Cambridge Healthtech Institute's 11th Annual

Immunogenicity Case Studies and Clinical Management

( 免疫原性的个案研究与临床试验管理 )

Improving Clinical Design and Tailoring Therapy Choices

2018年4月30日-5月1日 | World Trade Center | 马萨诸塞州波士顿


As the immunogenicity field is moving forward, the focus has shifted from detection to outcome management in clinical settings and what it means to patients when realizing the clinical manifestation of immunogenicity. This year's conference will focus on new case studies and how to use immunogenicity data in clinical trial design and patient therapy choices.

Final Agenda

Sunday, April 30

Recommended Short Course(s)*

SC1: Preclinical and Clinical Assessment of Immunogenicity: Multidomain Therapeutics and New Modalities, Including Gene Therapy and CAR T

SC5: In silico Immunogenicity Predictions (Hands-On) Workshop

*Separate registration required.


7:00 am Registration and Morning Coffee


8:30 Chairperson's Remarks

JawaVibha Jawa, PhD, Director, Immunogenicity Strategy for Biologics and Vaccines, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc.

8:40 KEYNOTE PRESENTATION: Ten Years of Clinical Experience with Immunogenicity in Pompe Disease: Lessons Learned

Priya KishnaniPriya Kishnani, MD, C.L. and Sue Chen Professor of Pediatrics, Division Chief, Medical Genetics, Duke University Medical Center

Cross reactive immunological material (CRIM)-negative infantile Pompe disease (IPD) usually develop high anti-drug antibodies (ADA) and a prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and/or IVIG is a standard of care. However, predicting the development of ADA is challenging in CRIM-positive infantile Pompe disease. We evaluated a scoring method for predicting individualized risk of ADA based on the sequence of their residual GAA and their HLA DR1 alleles. This and other clinical updates will be presented.

9:10 FDA Perspective on Clinical Management

Amy RosenbergAmy S. Rosenberg, MD, Division Director, Office of Biotechnology Products, FDA/CDER

Immune responses to therapeutic proteins can be highly problematic if they neutralize life-saving therapeutics, cross react to endogenous proteins with non-redundant functions, or abrogate the efficacy of highly effective therapeutic proteins. Two strategies are increasingly being explored for mitigation: deimmunization of protein therapeutics and Immune tolerance induction (ITI). ITI is being increasingly explored in the context of autoimmune diseases, transplantation, and immune responses to life saving therapeutic proteins. Approaches that focus on antigen specificity, rather than global immune suppression are of greatest interest, but their utility may be limited by the clinical time frame for tolerance induction and clinical urgency. The development of "deimmunized" protein therapeutics has proven a daunting task but ultimately may have great utility. There is a clear need to better understand epitope spread and generation of subdominant T cell clones in this context.

9:40 Clinical Relevance of Detecting Anti-Infliximab Antibodies with a Drug-Tolerant Assay: Post Hoc Analysis of the TAXIT Trial

Ann GilsAnn Gils, PhD, Professor, Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium

To evaluate the clinical relevance of anti-drug antibodies (ADA), ADA of 76 patients of the TAXIT trial who presented with an infliximab trough concentration (TC)<3µg/mL at screening were measured using both a drug-sensitive (DS) and drug-tolerant (DT) assay. The immunogenicity detection rate increased from 21% (DS) to 63% (DT). Q4 patients required a higher cumulative infliximab dose. All but one patient of Q4 were also ADA positive using DS.

10:10 Networking Coffee Break

10:45 Chairperson's Remarks

JawaVibha Jawa, PhD, Director, Immunogenicity Strategy for Biologics and Vaccines, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc.

10:50 Clinical Immunogenicity Assessment: Decision-Enabling Immunogenicity Data and Analyses

M. Benjamin Hock, PhD, Director of Immunogenicity, BioMarin Pharmaceutical Inc.

The commentary, "A Proposal to Redefine Clinical Immunogenicity Assessment" [Mytych et al., 2017, AAPS J; PMID: 28247192] described criteria whereby ADA bioanalysis might not take place by default for a low-risk protein therapeutic. One principle behind that argument is that ADA data should facilitate patient/physician- or product/program- decision-making.

11:20 Demystifying Immunogenicity Testing for Biotherapeutics

George GunnGeorge R. Gunn, III, PhD, Head, Immunogenicity and Clinical Immunology, Bioanalysis, Immunogenicity and Biomarkers, In Vitro/In Vivo Translation Platform, GlaxoSmithKline

Immunogenicity assessment of biologic therapeutics is a scientific and regulatory expectation. Bioanalytical complexities, sampling strategies and interpretation approaches can contribute to differences observed for anti-drug antibody (ADA) incidences reported for biotherapeutics, even those with similar mode of action and patient population. Here we will put immunogenicity assessments into context regarding method limitations, capabilities and the interpretation of the clinical consequences of immunogenicity.

11:50 Rigorous Reagent Characterization and Life Cycle Management Is Critical for the Consistent Performance of Bioanalytical Assays: A Clinical Case Study

Kun LuKun Lu, PhD, Staff Scientist, Protein Biochemistry Group, Regeneron Pharmaceuticals, Inc.

