Immunogenicity Case Studies and Clinical Management

- 免疫原性案例研究和临床管理 -


As the immunogenicity field is moving forward, closing the gap between clinicians and assay developers is essential in the success of biologic development and accelerating the adoption of new biologic therapies in patient treatments. This year, CHI’s Immunogenicity Case Studies and Clinical Management conference will focus on new case studies of novel biologics, new modalities such as gene and cell therapies, and emphasize on closing this gap by providing multiple viewpoints from clinicians, technology developers and regulators on how to use immunogenicity data in clinical settings.

Final Agenda

5月3日(日)

Recommended Short Course(s)*

SC1: Clinical Assessment of Immunogenicity of New Modalities: Focus on Bispecific Antibodies, Gene Therapy and Oligonucleotides

SC5: In silico and in vitro Immunogenicity Risk Assessment: Overview and Real-Life Examples

*Separate registration required.

5月4日(一)

7:00 am Registration and Morning Coffee

CLINICAL STUDIES AND MANAGEMENT

8:30 Chairperson’s Opening Remarks

Sandra Garces, MD, PhD, Clinical Research Director, Global Drug Development, Amgen


8:40 KEYNOTE PRESENTATION: Benefits of Prophylactic Short-Course Immunomodulation in Patients with Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in a Large Cohort

Priya Sunil Kishnani, MBBS, Chen Family Professor of Pediatrics, Chief, Medical Genetics, Molecular Genetics and Microbiology, Duke University

Immunomodulation in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with cross-reactive immunologic material (CRIM)-negative infantile Pompe disease (IPD). We have previously demonstrated that immunomodulation with a short-course of rituximab, methotrexate, and IVIG is successful in achieving immune tolerance in a large cohort of IPD patients from various treatment centers. Data presented will support this carefully planned short-course of prophylactic immunomodulation is safe and efficacious in inducing immune tolerance to ERT.

9:10 Immunogenicity Profile of Subjects Receiving 60 mg/day Maintenance Dose of Pegvaliase

Johanna Abend, Senior Scientist I, Immunogenicity, Translational Sciences, BioMarin Pharmaceutical, Inc.

Pegvaliase, a PEGylated bacterially-derived enzyme substitution therapy received approval from the Food and Drug Administration (FDA) for maintenance dosages up to 40 mg/day in adult patients with PKU. We will provide comprehensive immunogenicity analyses in subjects receiving 60 mg/day maintenance doses including antibody responses, circulating immune complex levels, and complement (C3 & C4) levels to support the inclusion of doses up to 60 mg/day of pegvaliase.

9:40 Value of a Novel PD Biomarker in Assessing Response to Therapy and Clinical Consequence of ADA in Inflammatory Skin Conditions

Kristin Hollister, PhD, Senior Research Scientist, Clinical Advisory Group, Laboratory for Experimental Medicine, Eli Lilly and Company

In psoriasis and atopic dermatitis, activated keratinocytes and resident macrophages secrete interleukin-19 (IL-19), an inflammatory mediator integral to the disease process. Measurable in the systemic circulation, IL-19 levels correlate with disease severity and response to therapy, preceding visible improvement or worsening of skin lesions. Additionally, circulating IL-19 levels are effective in predicting the clinical significance of anti-drug antibodies against therapeutic proteins indicated in disease treatment.

10:10 Networking Coffee Break

CLINICAL STUDIES AND MANAGEMENT (CONT.)

10:45 Chairperson’s Remarks

Sandra Garces, MD, PhD, Clinical Research Director, Global Drug Development, Amgen


10:50 Immunogenicity in the Prescription Drug Labeling: Is It Time to Revise?

Sandra Garces, MD, PhD, Clinical Research Director, Global Drug Development, Amgen

It is difficult to come up with new topics when it comes to clinical relevance. However, I feel that many concepts we have been talking about in clinical relevance haven't yet reached FDA and part of the scientific community working on IMG, which are still very focused on bioanalytic aspects. So, I don't think there is an issue in repeating some topics.

