2019 Archived Content

Cambridge Healthtech Institute ’s 11th Annual

Immunogenicity Prediction & Control

Regulatory Perspectives, Risk Factors, and Management

October 17-18, 2019

The impact of immunogenicity on safety and efficacy and consequent cost to the industry is well understood. Accordingly, investigators are focusing on factors that contribute to immunogenicity as well as a number of different approaches to predict immunogenicity at the drug discovery stage. There are several major problematic areas such as gene therapy products with viral vectors, and Factor VIII for hemophilia, and efforts are being made to suppress immune responses to these products and to introduce tolerizing and deimmunization approaches.

Final Agenda

Thursday, October 17

1:00 pm Conference Registration

1:40 NEW: Chairperson’s Opening Remarks

Brandon DeKosky, PhD, Assistant Professor, The University of Kansas

1:45 KEYNOTE PRESENTATION: Predicting Immunogenicity of Biopharmaceuticals Through Integrating in silico, in vitro, and Immune Systems Data

Timothy Hickling, PhD, Immunogenicity Sciences Lead, Pfizer Inc.

Unwanted immune responses to therapeutic proteins can adversely affect clinical outcomes and may complicate product development. Reducing the risk of immunogenicity through application of ‘predictive’ assays during molecular design is appealing, though useful prediction via a single assay is not currently possible. I will describe an approach to integrate data relating to molecules and patients to simulate the outcome of clinical trials, including the introduction of an Immunogenicity Simulator consortium.

2:15 NEW: Towards Translational Immunogenicity

Forman_Daron Daron Forman, PhD, Principal Scientist, Bristol-Myers Squibb

In vitro and in silico immunogenicity tools can be utilized during biologics drug development to select clones with decreased clinical immunogenicity risk. Here we will discuss how these tools are used in drug development, as well as ongoing efforts to harmonize methods and establish clinical validation.

2:45 Phase 2 Clinical Data of ImmTOR Tolerogenic Nanoparticles Combined with Pegadricase Demonstrates Mitigation of Immunogenicity in Patients with Symptomatic Gout

Plotkin_Horacio Horacio Plotkin, MD, SVP and Head, Clinical Development, Selecta Biosciences

Immunogenicity is a common cause of treatment failure and hypersensitivity reactions with biologic therapies. We have shown that biodegradable ImmTOR nanoparticles encapsulating rapamycin can mitigate the immunogenicity of a wide variety of biologic therapies in preclinical studies. Here we provide data from a clinical trial showing mitigation in the formation of anti-drug antibodies in patients with symptomatic gout and hyperuricemia.

3:15 An Integrated Approach To Managing Immunogenicity Risk And Optimum Protein Design

Knowlton_Emilee Emilee Knowlton, Immunology Sales Specialist, Sales, ProImmune Inc.

Integrated platforms can be used to mitigate immunogenicity risk and characterize immune responses during the drug design and development stages. ProImmune offers mutational activity mapping for optimal protein design, DC-T/T cell proliferation assays for biologic lead selection/optimization, a Mass Spectrometry assay for characterization of antigen presentation; HLA-peptide binding assays to characterize individual epitopes & undiluted whole blood cytokine storm assays.

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

4:25 FEATURED PRESENTATION: Fc-Fusion Drugs Have C1q/FcγR Binding and Signaling Properties That May Affect Their Immunogenicity

Daniel Lagasse, PhD, Research-Regulator, FDA

Fusing the human immunoglobulin G1 (IgG1) constant region (Fc-domain) to therapeutic proteins or peptides increases their circulating plasma half-life via neonatal Fc receptor (FcRn) binding and recycling. However, Fc-mediated interactions with other molecules, including complement C1q and Fc gamma receptors (FcγR), can have immunological consequences and the potential to modulate the immunogenicity of Fc-fusion therapeutics. Our comprehensive assessment of five FDA-approved Fc-fusion therapeutics demonstrates: (i) that different Fc-fusion drugs have distinct C1q/FcγR binding and signaling properties; (ii) FcγR binding does not predict signaling; (iii) the fusion partner (effector molecule) can influence Fc-mediated interactions. Therefore, we advocate a case-by-case characterization of Fc-Fc-receptor interactions for Fc-fusion drug candidates.

