Day One

08.30    
Registration

09.00    
Welcome and opening remarks from the Chair
Harald Kropshofer, PhD, Senior Personalized Healthcare Leader, Switzerland

09.10    
Understanding the immunobiology of immunogenicity

This refresher on immunobiology will provide you with an overview of immune recognition and characteristics of protein antigens and their impact on immunogenicity; the humoral and cellular immune system as it relates to immunogenicity; immunoglobulin class switching and how it influences ADA and immunogenicity and the basics of HLA and genetic differences in immune recognition.

Charles Gullo, Ph.D.
Deputy Director, Immunology, Duke/NUS Graduate Medical School, Deputy Director for phase I, LKC School of Medicine, NTU Singapore, and Assistant Professor in the Department of Microbiology, NUS, Singapore

09.50    
Risk factors, clinical consequence and mitigation of immunogenicity

In the past 20 years, an increasing number of recombinant therapeutic proteins have received approval, and many more are under drug development. However, all recombinant therapeutic proteins have the potential to be immunogenic to some degree. Their general immunologic or safety concerns include the loss of efficacy, general immune and hypersensitivity reactions, serum sickness and neutralization of the natural counterpart, resulting in autoimmune disorder. There are several factors involved in the immunogenicity including host cell-derived impurities, aggregates generated during formulation and storage, immunogenic amino acid sequence, dosing frequency, period and routes, dose, immunological state and genetic background of patients. To overcome the adverse clinical consequences, the risk factors should be eliminated as much as possible. And alternative treatment strategy such as concomitant use of appropriate immune suppressor should be also developed. In the presentation, I would like to introduce the case studies of risk factors, clinical consequence and mitigation of immunogenicity aiming at the less immunogenic therapy.

Dr Shingo Niimi, Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Japan

10.30    
Morning refreshments and networking

11.00    
CASE STUDY: New concepts in immunogenicity: Induced-self antigens
Lucia Mori, Ph.D., Senior Principal Investigator, Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore

11.40    
Round-table discussion: Immunogenicity considerations for the Asian market
In this interactive session, participants will have the opportunity to share and discuss their experiences. Topics of discussion will include:

• Requirements for immunogenicity data across the region
• Are there Asian-specific immunogenicity concerns?
• Ethnic difference, do we really need it for biosimilars?  Is global immunogenicity data enough?
• Interface between Asian and international guidelines
• Local regulatory considerations in designing clinical trials
• Assessing how different populations will behave in assays: Is there a documented difference between the Asian and Caucasian audience?
• Methods for comparing
• How to manage differences

Led by: Sofie Pattjin, Senior Group Leader Immunology, Applied Protein Services, Lonza, UK

12.20    
Lunch

13.20    
Understanding the role of protein aggregates in unwanted immunogenicity

Large protein aggregates are known to be produced during the pharmaceutical manufacturing of therapeutic protein products. However, our understanding of how protein aggregate attributes such as size contribute to immunogenicity is limited. This talk will focus on subvisible protein aggregates, how they may interact with the immune system, their potential impact on product safety and efficacy, as well as current regulatory considerations pertaining to the control of these particulates.

Dr Jack Ragheb, Chief Medical Research Officer, Laboratory of Immunology, Food & Drug Administration, USA

14.00    
Immunogenicity of protein aggregates: Is it a safety hurdle? An industrial scientist's perspective

Protein aggregation is one of the key challenges in the development of protein biotherapeutics.  A variety of process, formulation or storage-related factors have been found to affect the aggregation tendency of a protein to a significant degree.  Protein aggregation is a critical product quality issue as protein aggregates may reduce the biological activity and more importantly, enhance the immunogenicity potential of a protein product.  The overwhelming safety concern has led to an increased regulatory scrutiny of product quality in recent years.  This presentation will provide and industry perspective on the causes and consequences of protein aggregation, and its immunogenicity potential.

Wei Wang, Ph.D, Research Fellow, BioTherapeutics R&D, Pfizer Inc, USA

14.40    
Q&A Discussion: To what extent are protein aggregates a safety hurdle?

15.00    
Afternoon refreshments and networking

15.30    
Lessons learned from translational immunogenicity

Translational immunogenicity is a new field of increasing importance after experiencing cases of poor correlation of pre-clinical versus clinical immunogenicity findings. While it is generally accepted that immunogenicity data obtained in animal models normally are not predictive for the findings in man, it is still the belief that immunogenicity-related safety events in animals may translate into humans. The scope of translational immunogenicity considerations is to deepen our understanding in two directions: (i) help define which immunosafety findings in which animal models are predictive for which patients, (ii) define which immunosafety findings observed in clinical trials; e.g. the Tegenero case, are worth-while being followed-up in the future in new pre-clinical models. Lessons learned on how translational immunogenicity may add benefit to R&D of drugs will be discussed.

