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Immunogenicity has always been a critical safety concern, especially when many biotherapeutics are becoming increasingly complex. Understanding and controlling immunogenicity-related risks are essential in the development of biotherapeutics to ensure meeting the regulatory requirements. The 11th Annual Immunogenicity Assessment and Regulatory Approval of Biologics conference brings industry, regulatory and scientific experts together to share best practices in assessing immunogenicity of biologics. We will also discuss the challenges and solutions for addressing new regulatory guidelines in assay development and validation.

Final Agenda

Recommended Short Course(s)*

SC1: Preclinical and Clinical Assessment of Immunogenicity: Multidomain Therapeutics and New Modalities, Including Gene Therapy and CAR T

SC13: Sub Visible Protein Particles in Immunogenicity: Measurement, Characterization and Impact


*Separate registration required.

WEDNESDAY, MAY 2

7:30 am Registration(Commonwealth Hall) and Morning Coffee (Harbor Level)

DRUG TOLERANCE AND INTERFERENCES IN ASSAYS
Beacon Hill Complex

8:30 Chairperson’s Remarks

Shan Chung, PhD, Principal Scientist and Group Leader, Genentech, Inc.

8:40 Acid Treatment of Serum Samples in ADA Assays: To Treat or Not to Treat?

Uma_KavitaUma Kavita, PhD, Senior Research Investigator, Analytical and Bioanalytical Operations, Bristol-Myers Squibb

Despite the common use of acid treatment to dissociate anti-drug antibody (ADA)-drug complexes, a systematic study of the impact of various acids at different pH levels on ADA of differing affinities and the resulting impact on assay drug tolerance and sensitivity has not been reported. Using a dimeric domain antibody therapeutic and several mouse monoclonal antibodies of well-defined association and dissociation rate constants and differing relative affinities as well as a rabbit pAb as ADA controls, we have addressed several important issues related to acid pre-treatment and impact on ADA assay sensitivity and drug tolerance.

9:10 Sample Pre-Treatment to Resolve Matrix Interference in a Neutralizing Antibody Assay

Lynn KamenLynn Kamen, PhD, Scientist, BioAnalytical Sciences, Genentech

Neutralizing antibody (NAb) assays detect the presence of anti-drug antibodies that neutralize the mechanism of action of a therapeutic. While interference from the drug is a common problem in development of NAb assays, interference from the sample matrix itself can also interfere. This presentation will highlight a case study in which matrix interference in a NAb assay was identified and resolved via sample pre-treatment, allowing the successful detection of NAbs.

9:40 Using ICP-MS to Measure Total Drug Levels and Differentiating between Free Drug and Bound Drug to Anti-Drug Antibodies

Julio DelgadoJulio Delgado, MD, MS, CMO, ARUP Laboratories; Division Chief, Clinical Pathology, University of Utah School of Medicine; Associate Professor, Pathology, University of Utah

Development of anti-drug antibodies (ADA) against biological agents contributes to therapeutic failure. An ICP-MS assay was developed for detection of free Infliximab and Infliximab bound to ADA. The difference in concentrations between free and bound Infliximab indicates presence of ADA. The ICP-MS assay showed high tolerance to residual infliximab, so testing can be performed right after infusion. Early detection of ADA is helpful to optimize treatment in the inpatient setting.

10:10 Coffee Break in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

10:55 PANEL DISCUSSION

Moderator:

Shan Chung, PhD, Principal Scientist and Group Leader, Genentech, Inc.


Panelists:

Uma Kavita, PhD, Senior Research Investigator, Analytical and Bioanalytical Operations, Bristol-Myers Squibb

Julio Delgado, MD, MS, CMO, ARUP Laboratories; Division Chief, Clinical Pathology, University of Utah School of Medicine; Associate Professor, Pathology, University of Utah

Theo Rispens, PhD, Immunopathology, Sanquin Research, Amsterdam, The Netherlands

Susan Richards, PhD, Presidential Scientific Fellow, Translational Medicine Early Development, Sanofi R&D


  • Technical considerations for sample pre-treatment methods developed to reduce drug interference
  • Epitope integrity during pre-treatment (e.g. non-denaturing)
  • Subject, patient interfering factors: Cross-reactive antibodies (e.g. rheumatoid factor, allo-antibodies)
  • Applicability of these methods in the clinical laboratory setting
  • Clinical significance/added value of ADA results generated from assays involving sample pre-treatment methods

IMMUNOGENICITY PREDICTION AND MITIGATION
Beacon Hill Complex

11:25 The Use of Non-Clinical Assessments in Immunogenicity Risk-Assessment during Drug Development

Zuben SaunaZuben E. Sauna, PhD, Research Biologist & Principal Investigator, Haemostasis Branch, Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, FDA/CBER

Immunogenicity (development of anti-drug antibodies) is an impediment to development and licensure of therapeutic-proteins. There has been significant progress in the development use of non-clinical assessments of immunogenicity-risk. The application of these tools will be illustrated using case studies and examples from our research. I will also present data evaluating different Factor-VIII products in a MHC-Associated-Peptide-Proteomics (MAPPs) assay. These results show that proteins with the identical primary sequence may present differently to the immune system.

