Immunogenicity and Bioassay Summit

Immunogenicity Prediction and Mitigation

CHI's Seventh Annual Immunogenicity Prediction and Mitigation conference, part of the Immunogenicity and Bioassay Summit 2015, focusses strongly on product characteristics and quality features that impact on immunogenicity, following this up with approaches for controlling these characteristics to induce tolerance and minimize immunogenicity. Highlights include FDA experiences and advice (3 presentations), models for risk assessment, a clinical case study on tolerance induction, the impact of epitope depletion on immunogenicity and additional innovative deimmunization and tolerance mechanisms. 

Quote from 2014: “Phenomenal presentations of great advances in multiple fronts. The most exciting meeting pertaining to immunogenicity of biotherapeutics.” 

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1:00 pm Conference Registration

2:00 Chairperson’s Opening Remarks

Stephan Kontos, Ph.D., Co-Founder, Director, Research, Anokion


2:05 Evaluating Relative Risk of Immunogenicity of Biotherapeutics with Chemical Modifications and Impurities

Marisa JoubertMarisa Joubert, Ph.D., Senior Scientist, Process Development, Amgen, Inc.

We have investigated the potential biological impact of different product quality attributes, including oxidation of amino acid residues and the level of host cell impurities, in an in vitro comparative immunogenicity assessment (IVCIA) assay. The results highlight the relative risk of immunogenicity of product specific factors and point to a dependency on multiple parameters including the type of attribute, amount of attribute, the presence of multiple attributes, and the immune status and medication regimen of the individual.

2:35 Development of Mechanistic Models for the Prediction of Immunogenicity Outcomes in the Clinic

Hickling TimTim Hickling, Ph.D., Associate Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.

This presentation will describe a mathematical approach to quantitatively forecasting the outcome of immunogenicity in clinical trials. A generic model will be described that incorporates immunogenicity risk assessment data, e.g. Epitopes, patient HLA-type, ADA assay characteristics (Sensitivity/Drug-tolerance). A case study will be presented with fitted clinical data to demonstrate predictive capability. Application of this approach in the context of inflammatory disease and to other therapeutic areas will be discussed.

3:05 Relevance of Animal Models for Immunogenicity Prediction

Jack RaghebJack Ragheb, Ph.D., Principal Investigator, Therapeutic Proteins, CDER/FDA

The immunogenicity of therapeutic proteins in humans cannot be assessed by testing these drug products in non-human species as the immune system can distinguish orthologous proteins as foreign and will mount an immune response. The recent advent of humanized mice may represent a relevant preclinical model for in vivo testing of the human immunogenicity of a therapeutic protein. The qualification of such a model should lead to identification of critical attributes responsible for immunogenicity, permitting the design of suitable control strategies that ensure product quality and mitigate risk.

3:35 Sponsored Presentation (Opportunity Available)

3:50 Refreshment Break in the Exhibit Hall with Poster Viewing


4:30 Innate Immune Response Modulating Impurities in Therapeutic Proteins

Daniela VerthelyiDaniela Verthelyi, M.D., Ph.D., Chief, Immunology Lab, CDER/OBP/FDA

Therapeutic proteins can contain impurities derived from the cell substrate and the manufacturing process that have the potential to activate innate immune cells fostering product immunogenicity. This talk will describe different approaches for the detection of innate immune response modifying impurities in therapeutic proteins and discuss how that may inform immunogenicity risk assessments, particularly in the context of comparability exercises.

5:00 Immunogenicity of Therapeutic Proteins: Impact of Aggregates, Glycosylation and Other Post-Translational Modifications.

Naren ChirmuleNaren Chirmule, Ph.D., Vice President, Scientific Research, Biocon

During the manufacturing of protein therapeutics several post translational modifications occur, the majority of which have been attributed to immunogenicity risk potential. A systematic analysis of various critical quality attributes such as aggregation, glycosylation etc. has been studied. 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.

5:30 Immunogenicity of Sub-Visible Particles: Are We Barking Up the Wrong Tree?

