Innovators in the field of immunogenicity are constantly furthering our understanding of factors that contribute to immunogenicity and developing new and advanced approaches for predicting immunogenicity, for reducing immunogenicity, and for tolerance
induction. Presentations at Immunogenicity Prediction and Mitigation will enable attendees to make informed decisions on candidate selection, dosing and formulation, with a view to producing safe and efficacious products in the clinic
MONDAY, MAY 4
7:00 am Registration and Morning Coffee
plenary keynote session
8:30 Chairperson’s Opening Plenary Remarks
8:40 Cancer Stem Cells and Mechanisms of Malignant Progression
Robert A. Weinberg,
Ph.D., Founding Member, Whitehead Institute for Biomedical Research; Professor, Biology, Massachusetts Institute of Technology
The cell-biological program termed the epithelial-mesenchymal transition (EMT) plays a role in conferring aggressive traits on carcinoma cells. In addition, it generates cancer stem cells (CSCs) that have the ability, following dissemination, to serve
as founders of new metastatic colonies. The relationship between these CSCs and the SCs residing in normal tissues, and the participation of the CSCs in metastatic dissemination will be described.
9:25 Building an Antibody Discovery Company in a Crowded Field – the Adimab Story
Ph.D., CEO, Co-Founder, Adimab
The presentation will cover the evolution of Adimab from its founding in 2007 to becoming one of the few privately held profitable biotech companies in the last decade. Industry trends and specific strategic decisions along the way will be discussed
and used to illustrate the importance of integrating finance and scientific information to build successful capital efficient biotech companies.
10:10 Coffee Break
10:45 Chairperson’s Remarks
Ronit Mazor, Ph.D., Post Doctoral Fellow, Molecular Biology, National Cancer Institute (NCI)
10:50 KEYNOTE PRESENTATIONS
Immunogenicity Risk Assessment
Steven J. Swanson, Ph.D., Immunogenicity Consultant, Steven J Swanson Consulting
An important consideration when developing a new protein therapeutic is the potential and consequences of the therapeutic inducing an immune response. A careful analysis of the amino acid sequence can identify the presence of regions that are associated
with higher rates of immunogenicity. Other tools are available to further help predict if a therapeutic will induce an immune response. Risk assessment includes deciding if any of the available prediction tools should be utilized. The possible
consequences of an immune response are also evaluated when completing a risk assessment.
11:20 Case Studies on Immunogenicity Prediction Strategies for Early Decision-Making in Therapeutic Protein Development
Tim Hickling, Ph.D., Associate Research
Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.
Identification of immunogenicity risk is performed for all therapeutic proteins. However, not all proteins undergo a complete investigation of risk potential through the suite of assays available. I will present case studies of risk assessment, including
application of in silico and in vitro methods to contribute to protein engineering and the selection of clinical candidates. Strategies for low immunogenicity risk and de-immunization will be discussed.
11:50 Human in silico and in vitro Tools for Immunogenicity and Developability Risk Assessment and Risk Mitigation
Yvette Stallwood, Ph.D., Head, Applied Protein Services, Lonza Biologics
Incorporating immunogenicity and developability risk assessment into the early stages of development is important for optimal lead selection. This presentation will focus on the human immunogenicity risk assessment platforms and other developability
assessment tools at Lonza to aid the selection and optimization of lead candidates. Platforms include Epibase™ In Silico for the prediction of T cell epitopes and Epibase™ In Vitro for the assessment of T cell and
B cell responses in human donor PBMC.
12:20 pm Luncheon Presentation (Sponsorship Opportunity Available)
or Enjoy Lunch on Your Own
1:20 Session Break
1:50 Chairperson’s Remarks
Tim Hickling, Ph.D., Associate Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.
1:55 The Role of the Target in Antibody Biodisposition
Enrique Escandon, Ph.D., Principal Scientist, DMPK and Disposition, Merck Research Laboratories
For therapeutic antibodies, proximal target engagement is equivalent to immune complex formation; therefore, depending on the nature of the target (valence, abundance, location, metabolism, and its intrinsic biology), antibody-target and off-target
mediated mechanisms of disposition and clearance will be affected by interactions with the Fc Gamma family of receptors. Here we present specific experimental examples where dramatic changes in exposure and biodisposition relate to target engagement.