11:20 Managing the Clinical Risks of Immunogenicity: Rethinking Premedication to Prevent Infusion Related Reactions

Paul A. Ardayfio, PhD, Clinical Research Advisor, Global Patient Safety-Medical, Eli Lilly and Company

Immunogenicity can increase the risk for a variety of immune related adverse events including infusion related reactions.  Premedicating with antihistamines, steroids and NSAIDs is a common practice thought to reduce the severity or frequency of infusion related reactions. This meta-analysis reviewslooks at the effectiveness of this practice and whether there is data to support the widespread use of premedication as a risk minimization strategy for monoclonal antibody infusion. 

11:50 PANEL DISCUSSION: Bridging the Gap between Pharma, Tech Developers and Clinicians

Moderator: Mark Milton, PhD, Executive Director, PK Sciences, Global Head Ophthalmology TA, Novartis Institutes for BioMedical Research, Inc.

Panelists: Sandra Garces, MD, PhD, Clinical Research Director, Global Drug Development, Amgen

Priya Sunil Kishnani, MBBS, Chen Family Professor of Pediatrics, Chief, Medical Genetics, Molecular Genetics and Microbiology, Duke University

Additional Panelists to be Announced

  • Current understanding of immunogenicity in the clinic
  • How to provide useful immunogenicity data for actionable decision in the clinics?

 

12:20 pm Sponsored Presentation (Opportunity Available)

12:50 Session Break

12:55 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:55 Session Break

2:20 Problem-Solving Breakout Discussions - View All Breakout Discussion Topics

TABLE: Immunogenicity of PEG: Impact and Analysis

Co-Moderators: Johanna Abend, PhD, Senior Scientist I, Immunogenicity Assessment, Translational Sciences, BioMarin Pharmaceutical Inc.

Madhukar Aryal, MS, Senior Research Associate, BioAnalytical Sciences, BioMarin Pharmaceutical Inc.

  • How is our understanding of anti-PEG responses evolving (eg, pre-existing PEG antibodies, drug-induced anti-PEG responses)?
  • Can dosing regimens affect the anti-PEG response (eg, is desensitization / tolerance possible)?
  • Can other strategies be used to overcome the effect of anti-PEG response (eg, administration of free PEG)?

TABLE: How to Optimize Sample Pretreatment Methods

Moderator: Lynn Kamen, PhD, Senior Scientist, BioAnalytical Sciences, Genentech Inc.

  • ACE vs BEAD vs SPEAD
  • How much positive control antibody recovery is sufficient?
  • How to optimize assay sensitivity while maintaining drug tolerance?
  • What is the best sample pretreatment method for cellular assays?

3:20 Networking Refreshment Break

PLENARY KEYNOTE SESSION

4:00 Chairperson’s Remarks

K. Dane Wittrup, PhD, J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology

4:10 From Energy to Machine Learning

George-ChurchGeorge Church, PhD, Professor of Genetics, Harvard Medical School; Professor of Health Sciences and Technology, Harvard and the Massachusetts Institute of Technology (MIT)

In 1974, I adapted energy optimization methods for use in models of nucleic acids, protein and their interactions, and then for use in crystallographic refinement. In the last days of the second millennium, David Baker's team won the Critical Assessment of Structure Prediction (CASP) by an unbelievable margin. Since then, our labs exchanged 3 PhD students (Dantas, Raman, Lajoie), for Wannier from Mayo's group, Stranges from Kuhlman, and Mandell from Kortemme. We engineered new sensor proteins for metabolic engineering, essential proteins with non-standard amino acids for biocontainment, and polymerase-pore fusions for nanopore sequencing. None of this prepared us for the revolution following Gleb Kuznetsov joining our lab in 2012, joined soon by Surge Biswas, Pierce Ogden, Ethan Alley, and Sam Sinai. Together we abruptly moved to "sequence only" deep machine learning for protein design – ranging from fluorescent proteins to AAV capsids to antibodies. When combined with libraries of millions of designed gene segments from chip-synthesis and rapid testing, each design cycle can take large leaps in sequence space and function space.