11:55 T Cell Response to Biologics: From T Cell Epitope Mapping to Immunomonitoring

Bernard_MaillereBernard Maillere, PhD, Director, Research and Head of Immunochemistry Laboratory, Institute Frederic Joliot, SIMOPRO, CEA, University Paris-Saclay

As the T cell activation precedes and contributes to antibody response we evaluated the T cell response to biologics in heathy donors and in patients. With the perspective of immunogenicity prediction, we identified T cell epitopes from T cells collected in healthy donors of multiple biologics including infliximab, rituximab, adalimumab, natalizumab, FVIII en IFN-b. T cell epitopes identified from the healthy donors were shown to participate to the T cell response in the treated patients. Using a new triple-cytokine fluorospot assay we revealed a T cell response in multiple ADA- patients qualitatively different from that of ADA+ patients demonstrating that the lack of ADA did not imply an absence of immune response.

LONZA tagline12:25 pm Immunogenicity Risk Assessment: Using Preclinical Tools during Lead Selection and Optimization

Noel_SmithNoel Smith, PhD, Principal Group Leader, Applied Protein Services, Lonza Biologics

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.

 Abzena 12:55 Luncheon Presentation: Managing Unwanted Immune Responses to Antibodies including utilisation of MHC-Associated Peptide Proteomics (MAPPs)

Mark Fogg, PhD, Head, Immunology, Abzena

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

Introducing MHC-Associated Peptide Proteomics (MAPPs) to augment data sets to better inform immunogenicity risk

1:55 Session Break

2:10 Assessment, Observation and Mitigation of Immunogenicity: A European Perspective

Sophie_TourdotSophie Tourdot, PhD, BioMedicine Design, Pfizer

The talk will review emerging data and immunogenicity strategy from European investigators, including activities of the European Immunogenicity Platform (EIP), work from the Innovative Medicine Initiative - funded ABIRISK program (Anti-biopharmaceutical immunization: prediction and analysis of clinical relevance to minimize the risk), and the implications of the latest EMA guidelines.

RISK ASSESSMENT OF PRODUCT AND PROCESS-RELATED ATTRIBUTES
Beacon Hill Complex

2:40 Chairperson’s Remarks

Marisa K. Joubert, PhD, Principal Scientist, Process Development, Amgen, Inc.

2:45 Impact of Chemical Modifications on the Immunogenicity of IgG Subvisible Particles

Björn BollBjörn Boll, PhD, Head, Particle Lab and Higher Order Structure Protein Analytics, Physical Chemical Analytics, Novartis Pharma AG

The theoretical concerns regarding the potential immunogenicity of proteinaceous aggregates and subvisible particles in protein therapeutics have been widely debated. This talk will present the detailed mechanistic studies on the biological impact of aggregates and sub-visible proteinaceous particles in a hIgG1 transgenic mouse model. The results are discussed within the current status of related literature of in vivo and in vitro studies.

3:15 pm Immunomodulatory Effects of Host Cell Impurities in Biotherapeutic Monoclonal Antibodies

Shraddha RaneShraddha Rane, PhD, Postdoctoral Research Associate, Infection Immunity and Respiratory Diseases, The University of Manchester

The ability of monoclonal antibodies to induce immune responses in patients, and the production of anti-drug antibodies (ADA), can reduce efficacy and provoke adverse health effects. There is increasing evidences that aggregation and presence of host cell impurities (even at very low levels) can enhance and modify the immunogenic potential of monoclonal antibodies (mAb) and other protein therapeutics. Here we examined the ability of low levels of a common host cell impurity to modulate the immune responses to aggregates of two mAbs. The fact that HCP preferentially binds to mAb aggregates suggests that HCP impurities, although low, could be selectively concentrated by aggregate formation and thus contribute to an adjuvant-like stimulation of the immune responses.

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

4:45 Problem-Solving Breakout Discussions (Commonwealth Hall)

Understanding of Aggregates Structures, a Key Factor in Understanding Aggregates Immunogenicity

Tudor Arvinte, PhD, Professor, Biopharmaceutics, School of Pharmacy Geneva-Lausanne, University of Geneva and Therapeomic, Inc.

