Protein Aggregation & Stability

Aggregates and particles are redefining the way companies and regulators approach a molecule – from determining its developability to deciding its formulation. This is because aggregation impacts stability which may affect safety and efficacy and cause immunogenicity.

Thus the study of protein aggregation, particles and sub-visible particles, have become of increasing importance in recent years. The mechanisms of aggregation formation, and its impact on developability and formulation, have become the subject of much study and discussion. Scientists will share aggregation kinetics aimed at understanding the causes of aggregation, while highlighting analytical and formulation strategies targeted at optimizing stability and controlling aggregation.

Final Agenda

TUESDAY, MARCH 28, 2017

7:30 am Registration and Morning Coffee


PLENARY KEYNOTE SESSION

8:50 Chairperson’s Opening Remarks

Zhenping Zhu, Ph.D., Executive Vice President, Global Biologics R&D, Kadmon Corp, LLC

Mitchell Ho9:00 Engineering Single-Domain Antibodies for Cancer Therapy

Mitchell Ho, Ph.D., Senior Investigator, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health

Antibodies have a major role in cancer treatment. For increased efficacy, antibodies can be designed to inhibit signaling pathways responsible for cancer development. By decreasing antibody size, cryptic or buried functional regions in receptors can be targeted. There is also a need to identify new therapeutic targets in cancer.

Xiangyang Zhu9:30 Antibody Drug Developments: Biosimilar vs Innovation – Finding a Way to Meet the Needs in China

Xiangyang Zhu, Ph.D., CEO, Huabo Biopharma (Shanghai) Co., Ltd.

A landscape for antibody development in China will be discussed, especially on the pros and cons between biosimilar and innovative drugs. This presentation will also explore strategies to meet China’s medical needs; and discus how companies can generate profits given the competitive drug development landscape.


10:00 Coffee Break

10:35 Chairperson’s Remarks

Joy Zhou, Ph.D., Principal Scientist/Associate Director, DP MST, Shire

CHALLENGES IN PROTEIN STABILITY

10:40 Oxidative Post-Translational Modification - Impact on Stability and Formulation of Protein Therapeutics

Christian_SchoeneichChristian Schoeneich, Ph.D., Takeru Higuchi Distinguished Professor and Chair, Pharmaceutical Chemistry, University of Kansas

Antibodies are target for a large variety of chemical degradation reactions during processing and storage. This presentation will provide new examples, where forced and long-term degradation studies have led to the characterization of novel degradation products. Experimental evidence for the effect of glycoform diversity and antibody-drug conjugation on the chemical degradation of antibodies will be presented.

11:10 Heavy Chain of Mouse IgM Can Be Cleaved between CH1 and CH2 Domains by a Protease Present in Serum

Tomasz_KlausTomasz Klaus, MSc., Research Assistant, Malopolska Centre of Biotechnology, Jagiellonian University in Krakow

During research on IgM stability we discovered that N-terminal part of a mouse IgM heavy chain can be cleaved off by a factor present in serum. We identified the sequence prone to fragmentation and developed mutated molecules which are resistant to N-terminus trimming. Importantly, we observed that IgM fragmentation occurs in blood typing reagents and it reduces their shelf life. Thus, the mutated IgMs may become novel highly stable diagnostic reagents.

11:40 Issues to be Considered During Protein Biopharmaceutical Formulation Development and Process Technology Transfer

  Li Shi, Ph.D., CEO, Zerun Biotechnology

Unchained Labs 12:10 Biologic Stability Cranked Up to 11
Lucas_HuangLucas Huang, Field Application Scientist, Unchained Labs 
Biologic stability characterization traditionally requires juggling disjointed data from multiple instruments. UNcle reduces these complications and conserves samples by combining fluorescence, SLS, and DLS detection modes in one instrument.This enables 11 different protein characterization applications, and allows for sizing, polydispersity, thermal melting, and aggregation data to be obtained at the same time from the same sample. We will demonstrate how UNcle can thoroughly characterize more biologics and formulations quickly and easily. 