4:55 The Case for Intelligent Design in Protein Engineering

spangler-jaimeJamie Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University

Directed evolution is in its prime, and it is deepening our understanding of biological systems and empowering therapeutic design. Recent breakthroughs in structural biology, computational design, and high-dimensional data analytics afford us the unprecedented opportunity to apply molecular, structural, and computational principles to guide protein engineering, employing a so-called “intelligent design” approach. This talk will highlight how my lab harnesses this interfacial approach to overcome the deficiencies of natural proteins.

5:40 Welcome Reception in the Exhibit Hall with Poster Viewing (Co-Sponsorship Opportunity Available)

7:15 End of Day

5月5日(二)

8:00 am Registration and Morning Coffee

CASE STUDIES OF NEW MODALITIES

8:25 Chairperson’s Remarks

Darshana Jani, PhD, Associate Director & Global Lead Biologics, Pfizer Inc.


8:30 Immunogenicity Assessments in the Development of AAV Gene Therapies

Mark Milton, PhD, Executive Director, PK Sciences, Global Head Ophthalmology TA, Novartis Institutes for BioMedical Research, Inc.

The assessment of the immunogenicity is a pivotal aspect of the development of AAV-based gene therapies. The humoral and cellular immune responses can have an impact on the efficacy and/or safety of these gene therapies. This presentation will illustrate the challenges that the immune response poses to the safe and effective development of gene therapies and strategies to mitigate the impact of the immune response.

9:00 Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A

Brian Long, PhD, Associate Director, Immunogenicity Assessment, BioMarin Pharmaceutical, Inc.

This presentation describes the clinical immunogenicity profile for Valoctocogene roxaparvovec, an AAV5 mediated gene therapy encoding FVIII for the treatment of Hemophilia A. The development and characterization of assays used to detect pre-existing AAV5 immunogenicity, and to characterize the post-dosing humoral and cellular immune responses will be discussed.

9:30 Approaches to Reduce Target Interference in the Anti-Drug Antibody Assays, a Case Study

Erik Meyer, PhD, Investigator, Bioanalysis, Immunogenicity and Biomarkers (BIB), IVIVT, R&D, GlaxoSmithKline

When a therapeutic binds its target, the target's natural catabolism is altered. The use of acid dissociation for better drug tolerance can also dissociate the drug bound target. With multimeric targets, free target can now result in false positive ADA assay responses. In-solution blocking antibody can eliminate this interference, if the Kd are comparable. With a high target affinity therapeutic, this may not work. Using a solid phase extraction process with the blocking antibody, acid dissociation released target is removed from the samples, with minimal loss of drug or ADA but no drug tolerance. A second acid dissociation ensures sufficient drug tolerance for an accurate ADA evaluation.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

CASE STUDIES OF NEW MODALITIES (CONT.)

10:45 Chairperson’s Remarks

Darshana Jani, PhD, Associate Director & Global Lead Biologics, Pfizer Inc.

10:50 Immunogenicity Studies on the Recently Approved Recombinant FVIII Product

Pedro Paz, PhD, Director, Principal Scientist, ImmunoProfiling Group in Biologics Research, Bayer Healthcare


11:20 Characterization of Immune Response to Bispecific Antibody Therapeutics

Kate Peng, PhD, Group Leader/Senior Scientist, BioAnalytical Sciences, Genentech

Bispecific mAbs (bsmAbs) are a novel class of mAbs that aim to improve drug efficacy by simultaneously working on two targets. This is a relatively new approach with limited experiences in clinical development. This presentation will use case studies to discusses our strategy for assessing the anti-drug antibody (ADA) responses to the bsmAb and summarizes the characterization results as well as the clinical impact of ADAs on drug exposure and safety.

11:50 Insight into Mechanisms of Immunogenicity Following Treatment with Therapeutic Monoclonal Antibodies

Yariv Wine, PhD, Assistant Professor, Molecular Cell Biology and Biotechnology, Tel Aviv University, Israel

We developed a new quantitative bio-immunoassay to determine ADA levels and their neutralizing capacity. Utilising NGS and proteomics we found that the B-cell response following mAb administration is a vaccine-like response that may be induced by immunocomplexes and that the response is diverted to the marginal zone rather to the germinal centers. The data obtained in the study will help to assess the immunogenicity of biologics under development and help to revise treatment strategies that may result in increased drug efficacy. Moreover, the methods developed in the study can be readily used in the clinic and facilitate decision making during treatment with biologics.

