ADA Assays and Cut Point Calculations

Instructors: Jim McNally, PhD, Senior Director, Therapeutic Area Lead, Non-Clinical Development, Shire

Michael Partridge, PhD, Senior Staff Scientist, Bioanalytical Sciences, Regeneron Pharmaceuticals, Inc.

Recommended Pre-Conference Symposium*

  • October 22: Immunology for Biotherapeutics

* Separate registration required

Wednesday, October 24

1:00 pm Conference Registration


1:40 Chairperson’s Opening Remarks

Ronit Mazor, PhD, Scientist, Antibody Discovery & Protein Engineering (ADPE), MedImmune, Inc.

1:45 FDA Regulatory Perspectives on Immunogenicity Risk Assessment from Phase I IND to BLA and Beyond

Steve Bowen, PhD, Team Leader, Chemist, Office of Biotechnology Products, CDER, FDA

Many factors can influence immunogenicity risk associated with biotherapeutic products including the patient population, impurity profile, post-translational modification, and homology to endogenous human proteins. A thorough immunogenicity risk assessment early in product development that evolves throughout clinical development, licensure, and post marketing phases can help avoid costly regulatory delays. This presentation will discuss important considerations for immunogenicity risk assessment at various stages of product development.

2:15 FEATURED PRESENTATION: Case Studies: Updating Immunogenicity Risk Assessment during Study Conduct

Joleen T. White, PhD, Director, Head of Project Support, NBE Drug Disposition, EMD Serono

Immunogenicity risk assessment is a scientific process that evolves as data emerge. This presentation will discuss when and how you revisit a strategy including case studies about updating immunogenicity risk assessment and adding, removing, or amending associated analyses. It includes: changing the cut point in response to in-study validation results, adding characterization assays for specific purposes, modifying an immunogenicity sampling schedule, and including additional statistical analyses based on preliminary findings.

2:45 Aggregates and Impurities as Immunogenicity Risk Factors: Case Studies

Daniela Verthelyi, PhD, Chief, Immunology Lab, Therapeutic Proteins, CDER, FDA

Product immunogenicity has emerged as one of the critical roadblocks in the development of biologics, complex generics and biosimilars. This talk will focus on the impact of process-related innate immune response modulating impurities and aggregates on the milieu where the products are delivered highlighting the complex interplay of different impurities on product immunogenicity risk.

3:15 Sponsored Presentation (Opportunity Available)

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

4:10 Detection of Memory B Activity for Pre-Existing and Treatment-Induced ADA

Karen Liao, MD, Investigator, GSK Associate Fellow, Immunogenicity and Clinical Immunology, GlaxoSmithKline

We applied a B cell ELISPOT method to evaluate memory B cell activity for pre-existing ADA and treatment-induced ADA against a domain antibody and a humanized monoclonal antibody, respectively. This novel application informs and characterizes immune memory activity associated with ADA responses and can provide a valuable tool for immunogenicity prediction for biologics with elevated risk of ADA.

4:40 Integrated Modelling Approach to Predict Safety and Immunogenicity of Immunomodulatory Biotherapeutics

Renu Singh-Dhanikula, PhD, Senior Research Investigator, Metabolism & Pharmacokinetics, Bristol-Myers Squibb

The presentation will show an integrated approach of using data from various in vitro assays as well as in silico predictions to assess safety and immunogenicity risk of biotherapeutics in early discovery and development. We will showcase how modelling approach can be used to select candidates with a better safety profile. We will also expand upon challenges in understanding the impact of the disease state and inter-patient variability in the immune response, and progress that has been made in this direction.

5:10 In vitro T-Cell Assay to Predict Immunogenicity of Biotherapeutic Products

Sivan Cohen, PhD, Scientist, BioAnalytical Sciences, Genentech, Inc.

Treatment of patients with biotherapeutic protein products may result in immune responses of varying clinical relevance including development of life-threatening anti-drug antibodies (ADA) that can limit product efficacy or impact its safety. Therefore, predicting the risk for immunogenicity of biotherapeutic products at early stages is a crucial need. This presentation will focus on in silico analyses and in vitro T-cell assay studies to characterize the immunogenic potential of different biotherapeutic proteins and their correlation to the clinically observed outcome.