Robust and reproducible bioanalytical assay performance depends on the quality of critical protein reagents (CPR). Data will be presented to demonstrate the quality of CPRs using a set of biochemical and biophysical characterization assays. Additionally, a clinical case study will be presented to demonstrate the importance of formulation conditions for CPRs when working with modified reagents, specifically ruthenium labeled reagents.


12:20 pm Early Development Strategy for Bacterial- or Viral-Vectored Gene Therapies: 2 Case Studies

Jennifer Sims, Non-Clinical Expert, NDA Advisory Board, NDA Group

Aligning product attributes & process variables with a preclinical program that enables translation into a risk management strategy for gene therapies is a challenge. We will present examples illustrating how an effective risk assessment may integrate a consideration of factors associated with transgene & vector components. This can be used to guide manufacture, product quality & preclinical study design decisions, while anticipating regulatory priorities for early clinical development, including mitigating the risks of undesirable immunogenicity.

12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own

1:50 Session Break

2:20 Problem-Solving Breakout Discussions

3:20 Networking Refreshment Break


4:00 Chairperson's Remarks

4:10 Challenges and Opportunities in Engineering Protein Biopharmaceuticals

K. Dane Wittrup, PhD, C.P. Dubbs Professor, Chemical Engineering and Biological Engineering; Associate Director, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT)

Arthur C. Clarke's First Law posits that "When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong." Bearing this in mind, in this talk I will highlight areas of protein drug development that appear poised for breakthroughs in the coming decade or so.

4:55 The Next Generation of Cancer Immunotherapy: Targeting Myeloid Immune Checkpoints

Kipp Weiskopf, MD, PhD, Resident Physician, Internal Medicine, Brigham and Women's Hospital

Immune cells of the myeloid lineage hold tremendous potential as effectors of cancer immunotherapy. The CD47/SIRPα axis is a key molecular pathway that governs the interaction between myeloid cells and tumors. Therapies that target the interaction are effective across multiple preclinical models of cancer and are now under investigation in clinical trials. Further studies have revealed additional regulators of myeloid cell activation that can be exploited as myeloid immune checkpoints.

5:40 Welcome Reception in the Exhibit Hall with Poster Viewing

7:15 End of Day


8:00 am Registration and Morning Coffee


8:25 Chairperson's Remarks

Ann GilsAnn Gils, PhD, Professor, Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium

8:30 Proactive Therapeutic Drug Monitoring and Improved Outcomes over Standard of Care or Reactive Therapeutic Drug Monitoring

Adam CheifetzAdam Cheifetz, MD, Director, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center; Associate Professor of Medicine, Harvard Medical School

Currently, empiric dose escalation or reactive TDM is standard of care in the treatment of inflammatory bowel disease (IBD). Reactive testing is cost-effective and better directs care in IBD. However, there is some evidence that proactive testing of anti-TNF concentrations and antibodies to anti-TNF and optimization to a therapeutic window improves outcomes when compared to empiric dose escalation or reactive testing.

9:00 Immunogenicity of Therapeutic Antibodies: Monitoring Antidrug Antibodies in a Clinical Context

Theo RispensTheo Rispens, PhD, PI Antibody Structure and Function, Sanquin

Immunogenicity is one of the factors that may impact efficacy and safety of therapeutic antibodies in patients. Many immunogenicity assays are available for testing anti-drug antibodies (ADA), but the relationship between ADA and clinical outcome is often not clear. This presentation will address different types of immunogenicity assays and their clinical relevance in terms of drug tolerance, relation with PK, neutralizing antibodies, potential adverse events associated with ADA and prediction of future loss of response.

9:30 Therapeutic Drug Monitoring in Routine Clinical Practice: Insights on Practicalities and Clinician's Perception

Jocelyne DemengeotJocelyne Demengeot, PhD, Principal Investigator, Instituto Gulbenkian de Ciencia, Portugal

A program ensuring the regular monitoring of patients treated with biologics was implemented in three clinical departments (Rheumatology, Dermatology and Gastroenterology) of a Portuguese hospital. This 24-month long experience reveals several challenges and limitations. Beyond technicalities and economic issues, clinicians' perception of drug pharmacodynamics and immunogenicity appears as critical determinants for the success and optimized usage of TDM in routine clinical practice.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing


10:50 Chairperson's Remarks

Darshana Jani, Senior Manager, Global Assay Lead, Drug Development, Pfizer

10:50 Associations of HLA Genotype with Immunogenicity Risk in Clinic

Vibha JawaVibha Jawa, PhD, Director, Immunogenicity Strategy for Biologics and Vaccines, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc.

It is tough to optimize the sequence in the idiotype/CDR region that binds to the target, linkers as seen in fusion proteins or bispecific modalities as well as other developability limitations. A strategy to mitigate risk due to sequence that has promiscuous T cell epitopes would require rational design where a few amino acids could be changed to reduce the overall potential of binding to the HLA and drive a cell-mediated response. Another approach could involve monitoring for immune mediated risk during clinical development. This talk is intended to provoke discussions on the predictability of algorithm and in vitro-based outputs and their utility in clinic.

