Characterization for Novel Biotherapeutics

As new product formats progress through development and into the regulatory process, the role of analytical characterization is taking on new meaning. Very new modalities present challenges to both analytical scientists and regulatory agencies alike, and this steep learning curve requires a near-constant cycle of adaptation and innovation. The Characterization for Novel Biotherapeutics conference explores the progression of analytical development for an exciting range of emerging modalities and offers a case study forum for those working in the field to share ideas, experiences and solutions that support the preclinical and clinical development of novel biotherapeutics.

Monday, August 31

TRANSITIONING FROM THERAPEUTIC PROTEINS TO CELL AND GENE THERAPIES

9:05 am

Key Assays and Methods for Generation, In-Process Testing and Characterization, towards CMC of AAV Vectors

Stefan Seeber, PhD, Sr Principal Scientist, Cell Line & Molecule Dev, Roche Innovation Ctr Penzberg

As AAV-based gene therapy is coming of age with clinical success and increasing numbers of market entries, the industry has set out to develop AAV vector production protocols according to CMC standards. We are leveraging our expertise in CMC for therapeutic proteins to adopt existing and integrate new protocols for AAV vector generation, purification, and quality control. A case study will be presented to illustrate the differences between therapeutic modalities.

9:25 am KEYNOTE PRESENTATION:

Expanding Analytical Capabilities from Protein Biologics to Gene Therapy Products

Julia Ding, PhD, Director, Global Process Analytical Development Network Lead, Bristol Myers Squibb Co.

With the advance of modern analytical technologies, protein biologics are well characterized at the molecular level. Product critical quality attributes are assessed through a structure-functional relationship and controlled throughout process and product development. Analytical paradigm of gene therapy products has brought significant challenges in analytical standardization and control strategy. Case studies in adapting and advancing analytical capability in support of viral vector development will be presented.

Rick Gordon, PhD, VP of Sales, Halo Labs

Distinguishing aggregated API from other particle types is important for understanding the root cause of instability. Existing methods are unreliable, too cumbersome and difficult to use in many workflows. With Aura, you can now finally count, size, and characterize aggregates and identify them as proteins, non-proteins, or other molecules.

10:10 am

The Experience of a Protein Biochemist Transitioning to Gene Therapy

George Bou-Assaf, PhD, Scientist, Analytical Development – Product & Technology Development, Biogen

Gene therapy products comprise a protein capsid and a nucleic acid packaged inside. We describe how analytical tools traditionally employed by biochemists for protein therapeutics are applied as is, or are adapted to GT products. We highlight similarities between gene therapy and protein-based products and discuss specific examples related to their critical quality attributes. We describe challenges unique to gene therapy products and how they were overcome with new methods.

10:30 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
George Bou-Assaf, PhD, Scientist, Analytical Development – Product & Technology Development, Biogen
Panelists:
Julia Ding, PhD, Director, Global Process Analytical Development Network Lead, Bristol Myers Squibb Co.
Stefan Seeber, PhD, Sr Principal Scientist, Cell Line & Molecule Dev, Roche Innovation Ctr Penzberg
Rick Gordon, PhD, VP of Sales, Halo Labs

BISPECIFIC AND MULTISPECIFIC ANTIBODIES

10:50 am

Analysis of Peptide-Exchanged MHCI Complexes by Native Mass Spectrometry

Wendy Sandoval, Principal Scientist, Genentech, Inc.

Immune monitoring provides insight into a patient’s immune response over the course of treatment. The challenge lies in making peptide MHCI complexes, since HLA are highly polymorphic. To successfully produce libraries, highly sensitive assays are necessary to validate peptide exchanges. Here, we describe a robust SEC-MS method and also a sensitive and high-throughput assay using capillary zone electrophoresis coupled to a high-resolution mass spectrometer for characterizing peptide-exchanged MHCIs under native conditions.

11:10 am

Bispecific Molecules and Characterization for Pharmacokinetics Studies

Mei Han, Principal Scientist, Pharmacokinetics & Drug Metabolism, Amgen Inc.

The sophistication required for proper molecular design causes the manufacturing and development of bispecific antibodies to be complex. Monitoring structural stability is critical for retention of the favorable drug distribution and pharmacokinetic of the antibody format. Classic ligand binding assays have limited resolution to capture some structural modifications in bispecifics. Here we will discuss characterization of bispecific molecules from pre-dose and post-dose pharmacokinetic samples.