Harald Kropshofer, PhD, Senior Personalized Healthcare Leader, F.Hoffmann-La Roche Ltd., Switzerland

16.10    
Using technology and innovation to overcome immunogenicity assays’ unique bioanalytical challenges

One of the most challenging aspects related to immunogenicity evaluation of biotherapeutics pertains to the bioanalytical assessment of anti-therapeutic antibodies (ATAs).  The assays employed to detect, confirm and characterize ATAs are unique. In several aspects, those assays face unique challenges as well, three of which will be covered in this presentation: i) determining the thresholds (cutpoints) for identification of positive samples;  ii) challenges to overcome drug interference; and iii) interference caused by soluble-ligands.  Examples of approaches and technologies to overcome, or avoid these hurdles will be reviewed, and case studies will be used to illustrate how to successfully implement them. 

Mauricio Maia, Ph.D., Scientist, Genentech, USA

16.50    
Case study: Development of an ELISA based analytical platform for determination of recombinant hepatitis B virus X (HBx) protein refolding yields

The Hepatitis B Virus X (HBx) protein has been well associated with the initiation and development of hepatocellular carcinoma (HCC) and is an ideal representative of the bioprocessing challenges associated with producing novel protein molecules. The current study focuses on the development of a novel ELISA platform to quantitate HBx refolding yields. HBx refolding yields were measured by determining the amount of HBx bound to immobilized GST–p53 on a GSH- functionalized maleimide surface. Refolding yields were distinguished from soluble yields, which were determined by measuring total HBx protein bound to a maleimide surface under reducing conditions. This platform is amenable to scaleup studies for HBx bio-production

Anindya Basu, Research Associate, Nanyang Technological University, Singapore

17.30    
Closing remarks from the Chair. End of Day 1

Day Two

09.00    
Opening remarks from the Chair
Michael G. Tovey Ph.D., INSERM Director of Research, Laboratory of Biotechnology & Applied Pharmacology, ENS-Cachan, France

09.10    
KEYNOTE: Review of the FDA Draft Guidance on Immunogenicity

Dr Jack Ragheb, Chief Medical Research Officer, Laboratory of Immunology, Food & Drug Administration, USA

09.50    
Overcoming challenges in immunogenicity assessment of biosimilars in preclinical through clinical development

This presentation will discuss the evaluation of robust regulatory approaches for successful and cost-effective immunogenicity assessment of biosimilars. You will gain an overview of successful design of immunogenicity testing strategies to ensure effective comparability exercise in addition to overcoming challenges around development of anti-drug and anti-HCP immunoassays for biosimilars.

Dr. Arumugam Muruganandam PhD., MBA, Chief Scientific Manager, Head Preclinical and Bioanalytical, Biocon Research Limited, India

10.30    
Round-table discussions: Risk assessment of immunogenicity needed for the approval of biopharmaceutical and biosimilar products

In this interactive session, participants will have the opportunity to share and discuss their challenges and experiences. Topics of discussion will include:

• Strategies for implementing a tiered approach to risk analysis
• Tools and data to assess the risk of immunogenicity prior to clinical studies
• Assessing the impact of immunogenicity: PK/PD correlations

11.10    
Morning refreshments and networking

11.40    
Immunogenicity assessment: Improved analytical methods for the successful development of biosimilars

Successful development of biosimilars is dependent upon the establishment of validated and standardized assays that allow direct comparisons of the immunogenicity of biosimilars and innovator products. Improved analytical methods based on normalized dual luciferase reporter gene assays have been developed that for the first time allow direct comparisons of the potency and relative immunogenicity of biosimilars and innovator products in fully validated and standardized assays. Case studies will be presented where these methods have been used to compare the relative immunogenicity of interferon beta products and TNF-alpha antagonists of different molecular structure.

Michael G. Tovey Ph.D., INSERM Director of Research, Laboratory of Biotechnology & Applied Pharmacology, ENS-Cachan, France.

