Immunogenicity Assessment and Regulatory Approval of Biologics conference, May 4-5 2020

Immunogenicity has always been a critical safety concern, especially when many biotherapeutics are becoming increasingly complex. Understanding and controlling immunogenicity-related risks are essential in the development of biotherapeutics to ensure meeting the regulatory requirements. The 13th Annual Immunogenicity Assessment and Regulatory Approval of Biologics conference brings industry, regulatory and scientific experts together to share the best practices in assessing immunogenicity of novel biologics along with biosimilar products. The sessions will also discuss the challenges and solutions for addressing new regulatory guidelines in assay development and validation for cell and gene therapies and other platforms.

Wednesday, September 2

DRUG TOLERANCE AND INTERFERENCES

9:25 am

Fully Automated Cell-Based Binding Neutralizing Antibody Assay on MSD Platform

Weifeng Xu, PhD, Principal Scientist & Group Leader, PPDM, Merck Research Labs

The newest FDA Immunogenicity Testing Guidance mentioned that LBA could be developed for antagonistic mAb NAb assay. However, in the case of dual-receptors drug target or hard-to-express drug target/ligand, it is also very challenging to have LBA NAb assay. Here, we share a case study of fully automated NAb assay development and validation using a MSD-based cell binding assay.

Noel Smith, PhD, Head, Immunology, Lonza Biologics

Immunogenicity and Immunotoxicity are common challenges to address during drug development and can impact both the efficacy and safety of the drug. To assess these risks, a variety of tools can be applied during preclinical development. These include a range of different human primary cell assays to assess the innate and adaptive immune response to the drug as well as both target and off-target mediated immune reactions. This presentation will focus on an overview of these human primary cell assays and how studies can be designed and executed for the assessment of immunogenicity and immunotoxicity risk during preclinical development.

10:10 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Boris Gorovits, PhD, Senior Director, Pharmacokinetics, Pharmacodynamics & Metabolism, Pfizer Inc.
Panelists:
Weifeng Xu, PhD, Principal Scientist & Group Leader, PPDM, Merck Research Labs
Noel Smith, PhD, Head, Immunology, Lonza Biologics
10:30 am Speed Networking Coffee Break - View our Virtual Exhibit Hall
10:55 am

ADA Analysis Demonstrates the Potential Impact of Insufficient Drug Tolerance

Kelli Phillips, PhD, Associate Director, PPD

An ELISA method with Acid Dissociation was developed for the detection of ADA against a biosimilar therapeutic at PPD (2015). Pre-validation data indicated that the method was able to detect up to 100 ng/mL of the positive control in the presence of 43.3 mcg/mL drug. This degree of drug tolerance was predicted to be fit-for-purpose for sample analysis; measured serum concentrations of the innovator drug during Phase III trials ranged from 0.50 to 6.00 mcg/mL. An alternate dosing strategy for a biosimilar drug was also tested. As a result, serum drug concentrations surpassed the drug tolerance of the originally validated assay. An improved ECL-Bead ADA method with increased drug tolerance was developed at PPD (2019) and the impact of the improved drug tolerance was evaluated using a subset of study samples.


ANTI-DRUG ANTIBODIES – KEEP CALM AND CARRY ON

11:15 am

Immunogenicity Risk Factors Associated with Multi-Domain Biotherapeutics

Boris Gorovits, PhD, Senior Director, Pharmacokinetics, Pharmacodynamics & Metabolism, Pfizer Inc.

Compounds containing two or more structural domains with a distinct mode of action-relevant functionality have been defined as multi-domain biotherapeutics (MDB). Several modalities, including endogenous protein fusions with Fc fragment or another polypeptide, bispecific antibodies, antibody-drug conjugates, as well as polyethylene glycol conjugates, have been viewed as examples of MDB type. Similar to other biotherapeutics, MDB compounds have a potential to induce host immune response, commonly detected in a form of anti-drug antibodies (ADA). The need to characterize ADA specificity to a particular domain of MDB has been identified as a potential requirement based on the compound nature and associated immunogenicity risk factors. MDB-related immunogenicity risk factors and related strategy of ADA specificity evaluation will be discussed.

