Immunogenicity Summit

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The Holy Grail for the biotherapeutics industry is for products with absent or reduced immunogenicity. In this track we examine factors that may impact on immunogenicity, particularly aggregates, sub-visible particles, and host cell proteins, and report on innovative tools used by the experts to predict immunogenicity. We also examine novel approaches for deimmunization and tolerance induction. Cambridge Healthtech Institute'sSixth Annual Immunogenicity Prediction & Mitigation conference is particularly important at the early stages of development for informed decision-making on candidate selection, dosing and formulation.


1:00 pm Conference Registration

2:00 Chairperson’s Opening Remarks

Vibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.


2:05 Innate Immune Response Modulating Impurities and Immunogenicity Risk: What Should We Be Looking for?

DanielaVerthelyiDaniela Verthelyi, Ph.D., Chief, Immunology Lab, Therapeutic Proteins, FDA/CDER

A critical factor associated with product immunogenicity is the presence of innate immune response modifying impurities (IIRMIs) that can stimulate the immune response directly. This talk will discuss the need to assess common impurities that activate immune cells in vivo and describe new in vitro systems that can be used to assess them.

2:35 Assessment of the Immunogenic Potential of Antibody Aggregates in Transgenic Mice

JulianaBessaJuliana Bessa, Ph.D., Scientist, Immunopathology, F. Hoffmann-La Roche

Transgenic (tg) mice expressing a mini-repertoire of human IgG1 antibodies (Ab) have been used for the assessment of immunogenicity of therapeutic Abs. The tg mice were found to be tolerant to a large range of human IgG1 Abs. Immunization with IgG1 aggregates generated by three different stress conditions demonstrated that extensive modifications within the primary amino acid structure (neoepitopes) were required to break immune tolerance whereas multimerization may have an enhancer factor on the immune response triggered by the neoepitopes. Taken together, this IgG tg mouse model appears suited to identify potentially immunogenic modifications in Ab preparations.

3:05 Detection and Characterization of Reversible Self-Association and Aggregation of Therapeutic Monoclonal Antibodies

Sophia Levitskaya, Ph.D., Scientist, Analytical Biotechnology, MedImmune LLC

Protein self-association is a form of solution intermolecular interaction which is important to consider during the successful development of protein therapeutics. Protein reversible self-association behavior is difficult to evaluate because the conditions of an assay can influence the observed size distribution. Our case study describes an unusual temperature sensitive reversible self-association (RSA) of an IgG2-subclass mAb, analytical methods tailored to characterize RSA, and measures to minimize RSA in drug product.

 antitope 3:35 Influence of Aggregates on in vitro T Cell Responses

GaryBembridgeAntitopeGary Bembridge, Ph.D., Director, Scientific Affairs , Immunology, Business Development, Antitope Limited 

Protein aggregates can trigger innate responses leading to distinct antigen presenting cell phenotypes which enhance T cell activation, a significant risk factor in the development of anti-drug antibodies (ADAs). This presentation will describe methods to measure the effects of aggregates on drug immunogenicity.


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


4:30 Computational and Experimental Mapping of Deimmunized Biotherapeutic Design Space 

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

We describe novel protein design algorithms that simultaneously optimize biologics for reduced immunogenic potential and high-level molecular function. Using combinatorial optimization methods, we are able to rapidly design an entire suite of “Pareto optimal” variants whose predicted immunogenicities and activities are not simultaneously dominated by any other single design. We have redesigned two different therapeutic enzyme candidates, and here we discuss in vitro and in vivo demonstration of their enhanced molecular and immunological performance.

5:00 Prediction of Clinical Immunogenicity of Adnectins: Guiding Lead Optimization

DaronFormanDaron Forman, Ph.D., Principal Scientist, Immunogenicity Prediction, Bristol-Myers Squibb

Protein biologics are making up an ever increasing proportion of the total drug market. Unlike their chemical counterparts, proteins are large enough to induce an anti-drug antibody (ADA) response. Here, we will discuss our strategy to predict ADA generation, and a few examples for minimizing the immunogenic potential of therapeutic proteins in the discovery stage.

5:30 Panel Discussion: Development and Application of Humanized Mice for Immunogenicity Predictive Studies

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

  • How predictive are these models: To what extent does the HLA restriction of a single humanized mouse clone impact on the interpretation of the results?
  • What information can these mice provide regarding B cell responses: the classes of antibody being produced and the levels of antibody?
  • Time, investment and skill in getting mouse models up and running
  • How to work out the appropriate dose
  • Applications and recent progress with biotherapeutics: e.g. recombinant cytokines, gene therapy, etc.
  • How might known differences in the human and mouse adaptive and innate immune systems impact the results?