4:55 The Use of Preclinical Risk Assessment Tools to Drive a Clinical Immunogenicity Strategy for Biologics

Jawa_Vibha Vibha Jawa, PhD, Director, Predictive and Clinical Immunogenicity Pharmacokinetics, Pharmacometrics and Drug Modeling Group, Merck & Co., Inc.

Immunogenicity to biologics is common during clinical trials. Both product- and host-specific factors have been implicated. Several risk assessment tools can be used to identify and mitigate the risk factors responsible for immunogenicity. An insight into recent advances in the risk assessment approaches will be presented. The outputs can define a risk score and guide the clinical bioanalytical and immunogenicity monitoring strategy. This risk assessment strategy can be shared with the regulators and immune monitoring personalized based on pharmacogenomics and other patient-related factors.

5:25 Immunogenicity Risk Assessment Considerations for Immune Oncology Products

Xue_li Li Xue, PhD, Senior Principal Scientist, Pfizer Inc.

Immune oncology (IO) biologics are designed to engage immune cells to enhance effective killing of targeted cancer cells. Pre-clinical in vitro immunogenicity risk assessment tools have been developed to assess the intrinsic risk factors of drugs without being confounded by the MOA’s manipulation of the immune system. The presentation will discuss IO-focused immunogenicity risk assessment strategies to inform the design and selection of IO drug candidates with lower immunogenicity risks.

Friday, October 18

7:30 am Breakfast Breakout Round Table Discussions

Enjoy a continental breakfast and join us for a moderated round table discussion with interactive problem solving. These sessions bring together attendees from diverse backgrounds to exchange ideas and develop future collaborations around a focused topic, in an informal environment.

TABLE 1:Viability of Immune Tolerance Strategies for the Treatment of Human Disease

Moderator: Stephen Miller, PhD, Professor of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University

What are the appropriate disease indications for testing tolerance therapy in initial clinical trials?
What factors are important in developing the ideal approach for tolerance induction?
What immune tolerance induction approaches are currently in development for disease prevention and therapy?
What are the similarities and differences in the mechanism(s) of action by the different tolerance approaches?

TABLE 2: Development of Robust T Cell Response Immunogenicity Prediction Assay

Moderator: Karen Liao, MD, Investigator, GSK Associate Fellow, GlaxoSmithKline

Selection of assay format: DC-CD4 T vs DC-PBMC, vs whole PBMC, vs CD8 depleted PBMC assay. Pros and cons for each format?
Considerations for assay controls, assay variation and assay acceptance criteria. How to treat replicates? Does replicate %CV apply to the low frequent Ag specific CD4 detection?
Data interpretation: Positive response criteria and rank responses
How do T cell responses correlate to the clinical immunogenicity? Is the response rate or the strength of response more relevant? Any magic number of CD4 T cell response for high immunogenicity risk clinically?

TABLE 3: Molecular Characterization of Immunogenicity

Moderator: Brandon DeKosky, PhD, Assistant Professor, The University of Kansas

How to rescue immunogenic lead candidates
Understanding the mechanisms of epitope spreading
Advantageous vs. benign vs. harmful immunogenicity
Optimal monitoring and assay development for immunogenicity analysis

TABLE 4: Practical Application of Prediction Tools and the T Cell Response

Moderator: Bernard Maillere, PhD, Research Director, Immunology, CEA

What methods are available for preclinical assessment of immunogenicity?
What are the principles, outcomes and value of each method?
How many formats are there? What are their respective advantages?
How to combine the information provided by the prediction tools with that coming from other factors contributing to immunogenicity

TABLE 5:Implementing an Immunogenicity Risk Assessment Strategy from Discovery to Preclinical to Clinical and Beyond

Moderator: Vibha Jawa, PhD, Director, Predictive and Clinical Immunogenicity, Pharmacokinetics, Pharmacometrics and Drug Modeling Group, Merck

8:30 Chairperson’s Opening Remarks

Alessandro Sette, Dr. Biol. Sci., Professor, Head and Member, La Jolla Institute for Immunology

8:35 KEYNOTE PRESENTATION: MHC Binding, Eluted Ligands and Immunogenicity: Benchmarking and Predictions

Alessandro Sette, Dr. Biol. Sci., Professor, Head and Member, La Jolla Institute for Immunology