2:25 Impact of Different Types of Aggregate on Immunogenicity
Narendra Chirmule, Ph.D., 7immune Consulting
Aggregation of proteins presents a significant safety concern in the development of this class of therapeutics. In recent years, there have been several elegant studies on delineating potential mechanism of action of aggregate induced immune activation.
This presentation will focus on comparing the impact of different types of aggregates on immune activation. These observations may inform the monitoring approaches of these aggregates during process development.
2:55 Particulate Matter in Injectable Drug Products-A Regulatory Perspective and Reflections from the Draft Immunogenicity Guidance
Jack Ragheb, Ph.D., Principal Investigator, Laboratory of Immunology, Division of Therapeutic Proteins, CDER/FDA
3:25 Predictive Studies with Factors VII and VIII based on Genetic Analyses of Patients
Zuben E. Sauna, Ph.D., Principal Investigator, Department of Haematology, Research and Review, CDER/FDA
Based on genetic analyses of individual hemophilia A patients, we developed a predictive algorithm for immunogenicity (Receiver-operator-characteristic curve analysis, AUC, 0.890, P=0.001). The algorithm can be applied to determine the putative
immunogenicity-risk of neo-epitopes introduced in bioengineered protein-therapeutics. A poof-of-principle study will be presented using a bio-engineered analog of Factor VIIa as an example. The development of this molecule was discontinued
due to the development of ADAs in some patients in a phase 3 clinical trial.
3:55 Refreshment Break in the Exhibit Hall with Poster Viewing
4:35 Problem-Solving Breakout Discussions
1. Immunogenicity Risk Assessment and Risk Management
Steven J. Swanson, Ph.D., Executive Director, Medical Sciences
(Clinical Immunology), Amgen, Inc.
- Management in the clinic of products with low and high risk of immunogenicity related adverse events
- Immunogenicity risk assessment as a function of the clinical condition: acute, chronic, malignant, autoimmune etc.
- Risk assessment at different stages of development
- Potential of emerging antibody products for greater immunogenicity
- Investigative approaches to consider when only a subpopulation mounts immune responses to a therapeutic protein product
- How to translate the identified risk into a testing strategy
- Features of a good risk analysis and risk mitigation plan
- Sharing of experiences of applying risk assessment in pre-clinical and clinical studies
- Experiences with reporting findings to the regulatory authorities
2. Immunogenicity Risk Prediction Tools and Current Approaches
Tim Hickling, Ph.D., Immunogenicity Sciences Discipline Lead, PDM, Pfizer, Inc.
- Experiences with implementation of new tools for use in early development
- In silico and in vitro approaches: tiered application and benefit of combining approaches
- Animal models: what aspects can be translated into clinical trials?
- Working towards clinical validation of in silico and in vitro tools
- Novel approaches – applying risk factors and systems immunology
3. Risk Factors that Contribute to Immunogenicity
Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc
- Relationship between product characteristics and immunogenicity
- Impact of production, purification, formulation, dosing and storage on immunogenicity
- The role of T cell epitopes
- Impact of the route and frequency of administration
- Roles of component peptides in immunogenicity
- Genotyping as a method for immunogenicity risk assessment
4. Sub-Visible Particles, Aggregates and Immunogenicity
Narendra Chirmule, Ph.D., 7immune Consulting
Jack Ragheb, Ph.D., Principal Investigator, Laboratory of Immunology, Division of
Therapeutic Proteins, CDER/FDA
- What does and does not cause immunogenicity
- Discussion on the types of aggregate that have been identified: native versus others, small versus large, high concentration formulation versus less high
- Factors contributing to aggregation
- Evidence that small aggregates act as an adjuvant
- Risk assessments and risk mitigation plans based on propensity to aggregate
- Means of mitigating against immunogenicity
- Threshold of SVPs that can lead to an inflammatory response
5. Immune Tolerance Approaches
Ronit Mazor, Ph.D., Post-Doctoral Fellow, Molecular Biology, National Cancer Institute
- Methods for immune tolerance induction
- The role of T cells in the immune response and the impact of epitope modification
- Methods for identification and removal of T cell epitopes and evidence for its impact on reducing immunogenicity
- Tools to use with protein engineering to design non immunogenic biotherapeutics
5:35 Welcome Reception in the Exhibit Hall with Poster Viewing
6:50 End of Day
TUESDAY, MAY 5
8:00 am Morning Coffee
8:25 Chairperson’s Remarks
Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.
