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Immunogenicity to Biologics

Biopharm Knowledge Publishing
October 19, 2007
170 Pages - SKU: BKP1784075

Abstract Table of Contents Search inside this report Related Reports

Immunogenicity, the body’s response to therapeutic proteins, is vitally important in the development and marketing of biotech drugs. Failure to predict and monitor levels of immunogenicity can have disastrous results for patients and for companies.

This comprehensive new report, written by industry experts, gives you the information you need to understand this vital subject and includes a chapter on the commercial implications written by PricewaterhouseCoopers (PWC).

This unique, 170-page report, edited by Dr Nicole Lyscom, is written by industry experts including:

Dr Stephen Swanson, Department of Clinical Immunology, Amgen
Meena Wadhwa, Cytokines and Growth Factor Section, Biotherapeutics Group
Robin Thorpe, National Institute for Biological Standards and Control, UK
Dr Deborah Finco-Kent, Immunogenicity Assay Coordinator, Pfizer
Dr Ingrid Caras, Preclinical and Clinical Development Sciences, PDL Biopharma
Dr Bonita Rup, Bioanalytical R&D, Drug Safety and Metabolism, Wyeth Research
Dr Christian Schneider, Division EU Cooperation/Microbiology, Paul-Erlich-Institute
PD Harald Kropshofer PhD, Immunosafety of Biologics, F. Hoffman La Roche

And it includes a chapter on the commercial implications written by Jo Pisani and Yann Bonduelle of PwC. It will enable you to:

Contents include:

Factors contributing to immunogenicity
Impact on safety and efficacy
Commercial implications
Assay development and validation with special section on neutralising antibody assays
NEW US White Papers
Regulatory advice on working with the FDA and EMEA with NEW CHMP Guidelines
Risk management strategy
Risk minimisation and de-immunisation

This report is essential reading for anyone in the biotech, pharmaceutical and clinical outsourcing industries from corporate management through development and research to marketing and sales. It gives an authoritative, detailed and clear explanation of the issues surrounding immunogenicity and their implications for the market and for the biotech and pharmaceutical industries.

Chapter 1 Immunogenicity: Commercial Threat to Biotechnology-Derived Therapeutic Proteins?

Jo Pisani and Yann Bonduelle, Pharmaceutical Strategy Consultants, PricewaterhouseCoopers LLP, UK

1. Summary

2. Impact of Biological Products on the Global Pharmaceutical Market

3. Commercial Potential of Monoclonal Antibodies

4. Key Therapy Areas Likely To Be Impacted by Immunogenicity

5. Potentially Immunogenic Drug Types

6. Key Commercial Metrics

6.1 Key Metric: Risk

6.2 Key Metric: Cost

6.3 Key Metric: Time

6.4 Key Metric: Value

7. Impact of Immunogenicity on Product Profile and Physician’s Choice of Treatment

8. Reported Immunogenicity of Major Biological Product Types

9. Conclusion

Chapter 2 Factors Contributing to Immunogenicity of Therapeutic Proteins and Clinical Consequences

Dr Steven Swanson, Department of Clinical Immunology, Amgen Inc, USA

1. Factors contributing to immunogenicity

1.1. The role of aggregates

1.2. The role of oxidation and deamidation

1.3. The role of contaminants and impurities

1.4. Role of sequences within the protein therapeutic

1.5. Route of administration

1.6. The influence of dose

1.7. Influence of immune status of patient

2. Clinical Consequences of an Immune Response

2.1. Examples of severe clinical consequences

2.2. Therapeutic proteins with reduced immunogenicity or no clinical consequences

2.3. Risk factors and the monitoring of potential immunogenicity

3. References

Chapter 3 Practical Approach to Assay Development and Validation

Meenu Wadhwa* and Robin Thorpe** * Section Leader, Cytokines and Growth Factor Section, Biotherapeutics Group ** Head, Biotherapeutics Group, National Institute for Biological Standards and Control, UK

1. Introduction

2. Strategy for immunogenicity assessment

3. Assays for detection of antibodies and their practical application 3.1. Screening assays

3.2. Technical challenges associated with screening assays

3.3. Antibody controls and reagents for antibody assays

3.4. Limits of detection, sensitivity, cut-points and other critical issues

3.5. Interpretation of results and data analysis

3.6. Guidance On Antibody Assays for Immununogenicity Assessment

3.7. Validation of assays

3.8. Impact of antibodies on clinical response

4. References

Chapter 4 Considerations for the Development and Validation of Assays for Neutralising Antibodies and Interpretation of Data

Dr Deborah Finco-Kent, Senior Scientist, Immunogenicity Assay Coordinator, Pfizer Inc., USA

1. Introduction

1.1. Impact of neutralising antibodies on clinical results: safety and efficacy

1.2. Significance of neutralising antibody assays for pre-clinical testing

1.3. When to determine neutralising activity

2. Design and development of neutralising assays

2.1. How to develop quickly and with minimum cost

2.2. Ligand-binding versus cell-based assays

2.3. Sensitivity required

2.4. Other assays

2.5. Factors affecting assay performance

2.6. How to deal with drug interference

2.7. Determination and detection of cut points

2.8. Challenges with monoclonal antibodies and other biologic products

3. Interpretation of results

3.1. Selection of reference standards and controls

3.2. Determination of cut-points

3.3. How do you work out if your results are significant or not - are the detected neutralising antibodies relevant in vivo?