  • The importance of using multiple methods to understand aggregation
  • Factors that can induce the formation of protein aggregates in the drug substance and drug product
  • Aggregation mitigations
  • Particulate matter in drug substance and drug product
  • Examples of aggregation issues in product development and in products on the market
  • Aggregation and immunogenicity: from loss of potency to severe side effects

Immunogenicity Assessments during Drug Development, Licensure and in the Clinic

Zuben E. Sauna, PhD, Research Biologist & Principal Investigator, Haemostasis Branch, Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, FDA/CBER

  • What are the key determinants (genetic and non-genetic) for predicting immunogenicity risk? How can they be identified?
  • Can this information be used? In the clinic? During drug development? In regulatory decision making?
  • What are the methods available for preclinical assessments of immunogenicity?
  • What is their relative value?
  • How should data from preclinical assessments be used during early stages of drug development?

5:45 Networking Reception in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

7:00 End of Day

THURSDAY, MAY 3

8:00 am Registration(Commonwealth Hall) and Morning Coffee (Harbor Level)

RISK ASSESSMENT OF PRODUCT AND PROCESS-RELATED ATTRIBUTES (CONT.)
Beacon Hill Complex

8:30 Chairperson’s Remarks

Marisa K. Joubert, PhD, Principal Scientist, Process Development, Amgen, Inc.

8:35 KEYNOTE PRESENTATION: Scientific considerations for the assessment of immunogenicity risk for proteins, peptides and other complex drugs

Daniela VerthelyiDaniela Verthelyi, PhD, Chief, Laboratory of Immunology, Office of Biotechnology Products, Office of Pharmaceutical Quality, CDER

This talk will discuss the impact of innate immune response modulating impurities and aggregates on the immunogenicity risk assessment for therapeutic peptides and proteins with a particular focus on how they can modulate the local innate immune and inflammatory responses.

ProImmune9:35 An Integrated Approach to Managing Immunogenicity Risk and Optimum Protein Design

Jeremy_FryJeremy Fry, DPhil, Director, Sales, ProImmune

Integrated platforms can be used to mitigate immunogenicity risk and characterize immune responses during the drug design and development stages. ProImmune offers mutational activity mapping for optimal protein design, DC-T/T cell proliferation assays for biologic lead selection/optimization, a Mass Spectrometry assay for characterization of antigen presentation; HLA-peptide binding assays to characterize individual epitopes & undiluted whole blood cytokine storm assays.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

11:05 Case Studies Assessing the Impact of Key Product Quality Attributes on Safety of Biotherapeutics

Marisa JoubertMarisa K. Joubert, PhD, Principal Scientist, Process Development, Amgen, Inc.


11:35 Complexity of Phenomena and Factors that Influence the Aggregation of Biopharmaceuticals in Human Plasma Revealed by New Case Studies

Tudor ArvinteTudor Arvinte, PhD, Professor, Biopharmaceutics, School of Pharmacy Geneva-Lausanne, University of Geneva and Therapeomic, Inc.

Biopharmaceutical formulations, despite successful release for particulates according to regulatory requirements, may aggregate during in vivo administration. New in vitro studies of the aggregation of biopharmaceuticals in plasma show that: i) plasma aggregation occurs in many types of biopharmaceuticals, ii) can be different in plasma from patients and healthy donors, iii) there are donor-to-donor and patient-to-patient variations, iv) aggregation in animal model plasma can be different from human plasma, v) plasma aggregation may depend on the manufacturing clone, vi) stable formulations that do not aggregate in plasma can be developed.

12:05 Highlighted Poster Presentation: A Novel In-Vitro Human Skin Explant Test to Predict Adverse Immune Reactions to Biopharmaceuticals

Louis_BibbyLouis Bibby, BSc (Hons) MRes, PhD Student, Alcyomics/ Academic Haematology, Newcastle University, United Kingdom

To aid preclinical prediction of adverse effects of a hypersensitivity nature, we have developed a human in-vitro skin explant test, which uses human blood and non-artificial autologous skin to assess for histopathological damage indicative of adverse immune activation which could be used as a valuable preclinical tool. We have further extended this tool to a reconstituted human 3D skin equivalent for large scale assessment of adverse effects to biologics.

12:20 Highlighted Poster Presentation: A Novel In-Vitro Assay for Detection of Immunotoxicity of Aggregated Monoclonal Antibodies

Ana Patricia RibeiroAna Patricia Ribeiro, Marie Curie PhD student, Institute Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK

We have developed a novel human in vitro skin test as a tool for the assessment of adverse immune reactions to aggregated mAbs. The output of this assay includes assessment of histopathological skin damage, T cell proliferation, cytokine release and cell death assays. In this study, aggregation of monoclonal antibodies was induced by a temperature stress protocol, followed by characterization of protein content by analytical ultra-centrifugation and transmission electron microscopy, revealing a 5% aggregation level of total protein content. Our results show that exposure to temperature can, in fact, cause conformational changes in the mAb structure that, ultimately, cause adverse immune reactions. Our novel in vitro assay showed that it was highly sensitive for determining an adverse reaction to mAb aggregation and demonstrates to be a promising tool to predict immunotoxicity caused by mAb aggregation.

12:35 End of Immunogenicity Assessment and Regulatory Approval of Biologics


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