11:30 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Wendy Sandoval, Principal Scientist, Genentech, Inc.
Panelist:
Mei Han, Principal Scientist, Pharmacokinetics & Drug Metabolism, Amgen Inc.
11:50 am Session Break
12:15 pm Lunch Break - View our Virtual Exhibit Hall
12:45 pm Session Break

DRUG COMBINATIONS

1:05 pm

Use of 2D Liquid Chromatography to Characterize Aggregates in Co-Formulated Drug Products

Xiaoqing Hua, PhD, Senior Scientist, Bioprocess, Merck Research Labs

Co-formulated monoclonal antibodies pose new challenges for analytical characterization due to their increased complexity. For example, aggregation is a common degradation pathway for mAbs and is often monitored under native state with size exclusion chromatography (SEC), but for co-formulation, new challenges appear due to similar size and shape of individual mAbs. A 2D-LC approach with orthogonal methods to SEC was adopted to improve product knowledge of single mAb profile in co-formulation and characterize aggregation in co-formulated DPs.


Shawn C. Owen, PhD, Assistant Professor, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, College of Pharmacy

Antibodies are the most rapidly growing form of therapeutic. High-throughput methods of characterization are essential as companies and researchers develop new candidates. Dr. Owen discusses advanced characterization techniques to assess antibody-drug conjugates. For ADCs, the level of payload and site of conjugation are determined using LC/MS. Thermal stability and binding affinity are characterized using DSC, IR, and ITC. These methods can be used for the in-depth analysis of these biologics and for routine product validation.

1:50 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Xiaoqing Hua, PhD, Senior Scientist, Bioprocess, Merck Research Labs
Shawn C. Owen, PhD, Assistant Professor, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, College of Pharmacy
2:10 pm Refresh Break - View Our Virtual Exhibit Hall
2:30 pm Problem-Solving Breakout Discussions Part A - View our Virtual Exhibit Hall

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.

TABLE 5: Co-Formulation of Therapeutic Proteins

Dennis Krieg, Graduate Student, Pharmacy, Ludwig Maximilians University
  • Analytical challenges (deconvolution of chromatographic and spectroscopic data, systematic and efficient method development
  • Formulation challenges (DoE approaches, setup of stability studies for co-formulations)
  • Regulatory
     challenges (demands for co-formulation characterization by the
    regulatory authorities, use of single formulation stability data for
    co-formulations)
  • Clinical challenges (setup of PK studies for
    flexible or fixed dosing ratios, extrapolation of clinical data from
    single to co-formulations)
3:00 pm Refresh Break - View Our Virtual Exhibit Hall
3:20 pm Problem-Solving Breakout Discussions Part B - View our Virtual Exhibit Hall

TABLE 6: Challenges Associated with Analytical Method Development for the Characterization of AAV-Based Therapeutics

George Bou-Assaf, PhD, Scientist, Analytical Development – Product & Technology Development, Biogen
  • Similarities and differences between AAV and protein-based challenges
  • Transferability of methods from proteins to AAV-based molecules
  • Sample limitations and design of experiments to take into account this limitation
  • Simplified and streamlined approaches to method development that still meets ICH guidelines and regulatory expectations
  • New tools and instrumentations that enable analytical method development of AAV based therapeutics
3:50 pm Refresh Break - View our Virtual Exhibit Hall

PLENARY KEYNOTE SESSION

4:10 pm

Chairperson's Remarks

K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
4:15 pm

From Energy to Machine Learning

George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School

In 1974, I adapted energy optimization methods for use in models of nucleic acids, protein and their interactions, and then for use in crystallographic refinement. In the last days of the second millennium,
David Baker's team won the Critical Assessment of Structure Prediction (CASP) by an unbelievable margin. Since then, our labs exchanged 3 Ph.D. students (Dantas, Raman, Lajoie), Wannier from Mayo's group, Stranges from Kuhlman, and Mandell from Kortemme. We engineered new sensor proteins for metabolic
engineering, essential proteins with non-standard amino acids for biocontainment, and polymerase-pore fusions
for nanopore sequencing. None of this prepared us for the revolution following Gleb Kuznetsov joining our lab in 2012, joined soon by Surge Biswas, Pierce Ogden, Ethan Alley, and Sam Sinai. Together we abruptly moved to "sequence-only", deep machine learning for protein design -- ranging from fluorescent proteins to AAV capsids to antibodies. When combined
with libraries of millions of designed gene segments from chip-synthesis and rapid testing, each design cycle can take large leaps in sequence space and function space.