3.4. How do results correlate with efficacy?

3.5. How to generate positive controls

3.6. How to prepare a calibration serum for an ELISA

3.7. Quantification of results: mass units v. titres

3.8. Dealing with drug interference with antibodies

4. Validation of neutralising assays

4.1. What needs to be validated in each clinical phase including pre-clinical.

4.2. Ensuring detection of low affinity as well as high affinity antibodies

5. Characterisation of antigen/antibody response and isotype determination

5.1. What do the antibodies bind to?

5.2. How do you identify the isotype?

5.3. What are the benefits of this?

5.4. Secondary characterisation

6. Comments on US White paper and EU guidelines to date

6.1. Guidelines on presentation of data

6.2. Risk-based assessment

7. Case studies if possible

7.1. Challenges with monoclonal antibodies and other biologic products

Chapter 5 Evaluation of Immunogenicity for Preclinical and Clinical Investigations

Dr Ingrid Caras, Senior Director, Preclinical and Clinical Development Sciences, PDL BioPharma, Fremont, CA, USA

1. Introduction

2. Preclinical immunogenicity safety assessment

2.1. Other options for pre-clinical immunogenicity assessments

3. Pre-clinical studies in animals

4. Clinical immunogenicity issues

4.1. Immunogenicity risk assessment

4.2. Implication of immunogenicity for the clinical program

4.3. Significance of low level immune responses

4.4. Incorporation of assays into the clinical program

4.5. Phase 1 studies

4.6. Drug interference and study design

4.7. Endpoints

4.8. Validation

4.9. When and how often should samples be collected for immunogenicity assessments?

4.10. Reporting of clinical immunogenicity results

5. Post-marketing immunogenicity commitments

6. References

Chapter 6 Regulatory Recommendations when dealing with the FDA

Dr Bonita Rup, Senior Director, Bioanalytical R&D, Drug Safety and Metabolism, Wyeth Research, USA

1. Recent White Papers on development, validation and implementation of immunogenicity testing and on risk assessment

1.1. Background to the papers, why produced, which companies and people made recommendations, their significance to the industry.

1.2. Recommendations for the design and optimisation of immunoassays

1.3. Report on neutralising antibody white paper

1.4. What is the benefit of the FDA-requirement for neutralising assays in phase II (they are difficult to develop and are only relevant at phase III)

1.5. Report on validation of immunoassays

1.6. Report on risk based strategies

1.7. Advice on methods to use for specific products

1.8. Sensitivity of screening assays

1.9. Dealing with low-affinity antibodies

1.10. Evaluation of drug interference

1.11. Confirmatory assays required: how effective are they as a predictive marker?

1.12. Immunogenicity method validation

1.13. Interpretation of the results: How do they correlate with the clinical outcome? 1.14. Assays for T-cell activation

2. Practical advice on dealing with the regulators at the various stages of development

2.1. Experiences of the industry

2.2. When to design the immunogenicity programme

2.3. Advice on selection of assays for the type of product

2.4. Acceptable levels of assay sensitivity

2.5. Ensuring assay results are not questionable

2.6. Proper validation and characterisation of assays

2.7. Requirements before going into patients

2.8. Validation for each stage

2.9. Amount of pre-clinical and clinical immunogenicity data required

2.10. Advice on dealing with impurities with host cell protein

2.11. How much information is enough and how much is too much?

2.12. Management of immunogencity aspects regarding product / process change during the clinical trial?

3. Post-marketing immunogenicity considerations

3.1. What kind or immune response monitoring is required?

3.2. What is the impact of formulation on immunogenicity

3.3. Influence of the route of administration on immunogenicity

3.4. How transport and storage can affect immunogenicity

3.5. Case study if possible: What changes were implemented and how were they monitored and dealt with regarding the regulatory authorities?

Chapter 7 EU Regulatory Guidelines and Advice on Working with Regulators

Dr Christian Schneider, Acting Head, EU Cooperation/Microbiology, Paul-Ehrlich-Institute
Part One: The CHMP Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Products

1. Background

1.1. Aims of the guideline

1.2. Regulatory background

2. Discussion of the guideline text

2.1. Risk factors

2.2. Predictivity of non-clinical models

2.3. Development of assays for humoral and cellular immune responses

2.4. Potential clinical consequences of immunogenicity

2.5. Pre-authorisation signal detection in the clinical setting

2.6. Risk management plan

3. Conclusion

Part Two: Practical Advice on Working with Regulatory Authorities

1. Possibilities for obtaining scientific advice in the European Union 1.1. Scientific Advice from National Competent Authorities (NCAs) 1.2. Scientific Advice and Protocol Assistance from the EMEA

2. Strategic planning of scientific advice

3. Rules in scientific advice

4. References

Chapter 8 Risk Minimisation & De-immunisation

PD Harald Kropshofer, PhD, Head of Immunosafety of Biotherapeutics, F. Hoffmann La Roche

1. Abstract

2. Introduction

3. Recognition of therapeutic proteins by immune cells

4. Modulators of immunogenicity 4.1. Drug-related modulators of immunogenicity 4.2. Patient-related modulators of immunogenicity

5. The origin of T cell immunogenicity: T cell epitopes

6. HLA polymorphism & diversity in immunogenicity

7. Identification of T cell epitopes

8. Immunogenicity Minimisation 8.1. Humanisation 8.2. Epitope depletion (Deimmunisation)

8.3. Humanisation combined with deimmunisation 8.4. Ranking via T cell activation potential

9. Conclusions

10. References

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