Immunogenicity Case Studies and Clinical Management, May 4-5 2020

 

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.

Monday, August 31

CLINICAL STUDIES AND MANAGEMENT

9:05 am

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

Ankit Desai, MBBS, Senior Research Associate, Duke University Medical Center

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.

9:25 am

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.

9:45 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Sandra Garces, MD, PhD, Medical Director, Global Drug Development, Amgen Inc.
Panelists:
Ankit Desai, MBBS, Senior Research Associate, Duke University Medical Center
Johanna Abend, Senior Scientist I, Immunogenicity, Translational Sciences, BioMarin Pharmaceutical, Inc.
10:10 am Session Break
10:30 am Coffee Break - View our Virtual Exhibit Hall
10:50 am KEYNOTE PRESENTATION:

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

Sandra Garces, MD, PhD, Medical Director, Global Drug Development, Amgen Inc.

ADA per se do not necessarily represent an undesirable outcome. Therefore, more important that simply determine ADA/NAb incidences, is to reveal which clinical consequences are found to be mediated by ADA and in which proportion of the population exposed to the drug. During drug development a risk based approach to IMG should be focus on the population rather than on the individual patient. Specific steps should be conducted to estimate the proportion of patients in a given population, which when exposed to the drug, are expected develop clinically relevant manifestation mediated by ADA. When the information obtained is able to affect the benefit-risk profile of the drug or affect the way prescribers can use the medicinal product, it should be communicated in the prescription drug labelling.  Otherwise, its usefulness is questionable. The goal of the prescription drug labelling is to provide prescribers relevant information on how they can use the product in a safe and effective way. Immunogenicity information should not be an exception.


CASE STUDIES OF NEW MODALITIES

11:10 am

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.

11:30 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Sandra Garces, MD, PhD, Medical Director, Global Drug Development, Amgen Inc.
Panelist:
Brian Long, PhD, Associate Director, Immunogenicity Assessment, BioMarin Pharmaceutical, Inc.
11:55 pm Session Break
12:15 pm Lunch Break - View our Virtual Exhibit Hall
12:45 pm

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.

1:05 pm

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

There are several options in developing anti-drug antibody assay to assess the immunogenicity of therapeutics. Each approach have limitations, in the quest for an assay that balance’s sensitivity and drug tolerance. This case study will describe one approach. Once the assay was developed validated, the study results did not correlate with PK profiles and suggested some type of assay interference. Considering more information about the target that was collected during the study, the ADA assay was re-development. With the improved ADA assay and re-analyses of study samples, the results provided a more focused assessment of immunogenicity for the study.

1:25 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Mark Milton, PhD, Executive Director, PK Sciences, Global Head Ophthalmology TA, Novartis Institutes for BioMedical Research, Inc.
Panelist:
Erik Meyer, PhD, Investigator, Bioanalysis, Immunogenicity and Biomarkers (BIB), IVIVT, R&D, GlaxoSmithKline
1:50 pm Session Break
2:10 pm Refresh Break - View Our Virtual Exhibit Hall
2:30 pm Problem Solving Breakout Discussions - Part A

This session provides the opportunity to discuss a focused topic with peers from around the world in an open, collegial setting. Select from the list of topics available and join the moderated discussion to share ideas, gain insights, establish collaborations or commiserate about persistent challenges.

TABLE 9: Immunogenicity of PEG: Impact and Analysis

Johanna Abend, Senior Scientist I, Immunogenicity, Translational 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)?
Madhukar Aryal, MS, Senior Research Associate, BioAnalytical Sciences, BioMarin Pharmaceutical, Inc.
3:00 pm Refresh Break - View Our Virtual Exhibit Hall
3:20 pm Problem Solving Breakout Discussions - Part B

TABLE 10: How to Optimize Sample Pretreatment Methods

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?
3:50 pm Refresh Break - View our Virtual Exhibit Hall

PLENARY KEYNOTE SESSION

4:10 pm

Chairperson's Remarks

K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
4:15 pm

From Energy to Machine Learning

George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School

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 Ph.D. students (Dantas, Raman, Lajoie), 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.