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

6:00 Dinner Short Course Registration

6:30 – 9:30 Dinner Short Courses*

SC3: Immunogenicity Risk Assessment and Regulatory Strategy 

SC4: Strategic Bioassay Design and Analysis 

*Separate Registration Required.

Wednesday, November 19


8:00 am Chairperson’s Remarks

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

8:05 Forecasting Clinical Immunogenicity from Human ex vivo/in vitro Assays

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

Although prediction of the incidence of anti-drug antibodies (ADAs) to therapeutic proteins is not yet possible, combining knowledge of the immunogenicity risk factors for a therapeutic protein enables assessment of overall risk. A mathematical model has been developed to integrate immunogenicity risk parameters and assay outputs to enable forecasting of ADA incidence and magnitude, and the impact of ADAs on PKPD. Examples of therapeutic proteins will be discussed.

8:35 Investigations in Immune Suppression for Monoclonal Antibody Therapeutics

VibhaJawaVibha Jawa, Ph.D., Principal Scientist, Clinical Immunology, Amgen, Inc.

Therapeutic proteins (TP) are often immunogenic and can induce formation of anti-drug antibodies (ADA) when administered to preclinical animal models. The ADA formation may neutralize the pharmacologic activity of the TP and hence impact the exposure and efficacy by modulating its pharmacokinetics (PK) properties and clearance via immune complexes. The objective of this study is to assess the impact of immune suppression on the ADA formation and consequent impact on PK profiles of a biotherapeutic mAb. This talk will evaluate immune suppressive regimens targeting the T and B cells that can help reduce this unwanted immune response to a biotherapeutic mAb in a preclinical setting.

9:05 Preclinical Immunogenicity Risk Assessment for Optimal Lead Selection 

NoelSmithNoel Smith, Ph.D., Senior Group Leader, Lonza Biologics, Lonza Applied Protein Services, Lonza

The ability to assess the “developability” of a therapeutic candidate in early preclinical and clinical phases of development can be a very powerful tool to enhance the chance of success. This presentation will focus on how immunogenicity risk assessment can be incorporated into a wider developability platform, exploiting a wide range of in silico and in vitro tools to predict immunogenic responses and the overall developability profile of lead candidates.

9:35 Problem Solving Roundtable Discussions

Risk Factors that Contribute to Immunogenicity

Moderator: 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

Sub-Visible Particles, Aggregates and Immunogenicity

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

  • 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

Methods for Examining Impurities that May Impact the Immune Response

Moderators: Daniela Verthelyi, Ph.D., Chief, Laboratory of Immunology, Therapeutic Proteins, FDA/CDER

Lydia Haile, Ph.D., Postdoctoral Fellow, Laboratory of Immunology, Therapeutic Proteins, FDA/CDER

  • Types of impurity commonly found in biotherapeutics
  • Sources of impurities
  • Means of detecting and characterizing impurities
  • How impurities may impact / act as adjuvants on the immune response
  • Means of setting up systems for detection and control of impurities

Current Tools and Approaches for Immunogenicity Risk Prediction

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

  • Experiences with implementation of new tools for use in early development
  • In silico and in vitro approaches: their benefits if applied in combination
  • Animal models: what aspects can be translated into clinical trials?
  • Clinical validation of in silico and in vitro tools: which tools withstand the reality check ?
  • Novel approaches

Progress towards Inducing Immunological Tolerance to Factor VIII and Other Biotherapeutics

Moderator: David C. Wraith, Ph.D., Professor, Experimental Pathology, University of Bristol, & CSO, Apitope International NV

  • Experiences with neutralizing “inhibitory” antibodies against biotherapeutics, for example Factor VIII
  • Benefits of identification of immunodominant T-cell epitopes
  • How these may be used as targets for tolerance induction
  • Progress being made in demonstrative efficacy / how effective the approach is
  • Applicability to allergies and autoimmune disease and protein drugs in general
  • Different approaches for tolerance induction

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


11:15 The Effect of Route of Administration on the Immunogenicity to Recombinant Murine Growth Hormone Particles

ChristieMerryMerry Christie, Scientist, Pharmaceutical Sciences, University of Colorado

Mice were injected with recombinant murine growth hormone (rmGH) via the subcutaneous, intraperitoneal, or intravenous (i.v.) routes. In addition to soluble, monomeric rmGH, the samples contained either nanoparticles of rmGH or both nano- and microparticles of rmGH. We found that multiple mechanisms contributed to the immune response, with the most pronounced response when i.v. administration was used. No dependence of the immune response on particle size and distribution was observed.