12:40 Networking Lunch in the Exhibit Hall with Poster Viewing

2:00 Chairperson’s Remarks

Jennifer McManus, Ph.D., Lecturer, Department of Chemistry, National University of Ireland Maynooth

AGGREGATION FORMATION

2:05 Generating Artificial Aggregation-Associated Phenotype

Frederic Rousseau, Ph.D., Professor and Principal Investigator, Cellular and Molecular Medicine, VIB Switch Lab/University of Leuven

We present a method by which specific aggregation-associated phenotypes can be generated by inducing misfolding of endogeneous proteins using artificial peptides bearing aggregation prone sequences of the target protein. As a proof-of-concept we here show how targeted protein aggregation can be used to generate antitumoral and antimicrobial peptides but also transgenic plants.

2:35 Determinant Factor for Aggregation and Fragment Formation: Oxidation

Joy_ZhouJoy Zhou, Ph.D., Principal Scientist/Associate Director, DP MST, Shire

Formation of aggregation and subsequent subvisible particles is a major concern to develop subcutaneous biotherapeutics and understanding of its formation mechanism is challenging. Employing various biophysical techniques for structure integrity and physical/chemical testing enabled us to understand that oxidation can lead to formation of both soluble and insoluble aggregates, and subsequent formation of subvisible particles. Furthermore, the fragmentation is identified as a parallel degradation mechanism to aggregation/particle formation. More interestingly, a high concentration formulation exhibited much less degradation than the diluted one under this degradation mechanism.

3:05 Aggregation Analysis at High and Low Concentrations

Jennifer_McManusJennifer McManus, Ph.D., Lecturer, Department of Chemistry, National University of Ireland Maynooth

Aggregation of proteins may occur by a number of different mechanisms, which can lead to a range of aggregate types. Using a range of analytical techniques, the formation of protein aggregates by various mechanisms has been assessed at low and where possible, at moderate to high protein concentrations. The effect of sugars on protein stability will also be discussed.

3:35 Aggregation Mitigation or Remediation of Engineered Antibodies

John Kawooya, Ph.D., Director, Biologics Optimization, Amgen Inc.

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

SOLUBILITY CHALLENGES

4:45 Specific Ion−Protein Interactions Dictate Solubility Behavior of a Monoclonal Antibody

Jifeng Zhang, Ph.D., Senior Director, Global Head of Device-ability, Global Biotherapeutics, Sanofi US

5:15 Modified Phosphate Buffered Saline (PBS) as a Viable Vehicle for Biotherapeutic Drugs

Tatyana_MezhebovskyTatyana Mezhebovsky, Ph.D., Principal Scientist, BioFormulations, Sanofi US

Phosphate buffered saline (PBS) is the most inert and neutral composition for biotherapeutics, however, notorious for freeze thaw instability, which makes a normal product life cycle for liquid formulations products virtually impossible. As lyophilization requires initial freezing of the protein solution, PBS is not suitable for lyo products. Here we present a systematic approach to PBS modification to render it a high quality vehicle for protein and potentially gene therapy products.

5:45 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 Close of Day One

WEDNESDAY, MARCH 29, 2017

8:30 Registration and Morning Coffee

8:50 Chairperson’s Opening Remarks

Mark Yang, Ph.D., Director, Fill Finish Operations, Biopharmaceutical Development, Genzyme

AGGREGATION CHALLENGES DURING FORMULATION

9:00 Protein Aggregation during Formulation and Drug Product Manufacturing and Mitigation Strategies

Mark_YangMark Yang, Ph.D., Director, Fill Finish Operations, Biopharmaceutical Development, Genzyme

Proteins are subjected to many different forms of stresses, including agitation, freeze/thaw, light exposure, and oxidation, during formulation and fill finish operations. These stresses can destabilize protein and compromise drug product quality. Common stress factors and the corresponding mitigation strategies to minimizing protein aggregation during these processes will be discussed.

9:30 Protein Aggregation: A Technical Challenge of Protein Drug Development and Manufacturing

Guangliang Greg Pan, Ph.D., Vice President, Technical Operations/CMC, MabSpace Biosciences (Suzhou) Co., Ltd.

Protein aggregation is one of the most critical stability concerns of protein drug development and manufacturing. This presentation will mainly cover the causing factors of and control strategies for protein aggregation during protein formulation development, manufacturing process, and clinical use. Several case studies will be included.