4:40 pm

The Case for Intelligent Design in Protein Engineering

Jamie B. 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.

5:15 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
Panelists:
George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School
Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University
5:35 pm Happy Hour - View our Virtual Exhibit Hall
6:10 pm Close of Day

Tuesday, September 1

CASE STUDIES OF NEW MODALITIES

9:00 am

Industry Overview 

Darshana Jani, PhD, Director, Global Bioanalysis, Agenus
9:05 am

Harmonization of Immunogenicity Bioanalytical Reports 

Laura Hay, PhD, Associate Director, PPD Inc.

Immunogenicity Bioanalytical Report Harmonization committee has organized to align reporting strategies for clinical immunogenicity studies across industry and regulatory authorities. To comply with regulatory recommendations on anti-drug antibody and neutralizing antibody validations, this team is working to standardize the  presentation of bioanalytical immunogenicity data to facilitate filings to health authorities. This AAPS sponsored effort is supported by ~50 industry representatives.

9:25 am

Characterization of Immune Response to Bispecific Antibody Therapeutics

Kate Peng, PhD, Associate Director/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.

9:45 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Darshana Jani, PhD, Director, Global Bioanalysis, Agenus
Panelists:
Laura Hay, PhD, Associate Director, PPD Inc.
Kate Peng, PhD, Associate Director/Senior Scientist, BioAnalytical Sciences, Genentech
10:10 am Session Break
10:30 am Coffee Break - View our Virtual Exhibit Hall
10:50 am

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.

11:10 am

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

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

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.

11:30 am LIVE Q&A :

Session Wrap-Up

Panel Moderator:
Darshana Jani, PhD, Director, Global Bioanalysis, Agenus
Panelists:
Yariv Wine, PhD, Assistant Professor, Molecular Cell Biology and Biotechnology, Tel Aviv University, Israel
Lynn Kamen, PhD, Senior Scientist, BioAnalytical Sciences, Genentech Inc.
11:55 pm Session Break
12:15 pm Lunch Break - View our Virtual Exhibit Hall

IMMUNOGENICITY RISK ASSESSMENT AND MITIGATION

12:50 pm

Increased Immunogenicity Associated with Combination Regimens with Immune Modulatory Biologic

Vibha Jawa, PhD, Director, Predictive & Clinical Immunogenicity, PK PD & Drug Metabolism, 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.

1:10 pm

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.

1:30 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Vibha Jawa, PhD, Director, Predictive & Clinical Immunogenicity, PK PD & Drug Metabolism, Merck & Co., Inc.
Panelist:
Jochem Gokemeijer, PhD, Associate Director, Molecular Discovery Technologies, Bristol-Myers Squibb
1:55 pm Session Break
2:15 pm Refresh Break - View our Virtual Exhibit Hall

ASSESSMENT OF PRE-EXISTING REACTIVITY

2:35 pm

Importance of Pre-Existing Abs to the Viral Capsid during Immunogenicity Assessment of Viral Vectors-Based Gene Therapy

Jim McNally, PhD, Principal, McNally Bioanalytical Consulting

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.

2:55 pm

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

Nicoletta Bivi, PhD, Director, Assay Development, Immunogenicity and Immunoassays, Laboratory for Experimental Medicine (LEM), Eli Lilly and Company

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.

3:15 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Vibha Jawa, PhD, Director, Predictive & Clinical Immunogenicity, PK PD & Drug Metabolism, Merck & Co., Inc.
Panelists:
Jim McNally, PhD, Principal, McNally Bioanalytical Consulting
Nicoletta Bivi, PhD, Director, Assay Development, Immunogenicity and Immunoassays, Laboratory for Experimental Medicine (LEM), Eli Lilly and Company
3:35 pm Close of Immunogenicity Case Studies and Clinical Management





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