11:45 Reverse Vaccination via the S.C. Route to Mitigate Immunogenicity

SathyBaluLyerSathy Balu-Iyer, Ph.D., Professor, Pharmaceutical Sciences, SUNY-University at Buffalo

Administration of therapeutic proteins via the subcutaneous (s.c.) route is challenging regarding unwanted immune responses. This talk will focus on mechanistic details into factors driving immunogenicity of proteins given via the s.c. route. Based on this mechanistic insight, a novel Reverse Vaccination strategy to mitigate immunogenicity was applied. The talk will discuss the induction of immunological hypo-responsiveness using this strategy.

12:15 pm Tools and Technologies for Comprehensive Immunogenicity Risk Management

Emilee_KnowEmilee Knowlton, Sales Specialist, Immunology, ProImmune Inc.

Low immunogenicity is a key product attribute of successful biotherapeutics. This talk provides an overview of the technologies available for immunogenicity risk management including antigen presentation assays, DC-T cell assays to measure responses to formulated biologics, HLA-peptide Binding Assays, and naïve T cell Proliferation Assays to quantify responses to individual epitopes. The potential risk of a cytokine storm first infusion reaction can also be determined using whole-blood cytokine release assays.

12:45 Networking Lunch in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)


1:45 Chairperson’s Remarks

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


1:50 Immune Tolerance Induction for Therapeutic Proteins: The FDA Perspective

Amy RosenbergAmy Rosenberg, Ph.D., Director, Therapeutic Proteins, FDA/CDER

Immune responses to therapeutic proteins can prove devastating when they abrogate the efficacy of life saving therapeutic proteins or cause anaphylaxis. Immune tolerance induction (ITI) protocols have been developed to either prevent or reverse such destructive immune responses in the setting of enzyme replacement therapy (ERT) for Pompe Disease, a rare lysosomal storage disease (LSD). The safety of these regimens supports their use for ERT in the setting of other LSDs in patients predicted to respond to ERT with a robust antibody response, and, potentially, for highly effective, yet not necessarily life-saving therapeutics such as monoclonal antibodies (mAbs) for autoimmune disease.

2:20 Generation of Antigen-Processing Independent Epitopes (APITOPES) for Induction of Tolerance to Factor VIII and Other Protein Antigens

DavidWraithDavid C. Wraith, Ph.D., Professor, Experimental Pathology, University of Bristol, & CSO, Apitope International NV

Suppression of immune responses to therapeutic proteins or hypersensitivity diseases currently requires the use of non-specific, immunosuppressive agents. Improved treatment can be achieved through the adoption of natural, immunoregulatory mechanisms. Scientists at Apitope have revealed how to design the peptide epitopes associated with these conditions and administer them in order to reinstate an immunological balance. This presentation will demonstrate that apitopes are a safe and improved approach to antigen-specific immunotherapy.

2:50 Networking Refreshment Break

3:15 Tolerogenic Nanoparticles for the Prevention of Anti-Drug Antibodies

KeiKishimotoKei 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 adalimumab for the treatment of arthritis as examples.

3:45 A Recombinant Immunotoxin for Cancer Treatment with Low Immunogenicity by Identification and Silencing of Human T Cell Epitopes

RonitMazorRonit Mazor, Ph.D., Post Doctoral Fellow, Laboratory of Molecular Biology, National Cancer Institute, NIH

Recombinant immunotoxins have produced complete remissions in leukemia patients where many doses can be given, but are less active in patients with solid tumors because their immune system makes anti-drug antibodies which inactive the immunotoxin. To suppress the immune response we have identified and largely silenced the T cell epitopes responsible for the immune response. A redesigned immunotoxin with T cell epitope mutations is highly cytotoxic to cell lines and to cells isolated from cancer patients and produces complete remissions in mice with human cancer xenografts. The approach described can be applied to de-immunize other therapeutically useful foreign proteins.

4:15 Tregitope - A Natural Immune System Off-Switch for Antigen-Specific Tolerance Induction

AnnieDeGrootAnnie S. de Groot, Ph.D., Research Professor & Director, Immunology and Informatics, University of Rhode Island

Tregitopes are regulatory T cell (Treg) epitopes found in IgG that expand and activate natural Tregs and can be coupled to biologic proteins for antigen-specific tolerance-induction. They are currently being integrated into products such as blood factors, enzyme replacement proteins and pharmaceutical toxins. The speaker will present recent Tregitope research validating antigen-specific tolerance induction and discuss their role in the treatment of immune-mediated diseases and the development of better biologics.

4:45 End of Immunogenicity Prediction & Mitigation

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