Atanas KoulovAtanas Koulov, Ph.D., Group Head, Pharma Technical Development Europe (Biologics), Analytics, F. Hoffmann-La Roche Ltd.

This presentation will discuss our recent findings using an IgG1 transgenic mouse model and newly developed methods for particle fractionation and selective particle modification. Using chemically characterized and well-defined size-fractions of subvisible particles afforded interrogation of the factors governing potential break of immune tolerance. Our findings demonstrate that only particles that are heavily modified chemically (oxidized) can break immune tolerance in this transgenic mouse model, whereas unmodified particles cannot.

6:00 End of Day One of Immunogenicity Prediction & Mitigation

6:00 Dinner Short Course Registration

6:30 – 9:30 Dinner Short Courses*

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7:30 am Registration and Morning Coffee

8:00 am Chairperson’s Remarks

Marisa Joubert, Ph.D., Senior Scientist, Process Development, Amgen, Inc.

8:05 Anti-Drug Antibody – A Challenge in the Field of Therapeutic Proteins, Lessons Learned from Pompe Disease; Immune Tolerance Induction in ERT

Zoheb KaziZoheb Kazi, MBBS, Postdoctoral Research Associate, Pediatrics/Medical Genetics, 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 responses 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.

8:35 Addressing Immunologic Sabotage of Dystrophin Replacement Therapies in Duchenne Muscular Dystrophy

Amy RosenbergAmy S. Rosenberg, M.D., Division Director, Office of Biotechnology Products, FDA

Clinical investigation for more definitive treatment of Duchenne Muscular Dystrophy (DMD), will only meet with success by addressing key immunologic features of the disease: the profound inflammatory response in DMD muscle mediated by innate immune system elements and the preexisting or potential cellular immune response to dystrophin, mediated by CD8+ and CD4+ T cells. Thus, taming inflammation is essential not only to reducing muscle cell loss and fibrosis per se, but as well to facilitate induction of immune tolerance to dystrophin by facilitating the conversion to, recruitment of, and function of regulatory T cells (Tregs).

9:05 Tools and Technologies for Comprehensive Immunogenicity Risk Management

Emilee Knowlton, D.Phil., Immunology Sales Specialist, ProImmune

Immunogenicity is a very complex issue to address in drug design and development. An overview of the best tools for immunogenicity risk mitigation will be provided, including Mass Spectrometry antigen presentation assays, DC-T cell assays to measure responses to fully formulated biologics, HLA-peptide Binding Assays, and naïve T cell Proliferation Assays to characterize individual epitopes. How the potential risk of first infusion reactions can be mitigated using whole-blood cytokine release assays will also be described.

9:35 Problem Solving Roundtable Discussions

These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

Table 1: Potential Immunogenic Risk of Drug Product Formulations

Moderator: Marisa Joubert, Ph.D., Senior Scientist, Process Development, Amgen, Inc.

Table 2: Current and Emerging Tools: Selecting Candidates and Predicting Clinical Outcome

Moderator: Tim Hickling, Ph.D., Associate Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.

Table 3: Protein Design Tools for Biotherapeutic Deimmunization

Moderator: Karl Griswold, Ph.D., Associate Professor, Thayer School of Engineering, Dartmouth

Table 4: Progress towards Inducing Immunological Tolerance to Biotherapeutics

Moderator: Stephan Kontos, Ph.D., Co-Founder, Director, Research, Anokion

10:35 Coffee Break in the Exhibit Hall with Poster Viewing


11:15 Decreasing Immunogenicity of Recombinant Immunotoxins by Identifying and Modifying B and T Cell Epitopes

Ira PastanIra Pastan, M.D., Co-Chief, Molecular Biology, National Cancer Institute, National Institutes of Health

Recombinant Immunotoxins are chimeric proteins designed to kill cancer cells. They consist of an Fv or Fab that binds to the cancer cell and a portion of pseudomonas exotoxin A that kills the cell. RITs have shown anti-tumor activity in some leukemias and in mesothelioma, but antibody formation limits the amount that can be given. We have developed experimental approaches to identify and remove T and B cells while maintaining high cytotoxic activity. Clinical trials with one of these have recently opened.

