Immunogenicity Summit
2013 Archived Content

Immunogenicity Risk Assessment and Mitigation 


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Wednesday, November 13


Risk Considerations for Biotherapeutics 

8:30 am Chairperson’s Remarks

Haiyan Jiang, Ph.D., Senior Director, Preclinical and Clinical Research (Hemophilia), Biogen Idec, Inc.

8:35 Understanding the Immune Response against Erythropoiesis Stimulating Agents that Can Lead to Pure Red Cell Aplasia

Steven J. SwansonSteven J. Swanson, Ph.D., Executive Director, Medical Sciences (Clinical Immunology), Amgen, Inc.

Antibody-mediated PRCA (amPRCA) is characterized by bone marrow devoid of red blood cell precursors and circulating antibodies capable of neutralizing erythropoietin. The anti-erythropoietin antibodies that are associated with cases of amPRCA have different characteristics than the antibodies observed in subjects that do not have PRCA. Those antibodies associated with PRCA tend to be of the IgG4 subclasss, have a higher circulating level, bind to the protein region of erythropoietin, and are more likely to have neutralizing capability than the antibodies from patients that do not have PRCA. This observation underscores the value in developing and validating assays to fully characterize clinically relevant anti-therapeutic protein antibodies.

9:05 Late-Onset Hypersensitivity to an SC Administered Peptide Drug: Lessons Learned

Harald KropshoferHarald Kropshofer, Ph.D., Senior Personalized Healthcare Leader, Pharmaceutical Development, F. Hoffmann-La Roche Ltd.

A clinical case study will be presented focusing on a peptide drug that gave rise to serious systemic hypersensitivity (SSH) in clinical phase 3. The case study will emphasize essentially three aspects which appear to be key for the understanding of drug-induced and anti-drug antibody-mediated hypersensitivity reactions: (i) the requirement of multiple risk factors that coincide, (ii) the diversity of underlying mechanisms leading to SSH, (iii) the fact that SSH may not be seen prior to clinical phase 3. Different ways of mitigating the risk of SSH will be discussed.

9:35 Novel Antibody Therapeutics with Engineered Features and Impact on Immunogenicity: Case Study of the Effect of an FcRn Mutation

Sally FischerSally Fischer, Ph.D., Senior Scientist and Group Leader, Bioanalytical Research & Development, Genentech, Inc.

To improve the effectiveness of antibody therapeutics, a variety of antibodies with engineered features have been generated. These engineered features are designed to improve various characteristics of the molecules. This presentation will focus on a case study where a mutation intended to increase FcRn binding affinity caused unforeseen challenges in the immunogenicity evaluation of the molecule.

10:05 Designing Therapeutic Drugs with Reduced Immunogenicity

Gary BembridgeGary Bembridge, Ph.D., Business Development Manager, Antitope (Polytherics Company)

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.

 

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


Measures to Reduce Immunogenicity 


KEYNOTE PRESENTATION

11:15 Novel Approach to B and T Epitope Removal from Immunotoxins with Retention of High Cytotoxic Activity

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

Recombinant Immunotoxins are chimeric proteins designed to kill cancer cells. They are composed of an Fv that binds to a cancer cell and a protein toxin that kills the cell. RITs have produced complete remissions in over 50% of patients with refractory Hairy Cell leukemia but in some patients antibodies form preventing complete remission. We have developed novel experimental approaches for the identification and removal of B and T cell epitopes. The properties of new immunotoxins predicted to have low immunogenicity in humans will be described.


11:45 Problem Solving Roundtable Discussions

Table 1: Product-Related Factors that Contribute to Immunogenicity

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

Table 2: Identification and Silencing of Immunogenic Epitopes

Moderator: Ira Pastan, M.D., NIH Distinguished Investigator, Co-Chief, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health

Table 3: Prediction Technologies for Immunogenicity

Moderator: Harald Kropshofer, Ph.D., Senior Personalized Healthcare Leader, Pharmaceutical Development, F. Hoffmann-La Roche Ltd.

Table 4: Risk Assessment and Risk Management

Moderator: Steven J. Swanson, Ph.D., Executive Director, Medical Sciences (Clinical Immunology), Amgen, Inc.


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

2:00 Chairperson’s Remarks

Harald Kropshofer, Ph.D., Senior Personalized Healthcare Leader, Pharmaceutical Development, F. Hoffmann-La Roche Ltd.

2:05 Integrated Computational and Empirical Identification of Anti-Drug Antibody Epitopes Supports Clinical Risk Assessment and De-Immunization of Therapeutic Proteins

Larry KauvarLarry Kauvar, Ph.D., Senior Vice President, CSO, Trellis Bioscience

Although most Anti-Drug Antibodies (ADAs) are innocuous, some low abundance or low frequency ADAs may pose a significant clinical risk which is difficult to evaluate at the serum level. Trellis’ established technology platform for cloning rare B-cells enables deconvolution of serum into its component monoclonal ADAs. Our computational epitope prediction technology accelerates cloning ADAs against all epitopes on the protein. The technology further enables efficient immunological silencing of problematic epitopes.


Tolerance Mechanisms 

2:35 Evidence for Immune Tolerance Induction in Hemophilia A Mice Treated with Factor VIII Fc Fusion Protein

Haiyan Jiang, Ph.D., Senior Director, Preclinical and Clinical Research (Hemophilia), Biogen Idec

Inhibitors to factor VIII (FVIII) are a significant impediment in treating hemophilia A (HemA). In contrast to rFVIII, therapeutic doses of recombinant FVIII Fc fusion protein (rFVIIIFc) were shown to induce immune tolerance to FVIII in HemA mice, partially via interactions with FcRn and FcgR. In a recently completed phase 3 study in severe hemophilia A patients, rFVIIIFc was well tolerated, and no inhibitors were detected. The immune tolerance potential of rFVIIIFc merits further investigation in previously untreated patients.

3:05 Refreshment Break

3:30 Progress towards Inducing Immunological Tolerance to Factor VIII

David W. ScottDavid W. Scott, Ph.D., Professor and Vice Chair, Research, Medicine, Uniformed Services, University of Health Sciences, Bethesda

Many hemophilia A patients treated with therapeutic factor VIII (FVIII) produce neutralizing antibodies to the product, thus rendering this therapy ineffective. Recently, significant progress has been made to modulate this undesirable immune response. Methods to identify immunodominant epitopes in FVIII and the generation of T cell clones against FVIII have aided this progress. Novel approaches to induce tolerance using IgG fusion proteins, nanoparticles, gene therapy and specific T regulatory cells will be discussed.

4:00 Tolerogenic Nanoparticle-Based Immunotherapies to Inhibit Anti-Drug Antibody Responses

Takashi KishimotoTakashi Kishimoto, Ph.D., Chief Science Officer, R&D, Selecta Biosciences

Anti-drug antibodies are a major concern for biological therapies and a particular challenge for biosimilars. Selecta Biosciences is a clinical stage company developing an entirely new class of tolerogenic nanoparticle-based immunotherapies to inhibit anti-drug antibody responses. We have demonstrated preclinical efficacy against model proteins and against human therapeutic proteins, such as Factor VIII and adalimumab. This presentation will provide insights into the application of tolerogenic nanoparticle immunotherapies in preclinical models that reduce immunogenicity and potentially improve the safety and efficacy profile.

4:30 Close of Immunogenicity Risk Assessment & Mitigation



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Podcast 

IMN Podcast iconReducing and Monitoring Bioassay Variability 

2013 Speaker: Janet L. Lathey, Ph.D., Director, Immunology and Assay Development, BioDefenseDivision, Emergent BioSolutions