The IEDB team has been actively involved in curating and making eluted ligand data accessible to the general community, and benchmarking different predictive strategies. MHC binding predictions predict MHC binding effectively, and several studies benchmarked MHC binding predictions for predicting T cell immunogenicity. Large elution datasets are being utilized to derive algorithms predicting eluted ligands, which can also be utilized for benchmarking elution data in terms of prediction of T cell epitopes. Integration of elution and binding data yields the best prediction accuracy, demonstrating the benefits of training with both data types. HLA class II epitope predictions are in general less accurate, likely because of the extensive repertoire overlap amongst different HLA molecules, and because of epitope promiscuity. Approaches considering reactivity at the population level and algorithms based on training with T cell epitope data are promising approaches.

9:05 Functional Analyses of Natively Paired Heavy and Light Human Antibody Repertoires

DeKosky_Brandon Brandon DeKosky, PhD, Assistant Professor, The University of Kansas

Antibody discovery requires paired heavy and light sequences from single cells, and recent advances in NGS technologies have enabled the elucidation of antibody function on a repertoire scale. We have applied these recently developed platforms to understand immune function and discover new antibody molecules with desired functional properties. We will discuss recent progress and how these antibody repertoire analysis platforms can be applied to enhance understanding of protein drug immunogenicity.

9:35 Evaluating Immunogenicity as Part of a Holistic Approach to Wider Developability Assessment & Lead Candidate Selection

Alyson Rust, Team Leader – Bioassays, Bioassays, Abzena

Immunogenicity risk needs to be assessed during development, but it should not be done exclusive of evaluating other developability factors. Developability assessment is based on multiple readouts that capture the fundamental characteristics of successful drug design: specificity, functionality, safety and manufacturability. Assessing these side by side allows the selection of the lead candidate with the least inherent liabilities that will inhibit its progress across a range of factors.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Circulating Stromal Cells Sequentially Monitor PD-L1 Expression and Predict Response of Immunotherapies

Adams_Daniel Daniel L. Adams, Director of Clinical Research & Development, Creatv MicroTech, Inc.

The LifeTrac assay is a non-invasive blood based test that sequentially monitors circulating tumor cells and circulating stromal cells in patients with local or advanced solid tumors. We will describe how the LifeTrac assay can be used to monitor immunotherapy response and predict efficacy in numerous cancers, including LifeTrac’s prognostication in 3 different types of IO therapies in NSCLC patients undergoing CRT.

11:15 NEW: PANEL DISCUSSION: How to Integrate Prediction Technologies into the Drug Development Process

Moderator: Bonita (Bonnie) Rup, PhD, Biopharmaceutical Consultant, Bonnie Rup Consulting LLC

Panelists:

Bernard Maillere, PhD, Research Director, Immunology, CEA

Li Xue, PhD, Senior Principal Scientist, Pfizer

Alessandro Sette, Dr. Biol. Sci., Professor, Head and Member, La Jolla Institute for Immunology

Which prediction technologies are chosen at each stage of drug development?
Immunogenicity prediction in Go/NoGo decisions
Consequences of ADA response (neutralisation, adverse effects, serum sickness) in the early phases of drug development
Feedback from the clinic and how to integrate it in order to improve prediction

11:40 NEW: Chairperson’s Remarks

Laura Santambrogio, MD, PhD, Associate Director, Precision Immunology, Englander Institute of Precision Medicine, Weill-Cornell

11:45 Mechanisms Underlying Tolerance Induction with Antigen-Encapsulating PLG Nanoparticles for Therapy of Immune-Mediated Diseases

Miller_Stephen Stephen Miller, PhD, Professor of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University

The utility of antigen-encapsulating carboxylated poly(lactide-co-glycolide) (PLG) nanoparticles (Ag-PLG) for tolerance induction in treatment of autoimmune and allergic diseases will be discussed. Data supporting the critical role of Ag-PLG uptake by tolerogenic spleen and liver APCs via the MARCO scavenger receptor and for activation of antigen-specific regulatory T cell subsets in tolerance induction and maintenance in Th1/17-driven animal models of MS and T1D, and Th2-driven allergic airway disease will be presented.