4:40 pm

The Case for Intelligent Design in Protein Engineering

Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University

Directed evolution is in its prime, and it is deepening our understanding of biological systems and empowering therapeutic design. Recent breakthroughs in structural biology, computational design, and high-dimensional data analytics afford us the unprecedented opportunity to apply molecular, structural, and computational principles to guide protein engineering, employing a so-called “intelligent design” approach. This talk will highlight how my lab harnesses this interfacial approach to overcome the deficiencies of natural proteins.

5:15 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
Panelists:
George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School
Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University
5:35 pm Happy Hour - View our Virtual Exhibit Hall
6:10 pm Close of Day

Tuesday, September 1

EMERGING MODALITIES

9:05 am

siRNA-mAb Conjugate Analysis: To Ioinise in Positive or Negative ESI Mode, That Is the Question

Iain Campuzano, Principal Scientist, Discovery Attribute Sciences, Amgen

Antibody-drug conjugates are important classes of molecules currently being used to treat multiple diseases. Advances in small-interfering RNA (siRNA) technology result in numerous RNAi-based therapies being pursued in clinical trials. Herein we present how native nESI-MS, in both positive and negative polarities, is the only bona fide analytical method for accurate intact MW and RAR (RNA-to-antibody ratio) calculation for siRNA-mAb conjugates.

9:25 am

Characterization of Conditionally Activating Biologics

Wendy Ritacco, Principal Research Scientist I, Global Biologics, AbbVie Bioresearch Center

Bispecific conditional dual variable domain immunoglobulins (cDVD-Igs) are targeted and locally activated biologics that offer new prospects for engineering efficacy, while minimizing systemic side effects. We will describe preclinical examples of tissue targeting and activation in in vivo disease models as part of a new generation of locally acting “regio-specific” biologics therapies.

9:45 am

Overcoming Challenges in Co-Formulation of Therapeutic Proteins with Contradicting Stability Profiles

Dennis Krieg, Graduate Student, Pharmacy, Ludwig Maximilians University

In this talk, we present our work on co-formulation of the model proteins, EPO and G-CSF, which are interesting from both clinical and physicochemical perspectives. These cytokines differ a lot in their structure and respective stability profile, so obtaining a stable co-formulation of both proteins in one solution is challenging. We present a systematic approach to study and stabilize these two physicochemical, very different therapeutic proteins in one formulation.

10:10 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Iain Campuzano, Principal Scientist, Discovery Attribute Sciences, Amgen
Panelists:
Dennis Krieg, Graduate Student, Pharmacy, Ludwig Maximilians University
Wendy Ritacco, Principal Research Scientist I, Global Biologics, AbbVie Bioresearch Center
10:30 am Coffee Break - View our Virtual Exhibit Hall

DEVELOPABILITY ANALYSIS

11:10 am

Developability As A Tool For Risk Mitigation In Early Drug Discovery

Christina G. Palmer, Scientist I, Antibody Discovery, Biogen

We will present several case studies following the developability assessment of our preclinical to commercial pipeline. These case studies will illustrate how the evolving field of developability can help inform antibody selection and progression through development. We will highlight several examples of red flags and red herrings in developability and shed light on some of the underlying mechanisms and how they relate to antibody development.

At Sanofi, we use peptide mapping to perform deep characterization of innovative multispecific biotherapeutics. We developed a custom data processing workflow that enables us to extract the maximum amount of molecular information from our biotherapeutic candidate molecules and created a knowledge base that allows us to leverage the insights gained throughout a molecule’s lifecycle for future analyses and development.

Arnd Brandenburg, PhD, Head, Professional Services, Genedata Expressionist, Genedata
Soraya Hoelper, PhD, Lab Head, Mass Spectrometry, Protein Therapeutics, Research & Development, Biologics, Germany, Sanofi-Aventis Deutschdland GmbH
11:55 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Christina G. Palmer, Scientist I, Antibody Discovery, Biogen
Arnd Brandenburg, PhD, Head, Professional Services, Genedata Expressionist, Genedata
Soraya Hoelper, PhD, Lab Head, Mass Spectrometry, Protein Therapeutics, Research & Development, Biologics, Germany, Sanofi-Aventis Deutschdland GmbH
12:15 pm Lunch Break - View Our Virtual Exhibit Hall
2:45 pm Close of Characterization for Novel Biotherapeutics





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