12.20    
Spotlight Presentation

This session will be hosted by a leading company who operates in the field of immunogenicity and will offer the opportunity to learn about the latest development and technical advancements in the industry. For details about speaking in this session or other sponsorship opportunities at this conference please contact Yvonne Leong, Tel: +65 6508 2489, Email: Yvonne.Leong@ibcasia.com.sg

12.40    
Lunch

13.30    
Prediction of immunogenicity

Tools to predict the immunogenic potential of therapeutic proteins or peptides have been used for at least half a decade with the aim to reduce the immunogenicity of drugs in clinics. However, these tools are still considered to be at an infancy state with regards to general acceptance. Although data derived from in silico, in vitro and in vivo models get more and more access to investigational new drug applications and other documents submitted to health authorities, there is still room for optimization. This is mainly due to the following reasons: (i) the need to apply these tools in combination rather than in isolation; (ii) the time it takes to link prediction data with clinical immunogenicity data, (iii) the need to understand the causal link between clinical immunogenicity data and the immunosafety profile of a drug. Case studies will be discussed to provide insight into the complexity of this topic.

Harald Kropshofer, PhD, Senior Personalized Healthcare Leader, F.Hoffmann-La Roche Ltd., Switzerland

14.10    
CASE STUDY: Monitoring patients for the presence of anti-drug antibodies in routine medical practice

Monitoring patients for the development of anti-drug antibodies (ADA), and their impact on clinical outcome is an important part of drug safety evaluation and is essential for the more effective and rational use of biopharmaceuticals. Quantification of neutralizing ADAs requires the use of cell-based assays that reflect the mode of action of the product. Results will be presented on monitoring patient with Crohn’s disease for the presence of neutralizing ADAs against TNF-alpha antagonists using engineered cells that express a normalized reporter-gene under the control of a drug-responsive promoter.

Michael G. Tovey Ph.D., INSERM Director of Research, Laboratory of Biotechnology & Applied Pharmacology, ENS-Cachan, France

14.50    
Afternoon refreshments and networking

15.20    
Drug eruption revisited

A drug eruption is an adverse drug reaction in the skin. Genetic associations between HLA haplotype and drug eruption have been reported. Recently, the immune response in Drug Reaction with Eosinophilia and Systemic Symptom (DRESS), previously thought to be directed against drug components, was shown to be also mediated by herpes-virus specific cytotoxic CD8+ T lymphocyte. We believe that it is essential to understand the immune mechanisms by which some drugs induce hypersensitivity in order to target these pathways to limit drug side effects. Our results suggest a new role for drugs in the pathogenesis of drug eruption.

Sebastien Calbo, Research Scientist, Group Leader, Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore

16.00    
Re-engineering biologics for reduced immunogenicity

Recombinant therapeutic proteins inherently carry the risk of inducing immunogenicity. While significant effort has been invested in prediction and assessment of immunogenicity, much less has been done with respect to de-immunization of biologics. Approaches ranging from synthetic modifications such as synthetic modifications to glycoengineering are being developed and starting to show promising results in pre-clinical models of immunogenicity. However, much effort remains to be done in validating existing de-immunization technologies and development of novel and innovative approaches for eliminating immunogenicity.

Fred J. Aswad, J.D., Ph.D., Senior Staff Scientist, Bayer HealthCare, USA

16.40    
Closing remarks from the Chair. End of conference

Post-conference Bioanalytical Masterclass

Method Development, Validation and Data Interpretation for Immunogenicity Assays

Date: Wednesday 17 October 2012
Time: Registration from 08.30 for a 09.00 start. Workshop will finish by 17.00
Additional Information: Lunch and refreshments will be provided.

This masterclass is designed to provide a comprehensive overview for those new to the field of immunogenicity testing, and as a refresher to those familiar with it. It will incorporate presentations, discussions and practical exercises, providing participants with a strong foundation in designing and validating immunogenicity assays, as well as critical knowledge on how to interpret preclinical and clinical immunogenicity data

Topics of discussion will include:

• Introduction to ADA assays
• Assay designs; assay development and technology platforms; screening, confirmatory and neutralizing antibody assays
• How to validate ADA assays to meet FDA and EU regulatory guidance
• Cut-point establishment
• Data analysis

About your workshop leaders:

Mauricio Maia, Ph.D.
Scientist
Genentech, USA

Dr Maia has over fifteen years’ experience in development, validation and interpretation of immunogenicity, pharmacokinetics (PK) and clinical diagnostic assays.  At Genentech, he is one of the scientists responsible for developing strategies and new procedures for immunogenicity testing.  Those responsibilities have also included defining technical aspects of immunogenicity testing, immunogenicity data interpretation, as well as providing key technical information and advice on the subject.  He is a member of a multidisciplinary group responsible for developing immunoassays and bioassays that support all development stages of multiple Genentech protein therapeutic programs. Co-authored the Mire-Sluis et al. immunogenicity assay recommendations white paper (JIM 2004). Prior to joining Genentech, he worked in a similar capacity at Protein Design Labs, Inc.; and as a Lab Supervisor at the Massachusetts Public Health State Laboratory Institute.