8:30 Development of Humanized Mouse Models for the Study of Immunogenicity
Michael A. Brehm,
Ph.D., Assistant Professor, Diabetes Center of Excellence, Program in Molecular Medicine, University of Massachusetts Medical School
The development of severely immunodeficient IL2rγnull mice that support engraftment of functional human immune systems has enabled the in vivo study of human immunity. This presentation will include a general overview of these humanized
mouse models, describing currently available strains, the protocols to generate humanized mice, the strengths of each system and a discussion of the application of these models to study immunogenicity.
9:00 A Systems Pharmacology Approach to Immunogenicity – A Multi-Scale, Mechanistic Mathematical Model and Its Applications
Xiaoying Chen, Ph.D., Principal Scientist Pharmacokinetics, Dynamics, and Metabolism (PDM) Pfizer, Inc.
We have developed a mechanistic, multi-scale mathematical model by recapitulating fundamental biological mechanisms. The key strength of this model lies in its capacity to integrate various risk factors, e.g., T- and B- epitopes, patients’
HLA background, and naïve T and B cell numbers into the underlying biology. The model can provide many clinical-relevant predictions. An example to illustrate potential applications in drug development will be provided.
9:30 Studies on Immunogenicity
of Subvisible Particles using an IgG1 Transgenic Mouse Model
Björn Boll, Ph.D.,
Pharma Technical Development Europe, F. Hoffmann-La Roche Ltd.
The theoretical concerns regarding the potential
immunogenicity of proteinaceous aggregates and subvisible particles in protein
therapeutics have being widely debated. This talk will introduce a novel hIgG1
transgenic mouse model that enables detailed mechanistic studies on the
biological impact of aggregates and sub-visible proteinaceous particles. Our
study uses for the first time detailed chemically characterized and well-defined
size fractions of subvisible particles to assess their ability to break
10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:50 Anti-Drug Antibody – A Challenge in the Field of Therapeutic Proteins, Lessons Learned from Pompe Disease
Priya Kishnani, M.D., C.L. and Su Chen Professor of Pediatrics, Division Chief, Medical Genetics, Pediatrics, Duke University Medical Center
Cross-Reactive Immunological Material (CRIM)-negative (CN) and a subset of CRIM-positive (CP) Infantile Pompe disease (IPD) mount an immune response against enzyme replacement therapy (ERT) resulting in clinical decline. Prophylactic
immune tolerance induction (ITI) protocol has prevented immune response in CN patients treated with ERT. We will present data on the safety and efficacy of ITI approaches for CP and CN IPD receiving ERT.
11:20 Modulation of Immunogenicity by T Regulatory Cells
Ethan M. Shevach, M.D., Chief, Cellular Immunology Section, Laboratory of Immunology, NIAID/NIH
Foxp3+ T regulatory cells (Treg) are essential for immunological tolerance and immune homeostasis. T follicular helper (TFH) cells provide help to B cells, while a new Treg subset (TFR) has been shown to suppress germinal center B
cell responses. Both TFH and TFR express the follicular homing receptor CXCR5, PD-1, and the transcription factors Bcl6. Enhancement of TFR function represents an attractive target for decreasing immunogenicity.
