The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

  • LOG IN
  • BECOME A MEMBER
  • About
    • Mission & Activities
    • Directors and Officers
    • Marketing & Promotions
    • The Antibody Society’s Committees
      • Meetings Committee
      • AIRR Community Working Groups & Sub-Committees
    • Sponsors & Partners
  • Society meetings
    • Computational Antibody Discovery: State of the Art
      • Computational Antibody Discovery Symposium Participants
    • Harnessing Cytokines for Cancer Immunotherapy Symposium
    • Biopharmaceutical Informatics Symposium
    • Emerging Cancer Therapies Leveraging Gamma-Delta Effector T cells Symposium
    • Emerging Immunotherapeutics for Ovarian Cancer Symposium
    • AIRR Community Meetings
    • Antibody Engineering & Therapeutics (US) 2024
      • 2022 Antibody Engineering & Therapeutics
      • 2020 Antibody Engineering & Therapeutics
      • 2019 Antibody Engineering & Therapeutics
      • 2018 Antibody Engineering & Therapeutics
      • What is INN a Name?
        • INN issue updates
    • Antibody Engineering & Therapeutics Europe 10 – 12 June, 2025 | Congress Center, Basel Switzerland.
      • Scientific Advisors, Antibody Engineering & Therapeutics Europe
    • FOCIS Symposia
  • AIRR Community
    • AIRR Community News
    • AIRR Community Newsletter
    • AIRR Community Seminar Series
    • AIRR Community Meetings
      • Zooming into the Community III
      • AIRR Community Meeting VII – Learnings and Perspectives
      • AIRR Community Special Event 2023  – Zooming in to the Community II
      • AIRR Community Meeting VI: “Exploring New Frontiers”
      • AIRR Community Meeting V: “Zooming in to the AIRR Community”
      • AIRR Community Meeting V Pre-Meetings
        • AIRR-seq in the Pandemic
        • AIRR-seq Biological Standards and Workflows
      • AIRR Community Special Event: “Response to COVID-19”
      • AIRR Community Meeting IV: “Bridging the Gaps”
      • AIRR Community Meeting III
        • Day 1
        • Day 2
        • Day 3
        • Day 4
      • AIRR Community Meeting II
      • AIRR Community Meeting I
    • On AIRR – An AIRR Community Podcast
    • AIRR Data Commons
    • AIRR-C Germline Database Resources
    • AIRR Community Publications
    • AIRR Community Working Groups
      • Biological Resources Working Group
      • Common Repository Working Group
      • Diagnostics Working Group
      • Germline Database Working Group
      • Legal and Ethics Working Group
      • Software Working Group
      • Standards Working Group
    • AIRR Community Sub-Committees
      • Communications Sub-Committee
      • Executive Sub-Committee
      • Inferred Allele Review Committee
      • Meetings Sub-Committee
      • Strategic Planning Sub-Committee
    • AIRR Community Webinar Series
    • AIRR Community Calendar
    • AIRR Community Resources
  • Members only
    • Login
    • Note to members
    • Member discount codes
    • 2025 Calendar of Events
    • James S. Huston Antibody Science Talent Award
      • 2024 James S. Huston Antibody Science Talent Award Recipient
      • 2023 James S. Huston Antibody Science Talent Award Recipient
      • 2022 James S. Huston Antibody Science Talent Award Recipient
      • 2021 James S. Huston Antibody Science Talent Award Recipient
      • 2020 James S. Huston Antibody Science Talent Award Recipient
      • Huston Award submission guidelines
    • Research Competitions
      • Research Competition Winners
    • Science Writing Competition
      • Science Writing Competition Winners
    • Imaging Competition
      • Imaging Calendar Competition winners
        • The Antibody Society 2025 Calendar
        • The Antibody Society 2024 Calendar
    • Antibodies in early-stage studies
    • Presentations
  • Upcoming meetings in 2025
  • Web Resources
    • Society Publications
    • Antibody News
    • Antibody News Podcast
    • Antibody therapeutics approved or in regulatory review in the EU or US
      • Antibody therapeutics product data
    • Antibodies in late-stage clinical studies
    • Research Resources
    • Education Resources
  • Career Center
    • Career Shorts
  • Learning Center
    • Upcoming Webinars in 2025
    • The Antibody Series Lectures
    • Antibody Discovery & Development
    • Adaptive Immune Receptor Repertoires
    • Antibodies to Watch
    • Commercializing Antibody Therapeutics
    • Antibody Validation
      • 4th International Antibody Validation Meeting, Sep 2023
    • Snakebite antivenoms: Global challenges and progress toward recombinant antibody therapeutics
You are here: Home / Manufacturing / Molecular Biology Can Improve Antibody Drug Developability

Molecular Biology Can Improve Antibody Drug Developability

March 16, 2020 by Janice Reichert

Contributed by  Nick Hutchinson, FUJIFILM Diosynth Biotechnologies

The discovery and development of antibody therapeutics often adheres to a series of stages starting with target identification and progressing through lead generation, lead optimization, then testing in preclinical and clinical studies. Molecular biologists engineer antibodies during lead generation and optimization to improve a range of characteristics, including antibody specificity and potency, or to reduce immunogenicity and the rate of elimination from the body (1).

Next-generation antibody biopharmaceuticals include bispecifics, glyco-engineered antibodies and antibody-fusion proteins with complex architectures. While drug development scientists may use antibody engineering techniques to generate candidates with very desirable or improved functional properties, at the same time, these can alter the biochemical, biophysical and in vivo properties of the antibody candidate, which can be detrimental to the overall target product profile (2). Engineering antibodies to improve their functional properties is frequently performed without consideration for the subsequent developability, including manufacturability, of the molecule. These issues are then often identified at a relatively late stage in the discovery process, after substantial resources have been invested in the molecule and, therefore, can have a real financial impact on drug development companies that may be being kept alive by funding from investors.

