Considerable progress is being made in predicting and controlling immunogenicity. At CHI's Eighth Annual Immunogenicity Prediction & Control conference, industry, academic and FDA experts will examine the causes of immunogenicity such as aggregates and impurities, the significance of epitopes and HLA-binding, and the importance of Quality by Design principles and of having manufacturing control systems in place. It will also focus on the benefits of working with protein engineers to pre-empt immunogenicity and on how humanized mouse models and in silico, in vitro and ex vivo tools can contribute to a risk assessment and mitigation strategy. The disparity often seen between predictive data and the outcome in the clinic will be highlighted and solutions for increasing predictive accuracy will be offered together with recommendations for the clinical trial design for this kind of study. Case studies on controlling immunogenicity will focus on gene therapy, ophthalmology, treatment for multiple myeloma, and on immunotherapy with the exciting new promising CAR-T cells. Finally, we present successful tolerance induction methods for Pompe disease, Factor VIII, and refractory gout.

Day 1 | Day 2 | Short Courses | Download Brochure

1:00 pm Conference Registration

2:00 Chairperson’s Opening Remarks

Susan Richards, Ph.D., Presidential Scientific Fellow, Translational Medicine Early Development, Sanofi R&D

Risk Factors that Contribute to Immunogenicity

2:05 FEATURED PRESENTATION: Understanding the Impact of Immunogenicity on Quality by Design

Valerie Quarmby, Ph.D., Staff Scientist, BioAnalytical Sciences, Genentech, Inc.

The incorporation of Quality by Design (QbD) principles into biotherapeutic development means that product quality must be closely linked to product safety. Since it is not possible to predict whether a biotherapeutic will elicit immune responses, it is important to monitor immunogenicity during clinical trials. At the same time, any putative critical quality attributes (pCQAs) which could affect immunogenicity must be identified and tracked in the manufacturing control system.

2:35 Impact of Aggregates on Immunogenicity of Protein Therapeutics: A Regulatory Perspective

Will Hallett, Ph.D., Product Quality and Immunogenicity Reviewer, CDER/FDA

Aggregates of protein therapeutics may impact a product’s immunogenicity. Aggregated protein therapeutics can promote immunogenicity through multiple mechanisms. Risk factors to consider when assessing aggregates include a product’s tendency to form aggregates during manufacturing and storage, the ability to adequately monitor and characterize aggregate species, and the potential clinical consequences that may occur. This presentation discusses the regulatory perspective on aggregates and their impact on immunogenicity.

3:05 Robust Immune Response to a Product-Related Impurity and Impact on Immunogenicity Rate of an Antibody Therapeutic

Sally Fischer, Ph.D., Principal Scientist & Group Leader, Assay Development & Technology (ADT), Genentech, Inc.

A product-related impurity was identified in the material used in the clinical study. To assess the potential ability of patients to develop an immune response to the impurity and the impact on immunogenicity of the therapeutic, two bridging ELISA were developed and validated. Samples from treated subjects were evaluated in both assays. This presentation will discuss the results of the immunogenicity assessment to the impurity and observed immunogenicity rate of the antibody therapeutic.

3:35 Sponsored Presentation (Opportunity Available)

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

Immunogenicity Predictive Studies

4:30 Benefits of Humanized Mouse Models for the Study of Immunogenicity

Michael Brehm, Ph.D., Associate Professor, 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.

5:00 Working with Protein Engineers to Predict and Pre-Empt Immunogenicity of Biotherapeutics

Tim Hickling, Ph.D., Immunogenicity Sciences Lead, Biomedicine Design, Pfizer, Inc.

Pfizer has developed a model for predicting clinical immunogenicity based upon the known processes of the immune system and in vitro assay data. Immune system parameters including danger signals and immune epitopes will be discussed, as will the effect of ADA on the PKPD relationship. In describing this approach, I will highlight the importance of designing out immunogenicity risk early during lead development and the necessity of refining parameters as development progresses.