11:20 How Can Clinicians Use Immunogenicity Information to Better Understand Clinical Heterogeneity?

Sandra GarcesSandra Garces, MD, PhD, Senior Medical Advisor for Immunogenicity, GPS Medical and Benefit-Risk Management, Eli Lilly and Company

Biologic therapies have significantly improved the prognosis of many patients with chronic inflammatory diseases. However, clinical responses to those therapies are very heterogeneous, varying from non-response to loss of response or to complete clinical remission. In cases of therapeutic failure, an empirical switch to any other approved biologic represents a common practice. In cases of clinical remission, no clear guidance exists to maintain, reduce or discontinue therapy. Therapeutic drug monitoring (drug levels and ADA) can work as a tool to help us understand clinical heterogeneity and adopt tailored therapeutic decisions that can improve the cost-effectiveness of biologic therapies.

11:50 Hemophilia A: A Case Study of Optimizing Patient Populations to Assess Immunogenicity

Steven ArkinSteven Arkin, MD, Executive Director, Clinical Programs, Rare Disease Research Unit, Pfizer Worldwide R&D

Replacement biologics generated through recombinant DNA technology are used to treat many rare diseases but carry the risk of novel antigenic epitopes. Antibody immune responses observed in clinical studies may occur as a class effect or in response to the novel epitopes. By use of sub-populations at minimum risk for background antibody immune response, it is possible to characterize immunogenicity risk for the respective drug in the context of the small studies that are feasible in rare disease conditions.

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own

1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing


2:00 Chairperson's Remarks

Darshana Jani, Senior Manager, Global Assay Lead, Drug Development, Pfizer

2:05 KEYNOTE PRESENTATION: Kymriah Case Study: First-Ever CAR T Cancer Drug and Its Journey to FDA Approval

Karen ThudiumKaren Thudium, PhD, Head, Clinical Pharmacology Program, Cell and Gene Business Unit, Novartis

Kymriah is the first-ever gene therapy that was approved by the FDA in the US to treat pediatric acute lymphoblastic leukemia. It's a type of cancer immunotherapy, which harnesses the body's immune system to take on cancer cells. Kymriah did not have to go through a Phase III trial because of the spectacular clinical responses in patients. Approximately, 83% of pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) showed complete responses within just three months of treatment. This talk will focus on the development of Kymriah and its journey to FDA approval.

2:35 Immunogenicity Profile of an Enzyme-Substitution Therapy and Impact on Safety and Efficacy

Soumi GuptaSoumi Gupta, PhD, Director of Immunogenicity, Translational Sciences, BioMarin Pharmaceutical, Inc.

We have developed an extensive suite of assays to characterize the immunogenicity profile of an enzyme-substitution therapy in late-stage development. Here we will discuss the interpretation of that ADA data, and the impact of immunogenicity on safety and efficacy of a novel therapeutic.

3:05 Sponsored Presentation (Sponsorship Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:25 Immunogenicity Screening for Designing Antibody Therapeutics, A Case of Emicizumab (Preclinical)

Chiyomi KuboChiyomi Kubo, PhD, DVM, Scientist, Research Division, Chugai Pharmaceutical Co., Ltd.

Immunogenicity of antibody therapeutics may reduce efficacy, safety and success rate of development. This talk will present a case study to screen anti-factors IXa/X bispecific humanized IgGs for a low immunogenic candidate on the basis of the activity observed in preclinical in vitro assay. In the Phase III-HAVEN1 trial where approximately 100 patients received the finally selected one, emicizumab, none tested positive for ADA (Oldenburg J et al. NEJM. 2017).

4:55 Cellular and Humoral Immune Responses in AAV-Mediated Gene Therapy

Katherine HighKatherine A. High, MD, Co-Founder, President and Head of R&D, Spark Therapeutics

Recombinant adeno-associated viral vectors (AAVs) are quickly becoming the preferred vector for gene delivery for the treatment of a wide variety of genetic disorders. However, since their use in a clinical trial targeting hemophilia B patients 10 years ago, immune responses to the AAV capsid have emerged as an issue that must be optimally managed to achieve therapeutic success. This talk will utilize data from clinical trials to illustrate optimal monitoring and management of human immune responses to the AAV vector, with a goal of achieving best outcomes in AAV-based gene transfer. A better understanding of both pre-treatment neutralizing antibodies, and cytotoxic T cell responses to recombinant AAV will lead to more efficacious gene transfer protocols in patients.

5:25 End of Immunogenicity Case Studies and Clinical Management

5:30 Registration for Dinner Short Courses

Recommended Dinner Short Course(s)*

SC13: Sub Visible Protein Particles in Immunogenicity: Measurement, Characterization and Impact

Bjorn BollBjorn Boll, PhD, Head, Particle Lab and Higher Order Structure Protein Analytics, Physical Chemical Analytics, Novartis Pharma AG

Anacelia Rios Quiroz, PhD, Scientist, Group Leader Particle Lab, Pharma Technical Development Europe (Biologics) Analytics (PTDE-A), F. Hoffmann-La Roche Ltd.

*Separate registration required.

* 活动内容有可能不事先告知作更动及调整。

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