5:40 Close of Day

5:40 Dinner Short Course Registration

Recommended Dinner Short Course*

6:159:15: SC6: Advice on Putting Together an Integrated Summary of Immunogenicity

Instructors: Joao Pedras-Vasconcelos, PhD, Biotech Quality and Immunogenicity Reviewer, Office of Biotechnology Products, CDER, FDA

Bonnie Rup, PhD, Bonnie Rup Consulting LLC

* Separate registration required.

Thursday, October 25

7:30 am Morning Coffee


7:55 Chairperson’s Opening Remarks

Joleen T. White, PhD, Director, Head of Project Support, NBE Drug Disposition, EMD Serono

8:00 Immunogenicity Risk Management

Valerie Quarmby, PhD, Staff Scientist, BioAnalytical Sciences, Genentech, Inc.

Every biotherapeutic has the potential to elicit unwanted immune responses, and these may compromise safety and efficacy. Immunogenicity risk ranking methods and tools are often used during lead selection and optimization to assess the likelihood that a biotherapeutic may be immunogenic. These tools can also be used retrospectively for root cause analysis. This talk will provide an overview of the use of these tools in the context of immunogenicity risk management.

8:30 KEYNOTE PRESENTATION: Application of Mechanistic Modelling to Prediction of Immunogenicity

Timothy Hickling, PhD, Immunogenicity Sciences Lead, Biomedicine Design, Pfizer, Inc.

This presentation will introduce an immunogenicity consortium that coordinates in vitro data to simulate clinical immunogenicity incidence and impact. Data related to product, patients and treatment are integrated into mechanistic models for predicting ADA incidence and impact on PK to allow for proactive decision-making when designing clinic trials. A case study of 8000 patients will be presented, showing an example of how Pfizer applies mechanistic modelling to their clinical development program, including an examination of the role of HLA and immune response genes. Additional retrospective analyses incorporating findings from the ABIRISK consortium will be discussed.

9:00 Presentation to be Announced

9:30 Problem Solving Roundtable Discussions

Table 1: Practical Application of Immunogenicity Preclinical Risk Assessment

Moderator: Steve Bowen, PhD, Team Leader, Chemist, Office of Biotechnology Products, CDER/FDA

Table 2: Current and Emerging Predictive Tools: Selecting Candidates and Predicting Clinical Outcome

Moderator: Jad Maamary, PhD, Senior Scientist, Merck and Co., Inc.

Table 3: Application of Mechanistic Modelling to Prediction of Immunogenicity

Moderator to be Announced

Table 4: Risk of Immunogenicity of Product and Process-Related Impurities, and Leachables/Extractables

Moderators: Daniela Verthelyi, PhD, Chief, Immunology Lab, Therapeutic Proteins, FDA/CDER

Mohanraj Manangeeswaran, PhD, Therapeutic Proteins, FDA/CDER

Table 5: Progress towards Inducing Immunological Tolerance to Biotherapeutics

Moderator: Ronit Mazor, PhD, Scientist, Antibody Discovery & Protein Engineering (ADPE), MedImmune, Inc.

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

11:10 Predicting Immune Responses to Therapeutic Proteins: The Promise of Safer Drugs and Improved Clinical Outcomes?

Zuben E. Sauna, PhD, Principal Investigator, Plasma Protein Therapeutics, CBER, FDA

Protein therapeutics have become an essential part of modern medicine. The development of immune responses to protein therapeutics can adversely affect safety and/or efficacy, concerns that are underscored by the discontinuation of development of several drugs due to immunogenicity issues. I will discuss progress in developing technological approaches that are useful for the non-clinical risk assessment of immunogenicity, as well as mitigation strategies such as the de-immunization of protein molecules.

11:40 In silico and in vitro Methodology to Assess the Immunogenicity Risk Associated with Target Mediated Effect in Mono versus Combination Therapies

Jad Maamary, PhD, Senior Scientist, Merck and Co., Inc.