Ideally, antibody therapeutics should be capable of being manufactured with high productivity and at high quality with low protein heterogeneity. From a developability perspective, it is preferable if they express to high titer from the mammalian cell expression system and are stable during production storage and delivery (1). Some antibody candidates can exhibit a propensity to partially unfold, revealing hydrophobic patches that are more normally buried inside the molecule. Once revealed, the patches can interact with one another, leading to aggregation. Other liabilities that reduce developability include low solubility, unstable amino acids, clipping and antibody fragmentation (1). These can be sufficiently severe that projects can be cancelled due to poor toxicology data and concerns around whether the candidate can be safely administered to patients during clinical trials.

One solution, advocated by investigators from Roche (2), is to assess developability during antibody drug discovery. Their workflow incorporates two separate assessments, the first following the initial candidate screening and selection and the second following humanization and re-engineering, but before the selection of the clinical lead. During the first phase of the assessment, complementarity-determining regions are analysed in silico for potential liabilities such as degradation sites. This can be followed by studies on stressed samples, with samples incubated at elevated temperatures for two weeks. Stable candidates can progress to the next stage or drug development scientists can use humanization and protein re-engineering to remove the identified liabilities. The second phase, which follows humanization, again employs in silico tools but evaluates the whole humanized molecule and assesses potential hotpots where post-translational modification, charge variations or degradation might occur. Researchers then perform a second stress test for the most likely or detrimental liabilities. During this phase, they can include tests for self-interaction and aggregation, such as apparent hydrophobicity by hydrophobic interaction chromatography, thermal stability by dynamic light scattering (DLS), protein-protein self-interaction by DLS and viscosity at high concentration by DLS with latex beads (2).

Other groups have gone further, and not only select for candidates with properties that limit manufacturing and storage risks, but also apply molecular engineering techniques in order to improve manufacturability proactively. For example, in 2019, a team from AstraZeneca described manufacturing challenges they encountered during downstream purification of an antibody that was undergoing liquid-liquid phase separation (3). This in turn resulted in the need for longer mixing times that can be damaging for proteins, yield losses, increases in pressure during processing and misleading analytical results from in-process samples. The team attempted to resolve the problem by optimize the bioprocessing conditions, but there were still substantial limitations to large-scale manufacturing. To fix the problem, they used in silico homology modelling and charged-patch analysis to identify problematic residues, and this ultimately lead them to substitute charged residues with those with a neutral or opposite charge. Their research showed that these substitutions minimized electrostatic interactions and allowed them to engineer a variant that maintained antigen-binding affinity, but eliminated the liquid-liquid phase separation behaviour.

The molecular engineering of therapeutic antibodies is allowing development of candidates with ever improved functional properties. However, researchers should consider, where possible, the impact of this engineering on the biochemical and biophysical characteristics of the molecule, which can have a negative effect on the developability of lead candidates. Incorporating screens for developability during drug discovery workflow can help eliminate candidates with liabilities that will prevent them from being successful drugs. The more sophisticated developers of antibody therapeutics are cleverly applying molecular biological techniques to improve the stability and manufacturability of their monoclonal antibody leads.

(1) Chiu, M.L. & Gilliland, G.L. (2016) Engineering antibody therapeutics. Current Opinions in Structural Biology, 38: 163-173.

(2) Jarasch, A., Koll, H., Regula, J.T., Bader, M., Papadimitriou, A. & Kettenberger, H. (2015) Developability assessment during the selection of novel therapeutic antibodies. Journal of Pharmaceutical Sciences, 104:1885-1898.

(3) Du, Q., Damschroder, M., Pabst, T.M. Hunter, A.K., Wang, W.K. & Luo, H. (2019) Process optimization and protein engineering mitigated manufacturing challenges of a monoclonal antibody with liquid-liquid phase separation issues by disrupting inter-molecule electrostatic interaction. MAbs, 11 (4): 789-802.

The Antibody Society is an authoritative source of information about antibody therapeutics development. We are pleased to provide original posts and news summaries on our homepage, as well as semi-monthly summaries of recent news to our members.  Archived news from 2019 can be found in the Web Resources section of the Society’s website.

Filed Under: Antibody discovery, Antibody therapeutic, Manufacturing Tagged With: antibody therapeutics, developability, manufacturing

Share this post

  • LinkedIn

mabs

mabs

The Official Journal of The Antibody Society

Career Center

Our Career Center is a premier resource to connect highly qualified talent with matching career opportunities. Visit for details on over 800 jobs!

AIRR Community

AIRR Community

The Adaptive Immune Receptor Repertoire Community is a research-driven group organizing around the use of high-throughput sequencing technologies to study antibody/B-cell and T-cell receptor repertoires.

Recent Posts

  • Zooming into the Community III Starts Tomorrow! May 20, 2025
  • Exciting news – The AIRR Community is turning 10! 🎂 May 8, 2025
  • The Antibody Society (TAbS): Win a FREE Attendance Pass to AET Basel & Present A Poster: Call For Abstracts! March 26, 2025

Archives

Follow us online

  • Email
  • LinkedIn
  • Twitter
  • YouTube
  • Home
  • Privacy & Terms of Use
  • About
  • Directors and Officers
  • Advisors
  • Sponsors & Partners
  • Mission & Activities
  • Join the Society
  • Membership Levels
  • Members only
  • Login
  • Antibody therapeutics approved or in regulatory review in the EU or US
  • Meeting reports
  • Presentations
  • Contact

©2015 - scicomvisuals