Streamlining Discovery and Reducing Development Risks
Bispecific antibodies (bsAbs) offer great therapeutic potential but pose development challenges. A thorough developability assessment at the discovery stage evaluates key properties like manufacturability, stability, and efficacy. This early evaluation helps identify risks, reduce development failures, and ensure only the most promising bsAb candidates advance, increasing the likelihood of creating safe, effective, and manufacturable therapies.
Bispecific antibodies (bsAbs) offer great therapeutic potential but pose development challenges. A thorough developability assessment at the discovery stage evaluates key properties like manufacturability, stability, and efficacy. This early evaluation helps identify risks, reduce development failures, and ensure only the most promising bsAb candidates advance, increasing the likelihood of creating safe, effective, and manufacturable therapies.
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A robust developability assessment study (DAS) involves a series of stress tests and evaluations. Typical stress conditions include freeze-thaw cycles, exposure to oxidative agents, temperature variations, and pH extremes. Each condition is carefully monitored over defined time points, with specific analytical tests conducted to assess structural integrity, potency, and stability.
A four-week study plan and stress conditions given to the BsAb candidates.
Repeated freezing and thawing to evaluate protein stability.
Exposure to 1% tBHP at 25°C for 24 hours to assess oxidative degradation.
Exposure to 25°C and 40°C for up to four weeks, with regular sampling.
Exposure to pH 3.5 and pH 9.5 for up to 24 hours to evaluate acid/base stability.
Optional testing under 5000lx light for up to ten days to simulate light-induced degradation.
These stress conditions provide critical insights into the long-term stability and resilience of bsAb candidates, guiding selection and formulation strategies.
A wide range of analytical techniques are employed to evaluate the physical and chemical properties of bsAb candidates during the developability assessment. Some of these include:
For assessing aggregation and purity.
For evaluating protein degradation and heterogeneity.
For detecting post-translational modifications and confirming molecular weight.
To confirm biological activity and binding capacity.
For assessing charge heterogeneity and isoform distribution.
A stability assessment using the UNCLE platform involves evaluating the thermal and colloidal stability of two bsAb candidates.
Parameters such as melting temperature (Tm), aggregation onset temperature (Tagg), and initial particle diameter provide valuable data for determining the resilience of each candidate to thermal stress and potential aggregation under physiological conditions.
Analysis of Different Species for Lead-1 Stress Samples by iCIEF (Imaged Capillary Isoelectric Focusing)
Incorporating a developability assessment early in the discovery stage of bispecific antibody development is essential for identifying and mitigating potential risks. By evaluating key parameters such as productivity, solubility, stability, and immunogenicity, researchers can make informed decisions about candidate selection, reducing the likelihood of failure during later stages of development. This process saves time and resources and increases the chances of delivering safe, effective, and manufacturable therapies to patients.
1. What is a bispecific antibody?
A bispecific antibody is a type of engineered antibody designed to simultaneously bind two different antigens, offering a unique mechanism of action for therapeutic purposes.
2. Why is developability assessment important?
Developability assessment helps identify potential challenges such as stability issues, immunogenicity, and manufacturability risks, which can impact the success of a therapeutic candidate.
3. What is thermal stability, and why is it important?
Thermal stability refers to a protein’s ability to remain structurally intact at varying temperatures. It is crucial to ensure that bispecific antibodies are effective during storage and administration.
4. How is aggregation measured in bispecific antibodies?
Aggregation is typically measured using size-exclusion chromatography (SEC), which separates aggregated species from monomeric forms of the protein.
5. What is the role of post-translational modifications in bispecific antibody development?
Post-translational modifications can alter the function, efficacy, and safety of bispecific antibodies. Monitoring PTMs is critical to ensure that the therapeutic maintains its intended activity.
6. How do pH and temperature affect bispecific antibodies?
Extreme pH and temperature conditions can cause bispecific antibodies to degrade, lose efficacy, or aggregate. Stress testing under these conditions helps identify candidates that are stable and resilient.
1. Productivity and Solubility
2. Aggregation
3. Stability
4. Heterogenicity
• LC-MS, CE To evaluate the uniformity of bsAbs, ensuring consistent quality and performance.
5. Post-Translational Modifications (PTMs)
• LC-MS and CE to identify and characterize PTMs of bsAbs to ensure maintaining functional integrity.
6. FcRn Binding
• SPR (Surface Plasmon Resonance) or BLI (Biolayer Interferometry) to measure the interaction of bsAbs with the neonatal Fc receptor, which influences their half-life and pharmacokinetics.