11:45 Design and Development of Deimmunized Lysostaphin for Treatment of Drug-Resistant Staphylococcus aureus Infections

Karl GriswoldKarl Griswold, Ph.D., Associate Professor, Thayer School of Engineering, Dartmouth

Using advanced protein design algorithms, predicted T cell epitopes were depleted from lysostaphin, a potent antibacterial drug candidate that exhibits undesirable immunogenicity. Aggressively deimmunized variants rescued humanized mice from recurrent infection by methicillin-resistant Staphylococcus aureus, whereas wild type lysostaphin failed due to high anti-drug antibody titers. These controlled experiments in a clinically relevant, immunocompetent disease model demonstrate for the first time that T cell epitope depletion enhances therapeutic efficacy.

12:15 pm Designing Therapeutic Drugs with Reduced Immunogenicity

Mark Fogg, Ph.D., Group Leader, Immunology, Abzena

The importance of T cell help has been widely accepted as a significant risk factor in the development of anti-drug antibodies (immunogenicity). Case study data will be presented on the deimmunisation of naturally immunogenic non-human protein therapeutics.

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:15 Cupcakes and Coffee in the Exhibit Hall with Poster Viewing


2:00 Chairperson’s Remarks

Tim HicklingTim Hickling, Ph.D., Associate Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.


2:05 Controlling Antibody Responses by Engaging CD22

Matthew MacauleyMatthew Macauley, Ph.D., Assistant Professor, Chemical Physiology, Scripps Research Institute

CD22 is an inhibitory B-cell co-receptor that recognizes glycans. We have shown that co-engaging it with the B-cell receptor (BCR) induces antigen-specific B-cell tolerance. This was first demonstrated using liposomes that co-present a high affinity CD22 and antigen. More recently, we have developed a cell-based platform that takes advantage of these same principles.

2:35 Creating Biologics Drugs with Improved Efficacy and Safety Profiles by Preventing Anti-Drug Antibodies with Tolerogenic Nanoparticles

Kei KishimotoKei Kishimoto, Ph.D., CSO, Selecta Biosciences

Anti-drug antibodies (ADAs) can adversely affect the safety and efficacy of biologic drugs. We will describe the development of Synthetic Vaccine Particles (SVPs) for the induction of antigen-specific tolerance to prevent ADAs, using coagulation Factor VIII for the treatment of haemophilia A and pegylated uricase for the treatment of refractory gout as case examples.

3:05 Induction of Tolerance Using Engineered Regulatory T and Cytotoxic T Cells with Chimeric Antigen Receptors

David ScottDavid W. Scott, Ph.D., Professor and Vice Chair for Research, Department of Medicine (MED), Uniformed Services University of Health Sciences

Human T cells engineered to express chimeric antigen receptors (CARs) have been utilized to successfully target cancer cells. We have adapted this approach to create specific T regulatory cells using both CARs and chimeric T-cell receptors from patients in two disease models. Application of engineered T cells to modulate adverse antibody responses in hemophilia and pathogenic responses to CNS proteins will be presented. Prospects with engineered cytotoxic cells will be discussed.

3:35 Inducing Immune Tolerance to Highly Foreign Therapeutics by Engineering for Erythrocyte Binding

Stephan KontosStephan Kontos, Ph.D., Co-Founder, Director, Research, Anokion

We sought to develop a recombinant, translational approach that exploits the tolerogenic potential of apoptotic cells without the need to manipulate cells themselves, with the goal of inducing antigen-specific tolerance to immunogenic therapeutics. In engineering erythrocyte-binding domains into the chemotherapeutic E. coli enzyme asparaginase, we show that in addition to greatly enhancing PK and PD profiles, erythrocyte-binding drives potent, long-lived antigen-specific humoral immune tolerance towards the therapeutic.

4:05 Close of Conference

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