11:35 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Boris Gorovits, PhD, Senior Director, Pharmacokinetics, Pharmacodynamics & Metabolism, Pfizer Inc.
Panelist:
Kelli Phillips, PhD, Associate Director, PPD
12:00 pm Session Break
12:20 pm Lunch Break - View our Virtual Exhibit Hall
12:45 pm

Evaluation of Statistical Approaches for the Monitoring of Anti-Drug Antibody (ADA) Assay Performance during Clinical Development

Ching-Ha (Vicky) Lai, PhD, Senior Staff Scientist, Bioanalytical Sciences, Regeneron Pharmaceuticals, Inc.

It is expected that immunogenicity will be monitored throughout the clinical development program of a biotherapeutic. The ADA assay used to monitor immunogenicity is needed to support multiple clinical studies through different development phases, over several years. Thus, it is important to have an assay life cycle management process in place, which monitors assay performance over time and in different clinical indications. In this presentation, case studies will be used to discuss and compare approaches for monitoring quality control (QC) performance of ADA assays, to study the factors that may potentially influence assay performance, and to address potential assay drifts during clinical bioanalysis.

REGULATORY PERSPECTIVES

1:05 pm

FDA Guidance on Bi- and Tri-Platforms

Mark Ma, PhD, Executive Director, Bioanalytical Development, Alexion Pharmaceuticals, Inc.

The FDA has licensed two bispecific antibodies (BsAbs) and the number in clinical development has steadily increased in recent years. I will discuss the current expectation and guideline from the FDA for novel modalities with a focus on bi- and tri-specific antibodies.

1:25 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Mark Ma, PhD, Executive Director, Bioanalytical Development, Alexion Pharmaceuticals, Inc.
Panelist:
Ching-Ha (Vicky) Lai, PhD, Senior Staff Scientist, Bioanalytical Sciences, Regeneron Pharmaceuticals, Inc.
1:50 pm Session Break
2:10 pm Refresh Break - View our Virtual Exhibit Hall
2:25 pm KEYNOTE PRESENTATION:

New Technologies and Approaches to Assess and Circumvent Immunogenicity

Wojciech Jankowski, PhD, Commissioner’s Fellow, CBER, FDA

We will describe examples of the use of novel assays to assess immunogenicity and use the information to de-immunize therapeutic-proteins. I will give examples how we: evaluated and re-designed immunogenic rFVIIa analog (Vatreptacog Alfa); redesigned variants exhibiting both desired functional activity and reduced immunogenicity-risk; evaluated plasma-derived FVIII vs. recombinant FVIII using the MAPPs assay; and gave the explanation for clinical findings. We have been developing new approaches and assays for immunogenicity assessments and applying these to specific proteins and immunogenicity issues. Thus, my talk will not only lay out the broad principles, but also provide specific examples where our approaches have been useful.

2:45 pm

Development and Validation of a Sensitive and Drug Tolerant Anti-PEG Antibody Assays

Madhukar Aryal, MS, Senior Research Associate, BioAnalytical Sciences, BioMarin Pharmaceutical, Inc.

Monitoring emerging immune responses to polyethylene glycol (PEG) is of critical interest to establish the safety and efficacy of pegylated therapeutics. In vitro drug tolerance assessments of an anti-PEG antibody assay suggested potential interference from high levels of pegylated therapeutic in serum samples. This presentation will discuss a Biotin-PEG Extraction Acid Dissociation (BEAD) strategy that reduced the concentration of pegylated protein and matrix components in samples before assay, and improved anti-PEG antibody assay drug tolerance.

3:05 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Wojciech Jankowski, PhD, Commissioner’s Fellow, CBER, FDA
Panelist:
Madhukar Aryal, MS, Senior Research Associate, BioAnalytical Sciences, BioMarin Pharmaceutical, Inc.
3:30 pm Session Break
3:50 pm Refresh Break - View Our Virtual Exhibit Hall
4:10 pm Problem Solving Breakout Discussions - Part A

This session provides the opportunity to discuss a focused topic with peers from around the world in an open, collegial setting. Select from the list of topics available and join the moderated discussion to share ideas, gain insights, establish collaborations or commiserate about persistent challenges.