Dr. Arumugam Muruganandam PhD., MBA
Chief Scientific Manager, Head Preclinical and Bioanalytical
Biocon Research Limited, India

Dr Muruganandam is a Cell biologist & Protein biochemist with 20+ years of experience in academia (USA & Canada); government (NRC, Canada) and corporate research environments (Dyax Corp, USA & Biocon India). Currently responsible for preclinical development of biotherapeutics for global markets, he provides scientific oversight, strategic planning, operations, resource and project management and business development for all internal and collaborative research projects. He leads a team to manage contract GLP, Non-GLP toxicology, safety pharmacology and efficacy studies in India and overseas. As head of the bioanalytical team,  he oversees the design, development and implementation of assays for assessing PK, immunogenicity and biomarkers. Dr Muruganandam has authored several regulatory reports, grant applications, patents and published in peer reviewed journals.

News / Updates

25.09.12 Speaker Announcement
We are delighted welcome a new speaker to the expert panel: Wei Wang, Ph.D, Research Fellow, BioTherapeutics R&D, Pfizer Inc, USA

Immunogenicity of protein aggregates: Is it a safety hurdle? An industrial scientist's perspective
Protein aggregation is one of the key challenges in the development of protein biotherapeutics.  A variety of process, formulation or storage-related factors have been found to affect the aggregation tendency of a protein to a significant degree.  Protein aggregation is a critical product quality issue as protein aggregates may reduce the biological activity and more importantly, enhance the immunogenicity potential of a protein product.  The overwhelming safety concern has led to an increased regulatory scrutiny of product quality in recent years.  This presentation will provide and industry perspective on the causes and consequences of protein aggregation, and its immunogenicity potential.

17.09.12 Speaker Change
Dr Katharina Steinitz of Baxter Innovations GmbH Austria will no longer be able to attend the event to deliver the presentation Using new transgenic mouse models for preclinical assessment of immunogenicity

09.08.12 Speaker Change
Dr Qibin Leng of the Institut Pasteur of Shanghai, Chinese Academy of Sciences  will no longer be able to attend the meeting to deliver the presentation Immunopathogenesis of hand, foot and mouth disease: cross-reactive and Th2-prone immunity

02.07.12 New Abstract
New concepts in immunogenicity: Induced-self antigens

The study of the lipid-specific T cell responses has revealed to immunologists a series of unexpected findings. Among them, the effects of up-regulation of lipid metabolism via Toll-like receptor stimulation, has been elucidated. This novel mechanism has important consequences on immunogenicity criteria when testing new compounds. The possible consequences for induction of autoimmune responses will be discussed.

29.06.12 New Abstract
Using new transgenic mouse models for preclinical assessment of immunogenicity

Current development of new therapeutic proteins for the treatment of hemophilia A focus on the extension of half life and on the reduction of immunogenicity. Therapeutic proteins with different modifications to improve pharmacokinetic properties enter preclinical development and need to be tested for their immunogenic potential. Chemical as well as molecular changes in the protein therapeutics might influence the immunogenicity of the protein therapeutic as neoepitopes for T cells and B cells might be generated by these alterations. Mouse models are a suitable tool to compare the relative immunogenicity of different candidates and to analyze differences in B cell and T cell responses. In our group human protein transgenic mice as well as human HLA-DR transgenic mice have been developed. Results on FVIII specific T cell epitopes in HLA-DR transgenic animals will be discussed as an example.

28.06.12 New Abstract
Using technology and innovation to overcome immunogenicity assays’ unique bioanalytical challenges

One of the most challenging aspects related to immunogenicity evaluation of biotherapeutics pertains to the bioanalytical assessment of anti-therapeutic antibodies (ATAs).  The assays employed to detect, confirm and characterize ATAs are unique. In several aspects, those assays face unique challenges as well, three of which will be covered in this presentation: i) determining the thresholds (cutpoints) for identification of positive samples;  ii) challenges to overcome drug interference; and iii) interference caused by soluble-ligands.  Examples of approaches and technologies to overcome, or avoid these hurdles will be reviewed, and case studies will be used to illustrate how to successfully implement them.