7. Viscosity and Hydrophobicity
8. PK Fitness
9. Immunogenicity Risk Assessment
Beacon® single B cell screening
Display technology
CAR-function based functional screening
Hybridoma
HCAb direct cloning screening
TCR Mimic Antibody
Functional characterization
Binding / Affinity
Antibody production
In vitro functional assay
Developability
Protein
Cell line
DNA
mRNA
Target assessment
Recombinant protein
Recombinant cell-line
Affinity maturation ▶
Humanization▶
Fc-Engineering▶
Structure-Based Protein Design
▶
Stable cell line
Process development
Manufacture
PK / PD
Efficacy
ADA
TOX
Dr. Jingsong Wang is Chairman of Nona Biosciences. Prior to that, Dr. Wang served as Head of China R&D and Head of Translational Medicine, Asia Pacific, at Sanofi. He is a former attending physician and clinical fellow at Harvard Medical School. Dr. Wang received his Ph.D. in Molecular Pharmacology from China Pharmaceutical University and has also completed a Molecular Immunology Research Fellowship at Dr. Laurie Glimcher’s laboratory at the Harvard School of Public Health.
Dr. Yiping Rong is our Chief Scientific Officer. He is a well-recognized scientist with about 20 years’ experience of biomedical research and drug discovery. Dr. Rong used to work at Sanofi, JNJ and Roche and built strong expertise in cancer biology and pharmacology. He led and contributed to >15 programs entering clinical trials. He is also involved in translational research work for a few drugs. Multiple mAb or bispecific antibodies generated from his team were out licensed to MNCs. Some highly innovative first-in-class projects are in clinical trials. He worked on apoptosis, epigenetics, immuno-oncology, and cancer cell signaling fields and led the drug discovery projects including kinase, enzyme, receptor/ligand, protein-protein-interaction targets by small molecules or monoclonal antibodies. Dr. Rong received his Ph.D. degree in Pharmacology from Case Western Reserve University (Cleveland, Ohio). He is the member of American Association of Cancer Research and has more than twenty publications in cancer research field, including Nature Genetics, Molecular Cell, PNAS papers. He is also the inventor of dozens of patents in drug discovery field.
Dr. Jiyong Zhang leads business development at Nona Biosciences, bringing vision and dedication to strategic growth and client satisfaction. With 15 years of experience in biotherapeutic research and development, Dr. Zhang’s understanding of market dynamics and ability to identify mission-aligned opportunities are evident.
Before overseeing business development at Nona, Dr. Zhang played key roles at Alexion and Abbvie, contributing to antibody discovery, engineering, and bispecific antibody R&D. His scientific experiences and knowledge in biotherapeutic innovation makes him a forward-thinking strategist focused on enhancing service offerings to meet evolving client needs.
With Dr. Zhang and his team driving business development, Nona Biosciences is poised to offer innovative solutions and unparalleled service. This solidifies the company’s position as a trusted and client-focused drug discovery partner in the dynamic landscape of biotherapeutic innovation.
Dr. Joe Zhao is Vice President and Head of External Innovation of Nona Biosciences. Joe holds a BS from Fudan University and a PhD from University of Delaware, followed by postdoctoral trainings at Lankenau Medical Center and Zeneca Pharmaceuticals. Prior to joining Harbour BioMed, he was in small biotechs (Pharmacopeia and Ligand Pharmaceuticals) and large MNC (BMS). Joe has 25 years of combined experience in drug discovery of both small molecules and biologics in therapeutic areas of immuno-oncology, immunology, and genetic diseases.
Mr. Louis Liu is Senior Vice President and Head of Scientific Operation of Nona Biosciences. He graduated from Bethune Medical University with Bachelor Degree of Medicine. He has over 30 years’ experience in antibody technology platform establishment, antibody discovery and discovery team management experience. Previously he worked in Syntron Bioresearch Inc as R&D manager, Strategic Diagnostic Inc as product development supervisor, Rockland Immunochemical Inc as Manager of Monoclonal Antibody service and product development, GenScript Ltd as vice president of Antibody Division, Shanghai ChemPartner as vice president of Biologics Discovery.
Dr. Yun He is Chief Technology Officer of Nona Biosciences. Before Nona Biosciences spun off from Harbour BioMed, Dr. He served as Head of Antibody Technology at Harbour BioMed. During his tenure there, Dr. He contributed to multiple discovery programs and led the team in establishing HBICE® platform. Prior to joining Harbour BioMed, Dr. He was an Investigator at Biologics Center in Novartis, where he was responsible for antibody engineering and bioinformatics. Prior to that, Dr. He was the group leader of Bioinformatics at GenScript. Dr. He received his Ph.D. from the Chinese Academy of Sciences, with a focus on molecular biology and bioinformatics.