4:40 pm Refresh Break - View Our Virtual Exhibit Hall
5:00 pm Problem Solving Breakout Discussions - Part B

TABLE 26: Fully Automated Cell-Based Binding Neutralizing Antibody Assay on MSD Platform

Weifeng Xu, PhD, Principal Scientist & Group Leader, PPDM, Merck Research Labs
  • NAb assay development: when to have an assay, which format: cell or non-cell?
  • How to overcome drug interference;
  • Interpretation of new 2019 Jan FDA Immunogenicity guidance
5:30 pm Close of Day

Thursday, September 3

PREDICTIVE IMMUNOGENICITY ASSAYS

9:05 am

Current Practice in Predicting Immunogenicity of Biopharmaceuticals for Candidate Selection and Risk Management

Timothy Hickling, PhD, Head of Immunosafety, Roche

Immunogenicity prediction through in silico and in vitro assays is widely employed for screening and selection of candidate biopharmaceuticals across our industry. During clinical development, these techniques, together with mathematical modeling and simulation, can help to understand the overall immunogenicity risk, pointing towards immunogenicity risk management strategies. I will review current practice and provide examples across the drug discovery and development pipeline.

9:25 am

A Case Study on Prediction of Immunogenicity Potential of Therapeutic Proteins

Sivan Cohen, PhD, Scientist, Genentech

Immunogenic response, such as generation of anti-drug antibodies (ADA), against biotherapeutic products can have detrimental effects on drug safety, efficacy, and pharmacokinetics. Therefore, prediction and quantification of the risk for immunogenicity of therapeutic protein drugs before clinical trials is a crucial need. This presentation will describe state-of-the-art in silico analyses and in vitro assays for characterization of the immunogenic potential of a panel of biotherapeutic proteins and their correlation to the clinically observed immunogenicity outcome. A novel T cell assay with shortened turnaround time, improved efficiency, and robustness will also be discussed.

Jeremy Fry, Director of Sales, ProImmune

Immunogenicity is one of the most complex issues to address in drug design and development and requires intelligent application of integrated platforms to mitigate the risk to your biologic. In this talk I will present case studies to illustrate the range of solutions that ProImmune provides including DC-T/T cell proliferation assays for lead selection/optimization, MAPPS assays for characterization of antigen presentation; HLA-peptide binding assays to characterize individual epitopes & undiluted whole blood cytokine storm assays.

10:10 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Timothy Hickling, PhD, Head of Immunosafety, Roche
Panelists:
Sivan Cohen, PhD, Scientist, Genentech
Jeremy Fry, Director of Sales, ProImmune
10:30 am Coffee Break - View our Virtual Exhibit Hall
10:50 am

Learning the Rules of HLA Class II Antigen Presentation from in-vitro Binding and MS Eluted Ligand Data: Applications for Epitope Discovery and Immunogenicity Prediction

Morten Nielsen, Professor, PhD, Department of Health Technology, The Technical University of Denmark & Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, Argentina
11:10 am

Case Study for In-Study Cut Point Evaluations According to the 2019 FDA Guidance

Megan Wiberg, Associate Director, PPD, Inc.

Validation of immunogenicity assays results in cut points that may or may not be relevant when applied to the study population once the method is implemented for clinical study support. The potential for the validated cut point to be unsuitable during sample analysis should be considered when determining cut point strategies during method validation. This talk will address approaches for choosing the population used to establish cut points during pre-study validation, evaluating the suitability of validated cut points during sample analysis, and highlight strategies for in-study cut point determination and implementation when the validated cut point is deemed unsuitable.

11:30 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Timothy Hickling, PhD, Head of Immunosafety, Roche
Panelists:
Morten Nielsen, Professor, PhD, Department of Health Technology, The Technical University of Denmark & Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, Argentina
Megan Wiberg, Associate Director, PPD, Inc.
11:50 am Close of Immunogenicity Assessment and Regulatory Approval of Biologics





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