12:20 pm Session Break

12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own

1:25 Ice Cream Break in the Exhibit Hall with Poster Viewing and Poster Award

IMMUNOGENICITY RISK ASSESSMENT AND MITIGATION

2:00 Chairperson’s Remarks

Vibha Jawa, PhD, Director and Lead, Predictive and Clinical Immunogenicity, PPDM, Merck & Co., Inc.

2:05 Increased Immunogenicity Associated with Combination Regimens with Immune Modulatory Biologic

Vibha Jawa, PhD, Director and Lead, Predictive and Clinical Immunogenicity, PPDM, Merck & Co., Inc.

The use of immune modulatory biologics to augment functionality of immune cells can also augment the risk of immunogenicity. The quality of such an immune response and its clinical relevance will be explored through this talk. Whether the activation of immune cells can break tolerance to otherwise tolerant sequences will also be explored.

2:25 Preclinical Immunogenicity Risk Assessment and Lead Optimization for Novel Biological Therapeutic Modalities

Jochem Gokemeijer, PhD, Associate Director, Molecular Discovery Technologies, Bristol-Myers Squibb

This talk will describe the drug development workflow and tools to identify and engineer lead therapeutic biologics with reduced immunogenicity risk. Novel biological modalities can have multiple pathways to an anti-therapeutic immune response and that require modification of tools and assays.

2:45 Development of a Novel Dendritic Cell-based Antibody Loading Assay to Predict Immunogenicity of Biotherapeutics

Lynn Kamen, Ph.D., Senior Scientist, BioAnalytical Sciences, Genentech

As therapeutic antibodies become increasingly complex, the potential for anti-drug antibody (ADA) responses become more common, making in vitro immunogenicity prediction assays an important tool for drug development.  A key component of the immune response is the uptake of antibody by antigen presenting cells (APCs) such as dendritic cells.  This presentation will highlight the development of a dendritic cell (DC) loading assay that measures antibody internalization and shows that highly immunogenic antibodies are internalized to a higher degree than antibodies with low immunogenicity.

3:05 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

ASSESSMENT OF PRE-EXISTING REACTIVITY

4:25 Importance of Pre-Existing Abs to the Viral Capsid during Immunogenicity Assessment of Viral Vectors based Gene Therapy

Jim McNally, PhD, Executive Director, Head of Research and Clinical Assays, Program Lead, CRISPR Therapeutics

This talk will focus on the assessment of pre-existing antibodies to the viral capsid and the implications for their impact on the successful dosing of gene therapy drug candidates. Case studies will show how the thought process about pre-existing antibodies is evolving. There will be a focus on the tools used to measure pre-existing antibodies against the viral capsid and their utilization as exclusion criteria for entry into clinical studies.

4:55 Investigation of Pre-Existing Reactivity to Biotherapeutics Can Uncover Potential Immunogenic Epitopes and Predict Immunogenicity Risk

Nicoletta Bivi, PhD, Director, Assay Development, Laboratory of Experimental Medicine, Eli Lilly

In this study, we use ADA assays to measure pre-existing reactivity, i.e. the ability of a molecule to produce an ADA-like response in normal human serum. The magnitude of pre-existing reactivity correlates with clinical immunogenicity. Furthermore, the domain specificity was the same in pre-existing ADA as in TE-ADA. Based on this, magnitude and domain specificity of pre-existing reactivity can be a powerful tool to understand the immunogenic potential of biotherapeutics.

5:25 End of Immunogenicity Case Studies and Clinical Management

5:30 Registration for Dinner Short Courses


6:00-8:30 pm Recommended Dinner Short Course*

SC9: Introduction to Biophysical Analysis for Biotherapeutics: Development Applications

*Separate registration required.

* 活动内容有可能不事先告知作更动及调整。

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