5:30 Immunogenicity Risk-Assessment Based on Computer Algorithms in Conjunction with in vitro and ex vivo Assays

Zuben Sauna, Ph.D., Principal Investigator, Division of Hematology Research and Review, FDA/CBER

There have been considerable improvements in the predictive performance of preclinical assessments of immunogenicity. These assessments however focus on specific steps of the immune response, not on the clinical manifestation of immunogenicity. Properly used and interpreted, these tools can be used to formulate a comprehensive strategy for the risk-assessment for immunogenicity. The presentation will discuss the various computational, in vitro and ex vivo tools and their proper use and interpretation.

6:00 End of Day One
  

6:30-9:30 Dinner Short Course: Advice on Putting Together an Integrated Summary of Immunogenicity*

*Separate registration required.

Friday, October 28

Correlation between Predictive Immunogenicity
and the Clinical Outcome

7:30 am Registration and Morning Coffee

8:00 Chairperson’s Remarks

Ronit Mazor, Ph.D., Post-Doctoral Fellow, Molecular Biology, National Cancer Institute, National Institutes of Health

8:05 Determination of Clinical Relevance of Predictive Immunogenicity

Vibha Jawa, Ph.D., Director, Biologics and Vaccines Bioanalytics, Merck and Co.

Predictive tools can be used during early development to decrease the likelihood of risk, and during process development for de-risking attributes that change from process to process. The next step to gain more value from these tools would be to understand their predictive accuracy as they apply in clinic. This talk will attempt to discuss new clinical data and the different approaches and challenges involved in the clinical validation of these tools.

8:35 Retrospective Immunogenicity Risk Prediction of Bioengineered Factor VIIa

Kasper Lamberth, Ph.D., Manager, Immunogenicity Prediction & Tolerance, Novo Nordisk A/S

The development of a bioengineered recombinant Factor VIIa (rFVIIa) analog was discontinued in Phase III trials due to development of ADAs. The FVIIa analog has three mutations compared to the unmodified parent molecule rFVIIa. By using computational and experimental methods we demonstrate that the observed ADAs could have been elicited by neo-epitopes in the engineered-protein. In addition, we show that the Human Leucocyte Antigen (HLA) type of the patients who developed ADAs is consistent with this hypothesis of a neo-epitope driven immune response.

9:05 An Integrated Approach to Managing Immunogenicity Risk and Drug Immune Modulation

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

Immunogenicity is one of the most complex issues to address in drug design and development. I will provide an overview of the best tools to mitigate immunogenicity risk, including Mass Spectrometry antigen presentation assays, DC-T and T cell proliferation assays for biologic lead selection/optimization, HLA-peptide binding assays to characterize individual epitopes, as well as undiluted whole blood cytokine storm assays.

9:35 Problem-Solving Roundtable Discussions

Table 1: Product Quality Attributes and Immunogenicity

Valerie Quarmby, Ph.D., Staff Scientist, BioAnalytical Sciences, Genentech, Inc

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

Vibha Jawa, Ph.D., Director, Biologics and Vaccines Analytics, Merck and Co. and Tim Hickling, Ph.D., Immunogenicity Sciences Lead, Biomedicine Design, Pfizer, Inc.

Table 3: Protein Design Tools for Biotherapeutic Deimmunization

Zuben Sauna, Ph.D., Principal Investigator, Division of Hematology Research and Review, FDA/CBER

Table 4: Progress towards Inducing Immunological Tolerance to Biotherapeutics

Ronit Mazor, Ph.D., Post-Doctoral Fellow, Molecular Biology, National Cancer Institute, National Institutes of Health

Table 5: Development of Mouse Models for Predictive Studies

Michael Brehm, Ph.D., Associate Professor, Molecular Medicine, University of Massachusetts Medical School

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

Measures to Control Immunogenicity

11:15 Strategies to Reduce Immune Responses to Immunotoxins

Ira Pastan, M.D., Co-Chief, and Ronit Mazor, Ph.D., Post-Doctoral Fellow, Molecular Biology, National Cancer Institute, National Institutes of Health

Recombinant immunotoxins are anti-cancer agents composed of an Fv targeting a protein on a cancer cell fused to a bacterial toxin. They have good anti-cancer activity in hematologic malignancies, where the immune system is suppressed and neutralizing antibodies do not develop. SS1P is an immunotoxin targeting mesothelin expressing tumors. It is composed of an anti-mesothelin Fv attached to a fragment of Pseudomonas exotoxin A. Its anti-tumor activity is limited by its immunogenicity in patients with normal immune function. We have pursued several strategies to reduce the immunogenicity of SS1P, which include identification and removal of B and T cell epitopes and the induction of tolerance using novel approaches.