LIFE CYCLE MANAGEMENT OF ANALYTICAL SYSTEMS  

 10:00 Life Cycle Management of Analytical Control System Post Approval, A Practical Perspective

Sherry_GuoSherry Guo, Ph.D., Head, Global MMTech, Analytical Chemistry and Life Cycle Management, Biologics QC Network (PTQBQ), Genentech, a member of Roche Group



 

10:30 Coffee Break in the Exhibit Hall with Poster Viewing

 

11:10 Poster Spotlight

Poster I: Monoclonal Antibodies Targeting Intrinsically Disordered Peptide Segment

Carmay Lim, Ph.D., Distinguished Research Fellow/Professor, Institute of Biomedical Sciences, Academia Sinica

IgE mediates hypersensitivity reactions responsible for most allergic diseases, which affect 20-40% of the population in developed countries. A 52-residue domain of membrane-bound IgE (mIgE) called CεmX is currently a target for developing therapeutic antibodies, but its structure is unknown. Here we show that two antibodies with therapeutic potential in IgE-mediated allergic diseases, which can cause cytolytic effects on mIgE-expressing B lymphocytes and down-regulate IgE production, target different conformations of an intrinsically disordered region (IDR) in the extracellular CεmX domain. This work provides an important example of antibodies targeting an extracellular IDR of a receptor on the surface of intended target cells as well as fundamental structural characteristics unique to human mIgE. It would stimulate further studies to investigate whether other monoclonal antibodies targeting intrinsically disordered peptide segments or vaccine-like products targeting IDRs of a membrane protein can be developed.

Poster II: An Integrated Approach for the Discovery of Functional Anti-Human ICAM-1 Antibodies

Wei Zhang, Ph.D., Research Associate Professor, Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University 

In the present study, by autocrine screening, we discovered a series of anti-human ICAM-1 antibody which can prevent rhinovirus induced cytopathic effect with varying efficacy. The most potent selected antibody was further optimized by yeast surface display to an efficacy equal to that of 14C11, an anti-human ICAM-1 antibody evaluated in several preclinical models. Moreover, in vitro ICAM-1/LFA-1 interactions that accounts for leukocyte activation and transmigration was not interrupted, implying the safety of this antibody on prevention of rhinovirus infections. By such a combined approach of in vitro display technologies and autocrine-based screening, antibodies with therapeutic interests can be discovered more efficiently.

11:40 Roundtable Discussion Session

Join your peers and exchange ideas and experiences in a lively and interactive discussion.

Topic: Differentiation of Antibody-Based Therapeutics

Moderator; Xueming Qian, Ph.D., Chairman & CEO, MabSpace Biosciences (Suzhou) Co., Ltd.

 

Topic: Enzyme Therapeutics: Challenges for Monitoring, Improving and Preserving Catalytic Activities

Moderator: Manfred Konrad, Ph.D., Head, Enzyme Biochemistry Laboratory, Max Planck Institute for Biophysical Chemistry

Biochemical assays and parameters essential for comparison of catalytic activities of enzymes from different sources

Critical quality attributes for the intactness of recombinantly produced enzymes as compared to the ones from natural sources

Should we put efforts into in vitro-evolution of catalytically poor enzymes of human origin, rather than developing strategies for mitigating immunogenicity of catalytically efficient microbial enzymes?

Tools of material science and nanotechnology for improving activity and stability of  therapeutically established protein drugs

 

Topic: Novel Biologics for Cancer Immunotherapies - Design and Development Strategies

Moderator: Jinming Gu, Ph.D., Executive Director, Biologics Discovery, Shanghai Hengrui Pharmaceutical Co. Ltd.

-What are the best bispecific platforms on the market?

-What target pairs shall we choose for cancer immunotherapies?

-Can ADC be applied for cancer immunotherapies?

- What else shall we consider, e.g. PK, ADCC, Glycosylation? 

 

Topic: Antibody Display Libraries

Moderator: Eunice Zhou, Ph.D., Associate Adjunct Professor, Anesthesia, UC San Francisco  

 

Topic: Strategies and Challenges of Analytical Control Strategy Life Cycle Management

Moderator: Sherry Guo, Ph.D., Head, Global MMTech Analytical Chemistry and Life Cycle Management, Genentech, a member of the Roche Group

 

12:40 Networking Lunch in the Exhibit Hall with Poster Viewing

2:00 Close of Protein Aggregation & Stability

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Celebrating 25 Years


Track 1

Protein & Antibody Engineering

Track 2

Protein Aggregation & Stability

Track 3

Immuno-Oncology

Track 4

Analytical Characterization of Biotherapeutics