Dr. Musheng Bao earned his Ph.D. in China and completed his postdoctoral training at MD Anderson Cancer Center and Baylor Institute for Immunology Research. Beginning his professional journey as a Scientist II at MedImmune, Dr. Bao later transitioned to Sanofi, where he served as a Principal Scientist. Following this, he joined Harbour BioMed, where he led a team dedicated to therapeutic antibody development utilizing the Harbour Mice® platform. Presently, Dr. Bao has taken on the role of Head of Biology at Nona Biosciences.
Dr. Arkinstall has demonstrated remarkable competence throughout his career. He is a respected leader in drug discovery with substantial roles under his belt, including Research Head, Chief Scientific Officer (CSO), and Chief Executive Officer (CEO) positions at various pharmaceutical or biotech companies. Dr. Arkinstall served as CEO of Elstar Therapeutics and Revitope Oncology, companies advancing novel classes of multi-specific antibody-based cancer drugs. He previously was also the CSO of Kymab, an antibody therapeutics company founded in Cambridge, UK, prior to which he spent 16 years in progressively senior research leadership roles at EMD (Merck) Serono, and its associated entities across Europe and the United States.
Dr. Grosveld is Co-founder and CSO of Harbour Antibodies and the inventor of Harbour Mice®, Professor and former Head of Department of Cell Biology and Department of Clinical Genetics at Erasmus University Medical Center, Rotterdam, a fellow of Royal Society and a member of Royal Netherlands Academy of Arts and Sciences. Dr. Grosveld’s research on the control of globin gene expression has been selected as one of the top ten achievements of Medical Research Council (UK) (MRC) in the 20th century by Higher Education and Research Opportunities in the U.K. Dr. Grosveld was awarded the Louis-Jeantet Prize for Medicine in 1991, the Spinozapremie (Spinoza Prize) in 1995.
Dr. Kamen is a Venture Partner at Third Rock Ventures. In 2005, he co-founded BioAssets Development Corporation and served as its Chairman. He currently serves as an independent non-executive Director of Harbour BioMed and a director of Jounce Therapeutics (NASDAQ:JNCE). He was previously a director of Neon Therapeutics and Harbour Antibodies. Earlier in his career, he was senior vice president of scientific affairs at the pioneering biotechnology firm named Genetics Institute, Inc. Dr. Kamen received his bachelor’s degree in biophysics from Amherst College, a Ph.D. in biochemistry and molecular biology from Harvard University Graduate School of Arts and Sciences. During his academic scientific career, he worked at the Imperial Cancer Research Fund.
Dr. Kramer serves as CSO of Portage Biotech Inc. Dr. Kramer previously served as Vice President and Head of Discovery for Oncology Therapeutics at Janssen Research & Development, LLC (the Pharmaceutical Division of Johnson and Johnson), where he was responsible for leading Global Discovery, focusing on aberrant signaling cascades in tumor cells, as well as epigenetic reprogramming and tumor immunology using both small molecule and protein-based large molecule approaches. Prior to joining Janssen Research & Development, LLC, Dr. Kramer served as VP Drug Discovery and Research for Bristol-Myers Squibb (BMS), where he provided scientific leadership and strategic oversight for many pre-clinical Oncology and Immunology programs and projects that entered development. Dr. Kramer was previously an Assistant Professor at Harvard Medical School. Dr. Kramer received his Ph.D. in pharmacology from the University of Vermont and completed his post-doctoral fellowship in Oncology at the National Cancer Institute, National Institutes of Health.
Peter Moesta, Ph.D., oversaw the development, production and worldwide launch of important medicines, such as Humira, Yervoy and Opdivo. Dr. Moesta previously served in executive roles at Bristol-Myers Squibb.
Dr. Tian is an academician of Chinese Academy of Engineering, a member of Academia Europaea and a medical immunologist. Currently, he is a professor at University of Science and Technology of China (USTC), where he also works as Dean at School of Basic Medical Sciences, and Director at Institute of Immunology. He is also the Director of the Key Lab of Innate Immunity and Chronic Diseases of Chinese Academy of Science.
Dr. Tian was awarded with the National Science Fund for Distinguished Young Scholars. He is the academic leader of Chang Jiang Scholars Program as well as the Innovation Research Program of National Natural Science Foundation of China. Dr. Tian is Head of National Science and Technology Major Project and Chief Scientist of National Major Research Plan Program.
Dr. Tian’s laboratory is credited with seminal discoveries regarding basic knowledge and clinical study of natural killer (NK) cells, particularly liver-resident NK cells, cytokine-producing NK cells, and NK cell-based immunotherapy.