12:05 Engineering Antigen-Carrier Cells to Induce Immune Tolerance by Cell Squeeze® Technology

Seidl_Katherine Katherine Seidl, PhD, Vice President Immunology, SQZ Biotech

Unwanted immune responses underlie diseases of autoimmunity, transplant, and some AAV gene therapies. To enhance efficacy and reduce the unwanted side effects of the current treatment paradigm of broad immunosuppression, there is a need to further develop antigen-specific tolerance. SQZ-Tolerizing Antigen Carriers (TACs) are derived from red blood cells loaded with antigen through the Cell Squeeze® process. Data showing the ability of TACs to reduce immune responses in several disease contexts will be presented.

12:25 Treg Cell Therapies to Induce Immune Tolerance for Haemophilia A

Kim_YongChan Yong Chan Kim, PhD, Vice President for Research, TeraImmune

Replacement therapy with factor VIII is used in patients with haemophilia A for treatment of bleeding episodes. A serious problem with this therapy is the formation of inhibitory antibodies against FVIII in the patients. We will introduce the Treg cells transduced with recombinant receptors (TCR, CAR, and B cell antibody receptor), and their therapeutic potential in the suppression of the antibody formation in vitro and in vivo.

12:45 Luncheon Presentation: Circulating Stromal Cells Sequentially Monitor PD-L1 Expression and Predict Response of Immunotherapies

Smith_Noel Noel Smith, Principal Group Leader, Applied Protein Services, Lonza Pharma & Biotech

Immunogenicity is a common problem for biotherapeutic proteins and can impact both efficacy and safety. Prior to first in human trials, human in silico and in vitro tools have been shown to be the most relevant platform to assess immunogenicity risk and are now routinely included in IND applications. This presentation will discuss how these technologies can be used to carry out early stage immunogenicity risk assessment aiding lead selection and optimisation.

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

1:55 NEW: Chairperson’s Remarks

Laura Santambrogio, MD, PhD, Associate Director, Precision Immunology, Englander Institute of Precision Medicine, Weill-Cornell

2:00 FEATURED PRESENTATION: Tolerance and Check Point Inhibitors

Jack A. Ragheb, MD, PhD, Senior Medical Fellow, Immunology, Global Patient Safety, Eli Lilly and Co.

Multiple biological drugs are linked with the development of autoimmune disease; prominent among these are the immune checkpoint inhibitors (ICI). While the use of ICI was originally limited to incurable cancers, their success has prompted investigation of their use as earlier lines of treatment. Here we review the immune-related adverse events (irAE) associated with their use, the clinical management of these irAE, and the preclinical literature that suggests the bases of these irAE.

2:30 KEYNOTE: Dissecting the Immunogenicity of AAV Vectors

Mazor_Ronit Ronit Mazor, PhD, Principal Investigator, FDA

Adeno associated viruses (AAV) are potent vectors used for gene delivery in gene therapy products. Recent clinical findings revealed immunogenicity related challenges including pre-existing antibodies, formation of neutralizing antibodies after the first administration and formation of a cytotoxic immune response against transfected cells. In this talk I will describe the immunogenicity of AAV vectors and strategies for mitigation it.

2:50 Lessons Learned from the MHC II Immunopeptidome

Santambrogio_Laura Laura Santambrogio, MD, PhD, Associate Director, Precision Immunology, Englander Institute of Precision Medicine, Weill-Cornell

The presentation will address fundamental open questions on the dendritic cells MHC-II peptidome selection and composition, and its overall plasticity during physiological and pathological conditions. The quantitative balance between the self and non-self MHC II peptidome during infection and the quantitative analysis of how the MHC II peptidome reflects the cellular transcriptome and its metabolism will be addressed.

3:10 Challenges and Solutions in ADA Assay Development for a Multimeric PEGylated Molecule

Liu_Emma Emma Liu, PhD, Scientist, Genentech, Inc.

PEGylation is one of the long-acting delivery platforms to increase the half-life of protein therapeutics. However, PEGylation poses challenges in assay development to detect anti-drug antibody (ADA) to both protein and PEG portions. The presentation will use a new modality candidate: a multimeric PEGylated molecule as a case study to describe the challenges and how to successfully develop an assay enabling the detection of ADA to both protein and PEG.

3:30 Close of Immunogenicity Prediction & Control

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