11:50 Design of Immunotoxins with Reduced Immunogenicity
Ronit Mazor, Ph.D.,
Postdoctoral Fellow, Molecular Biology, National Cancer Institute (NCI)
Immunotoxins are highly immunogenic recombinant proteins designed to treat cancer. We identified and removed the T cell epitopes in immunotoxins in order to reduce its immunogenicity. In this talk we will discuss the methods we
used to identify and eliminate the T cell epitopes, show a comparison of in silico predicted and experimental T cell epitopes in PE38 and lastly show a proof of concept using a mouse model that shares the immune-dominant epitopes.
12:20 pm Luncheon Presentation (Sponsorship Opportunity Available)
or Enjoy Lunch on Your Own
1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing
2:00 Chairperson’s Remarks
Michael A. Brehm, Ph.D., Assistant Professor, Diabetes Center of Excellence, Program in
Molecular Medicine, University of Massachusetts Medical School
2:05 Biotherapeutic Deimmunization Using Computationally Designed, Combinatorial Libraries
E. Griswold, Ph.D., Associate Professor, Thayer School of Engineering, Dartmouth
Biotherapeutic deimmunization via T cell epitope deletion can enable therapeutic applications for otherwise highly immunogenic proteins. Here, we demonstrate the use of computationally designed, combinatorial libraries for aggressive
epitope deletion in challenging biotherapeutic candidates. Highly engineered variants of exogenous therapeutic enzymes were evaluated in humanized murine models where they mitigated immune cell responses, suppressed development
of anti-biotherapeutic antibodies, and enhanced efficacy in repeat dosing therapeutic regimes.
2:35 Immune Suppression of Humanized Antibodies
Vibha Jawa, Ph.D.,
Principal Scientist, Clinical Immunology, Amgen, Inc.
Fully human biotherapeutics such as mAbs may be potentially immunogenic when administered to preclinical animal models and in the clinic and are associated with the formation of anti-drug antibodies (ADA). In this work we assessed
the impact of various immunosuppressive regimens on ADA formation and the consequent impact on the PK profile of a fully human mAb in a rodent study . A better understanding of the mechanisms behind induction of tolerance with
chronic dosing of a biotherapeutic and the impact of different immune suppressive regimens will also be discussed.
3:05 Tools and Technologies for Comprehensive Immunogenicity Risk Management
Jeremy Fry, D. Phil., Director, Sales,
Immunogenicity is one of the most complex issues to address in drug design and development. I will provide an overview of the best tools for immunogenicity risk mitigation, including Mass Spectrometry antigen presentation assays,
Dendritic cell-T cell assays to measure responses to fully formulated biologics, HLA-peptide Binding Assays, and naïve T cell Proliferation Assays to characterize individual epitopes. I will also discuss how the potential
risk of first infusion reactions can be mitigated using whole-blood cytokine release assays.
3:35 Refreshment Break in the Exhibit Hall with Poster Viewing
4:25 Improving the Efficacy Profile of Biologic Drugs by Addressing Product Immunogenicity with Tolerogenic Nanoparticles
Kei Kishimoto, Ph.D., Chief Scientific Officer, Selecta Biosciences
A case example will be presented with adalimumab in a mouse model of a spontaneous arthritis. Co-administration of the tolerogenic nanoparticles with adalimumab at the beginning of therapy prevent the formation of ADAs, resulting
in normalized adalimumab PK and greatly enhanced protection from joint erosion. Other applications will also be discussed.
4:55 Induction of Immunological Tolerance to E. Coli Asparaginase by Engineering Erythrocyte Binding
Stephan Kontos, Ph.D., Co-Founder, Director, Research, Anokion SA
We report the application of an antigen-specific immune tolerance technology that harnesses natural immune regulation mechanisms of apoptotic cells to induce tolerance to the E. coli chemotherapeutic enzyme L-asparaginase.
We demonstrate that engineering an erythrocyte-binding variant of asparaginase (ERY1-ASNase) allows for repeated dosing in mice without the development of anti-asparaginase antibodies, while additionally driving prophylactic
immune tolerance that enables non-immunogenic follow-on therapy with wild-type ASNase.
5:25 End of Conference
5:30 Registration for Dinner Short Courses