A methodology describing best practices when analyzing prediction algorithms, sequence databases and in vitro tools for immunogenicity assessment is presented. This methodology examines underlying assumptions in antigen processing, MHC-II binding, TCR cross-reactivity and germline prevalence in its impact on immunogenicity to biotherapeutics. Case study: in silico/in vitro assessment of immunogenicity to monoclonal antibodies in mono and combination therapy is assessed with the described tools.

12:10 pm Clinical Relevance of Immunogenicity Risk Assessment Tools and Application for Product Engineering and Selection

Li Xue, PhD, Senior Principal Scientist, BioMedicine Design, Pfizer, Inc.

The immunogenicity risks of therapeutic proteins are evaluated with a variety of in vitro tools. These tools are used to assess the key immunological events that contribute to the anti-drug antibody (ADA) induction. The presentation will discuss the clinical relevance of the antigen presentation and T cell risk assessment tools. Case studies will be cited to illustrate the application for product testing.

12:40 Managing Unwanted Immune Responses to Antibodies Including Utilisation of MHC-Associated Peptide Proteomics (MAPPs)

Mark Fogg, PhD, Head, Immunology, Biology, Abzena

This presentation will present accurate and sensitive ways to assess the potential immunogenicity and development of anti-drug antibodies against proteins and antibodies ex vivo by measuring CD4+ T cell responses, methods for managing and reducing potential immunogenicity, and introduce MHC-Associated Peptide Proteomics (MAPPs) to augment data sets to better inform immunogenicity risk.

1:10 Luncheon Presentation: Immunogenicity Risk Assessment: Using Preclinical Tools during Lead Selection and Optimization

Noel Smith, PhD, Senior Group Leader, Applied Protein Services, Lonza Pharma & Biotech

High attrition rates of preclinical candidates are primarily caused by lack of efficacy or safety issues. Immunogenicity leads to problems including dangerous cytokine response and/or generation of anti-drug antibodies that neutralize protein activity and/or alter PK/PD. Lonza has developed a comprehensive set of preclinical safety and immunogenicity risk assessment tools. This presentation will describe how these tools, used early in development, aid selection and optimization of candidates and help reduce the risk of failure.

1:40 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing


2:20 Chairperson’s Remarks

Li Xue, PhD, Senior Principal Scientist, BioMedicine Design, Pfizer, Inc.

2:25 Mitigation of Immunogenicity to AAV Gene Therapy Vectors with Tolerogenic Nanoparticles Enables Re-Treatment for Systemic Gene Therapy Applications

Kei Kishimoto, PhD, CSO, Selecta Biosciences

Gene therapy using adeno-associated virus (AAV) vectors has shown great therapeutic potential. However, neutralizing antibody (NAb) responses to AAV prevent the ability to re-dose patients. Vector re-administration is important for pediatric applications, as transgene expression is likely to wane over time. We have shown that co-administration of vector with tolerogenic particles containing rapamycin can block formation of anti-AAV NAbs in mice and non-human primates to enable productive vector readministration.

2:55 Immune Tolerance Induction to Recombinant Immunotoxins

Ronit Mazor, PhD, Scientist, Antibody Discovery & Protein Engineering (ADPE), MedImmune, Inc.

Recombinant Immunotoxins (RITs) are a genetically engineered category of ADC that treats 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 lowered efficacy. This talk will discuss our recent findings of immune tolerance induction to RIT that allow multiple treatment cycles in naïve and mice with pre-existing antibodies. We used two approaches, using free low dose methotrexate and tolerogenic nanoparticles that contain rapamycin.

3:25 Removing T-Cell Epitopes with Computational Protein Design

Indigo King, PhD, Scientist, Immunology, Cyrus Biotechnology

Computational protein design has the potential to create a novel class of therapeutics with tunable biophysical properties, but immunogenicity remains a concern. We have combined machine learning with structure-based protein design to identify and redesign T-cell epitopes without disrupting function of the target protein or creating new epitopes. We have verified the method experimentally, removing T-cell epitopes from a gene therapy target, an immunotoxin, and GFP while maintaining folding and function.

3:55 Close of Immunogenicity Prediction & Control

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