11:45 How Do T Regulatory Cells (Treg) Suppress Immune Responses?

Ethan Shevach, M.D., Senior Investigator, Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Treg play critical roles in the control of all aspects of immune function including autoimmunity, transplantation, and tumor immunity. Modulation of Treg function with biologics and small molecules requires a detailed understanding of the mechanisms used by Treg to mediate their suppressive function. I will review the current status of the proposed suppressive pathways used by both polyclonal and antigen-specific Treg with a focus on preclinical in vivo models.

12:15 pm Influence of Aggregates on in vitro T Cell Responses

Gary Bembridge, Ph.D., Director, Scientific Affairs, Abzena

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.

12:45 Luncheon Presentation (Sponsorship Opportunity Available)

1:15 Awarding of Poster Prize PLUS Coffee and Cupcakes in the Exhibit Hall

HANDLING IMMUNOGENICITY IN POMPE DISEASE, ENZYME REPLACEMENT THERAPY AND GENE THERAPY

2:00 Chairperson’s Remarks

Vibha Jawa, Ph.D., Director, Biologics and Vaccines Analytics, Merck and Co.
  

2:05 KEYNOTE PRESENTATION: Induction of Immune Tolerance in Pompe Disease

Susan Richards, Ph.D., Presidential Scientific Fellow, Translational Medicine Early Development, Sanofi R&D

This presentation will describe how immunogenicity can be mitigated in Pompe disease using low dose methotrexate immune tolerance induction and propose mechanisms for how this is achieved. I will discuss the challenges encountered, including determining which patients to consider for this approach, the translatability shown between mouse and man and the challenges with determining the clinical threshold. Clinical data on tolerance induction will be discussed.

2:35 Induction of Antigen Specific immunological Tolerance Using Nanoparticles

Roberto Maldonado Ph.D., Senior Staff Scientist, Immunology, Selecta Biosciences

Synthetic vaccine particles (SVP) are biodegradable nanoparticles carrying rapamycin that, combined with an antigen, induce durable and antigen-specific immune tolerance. Treatment with SVP inhibit the differentiation of effector T and B cells, antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis (R-EAE) and induce regulatory T and B cells and durable B cell tolerance to various antigens including biologic drugs such as the coagulation factor VIII, adalimumab and pegylated uricase.

3:05 Immunogenicity of Immuno-Gene Therapy Products: Current State of Affairs and Future Developments

J. Joseph (Jos) Melenhorst, Ph.D., Director, Product Development & Correlative Sciences, Center for Cellular Immunotherapies, University of Pennsylvania

Over the past few decades, patients with various disorders have received gene therapy products to treat various disorders such as hematopoietic solid tumors. The potency of such products, driven largely by expansion and persistence, partly depends on "acceptance" of the infused cells by the host. In my talk I will describe such key learning moments in this relatively young field and provide concrete examples and how this changed the way we treat patients. I will also highlight new developments in the chimeric antigen receptor field where we wish to de-personalize the therapy.

3:35 Adeno Associated Viral Gene Therapy: Immunogenicity Challenges and Preclinical Risk Assessment

Jochem Gökemeijer, Ph.D., Associate Director, Molecular Discovery Technologies, Bristol Myers Squibb

Novel technologies to replace, alter or introduce new genetic material as a therapeutic modality have recently made significant inroads. Perceived potential immunogenicity risks and impacts can be appreciably different than more traditional antibody based biologics. In this presentation we will evaluate the specific challenges these novel AAV delivered therapeutics pose from a clinical immunogenicity as well as the preclinical de risking perspective.

4:05 End of Conference

Day 1 | Day 2 | Short Courses | Download Brochure