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Integrated continuous biomanufacturing on pilot scale for acid-sensitive monoclonal antibodies.

ABSTRACT: In this study, we demonstrated the first, to our knowledge, integrated continuous bioprocess (ICB) designed for the production of acid-sensitive monoclonal antibodies, prone to aggregate at low pH, on pilot scale. A high cell density perfusion culture, stably maintained at 100 × 10⁶ cells/ml, was integrated with the downstream process, consisting of a capture step with the recently developed Protein A ligand, Z_Ca ; a solvent/detergent-based virus inactivation; and two ion-exchange chromatography steps. The use of a mild pH in the downstream process makes this ICB suitable for the purification of acid-sensitive monoclonal antibodies. Integration and automation of the downstream process were achieved using the Orbit software, and the same equipment and control system were used in initial small-scale trials and the pilot-scale downstream process. High recovery yields of around 90% and a productivity close to 1 g purified antibody/L/day were achieved, with a stable glycosylation pattern and efficient removal of impurities, such as host cell proteins and DNA. Finally, negligible levels of antibody aggregates were detected owing to the mild conditions used throughout the process. The present work paves the way for future industrial-scale integrated continuous biomanufacturing of all types of antibodies, regardless of acid stability.

SUBMITTER: Schwarz H

PROVIDER: S-EPMC9541590 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Integrated continuous biomanufacturing on pilot scale for acid-sensitive monoclonal antibodies.

Schwarz Hubert H Gomis-Fons Joaquín J Isaksson Madelène M Scheffel Julia J Andersson Niklas N Andersson Andreas A Castan Andreas A Solbrand Anita A Hober Sophia S Nilsson Bernt B Chotteau Veronique V

Biotechnology and bioengineering 20220507 8

In this study, we demonstrated the first, to our knowledge, integrated continuous bioprocess (ICB) designed for the production of acid-sensitive monoclonal antibodies, prone to aggregate at low pH, on pilot scale. A high cell density perfusion culture, stably maintained at 100 × 10<sup>6</sup> cells/ml, was integrated with the downstream process, consisting of a capture step with the recently developed Protein A ligand, Z<sub>Ca</sub> ; a solvent/detergent-based virus inactivation; and two ion- ...[more]

PMID: 35470430

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Project description:BackgroundCancer cells activate different immune checkpoint (IC) pathways in order to evade immunosurveillance. Immunotherapies involving ICs either block or stimulate these pathways and enhance the efficiency of the immune system to recognize and attack cancer cells. In this way, the development of monoclonal antibodies (mAbs) targeting ICs has significant success in cancer treatment. Recently, a systematic description of the mechanisms of action (MOA) of the mAbs has been introduced in IMGT/mAb-DB, the IMGT® database dedicated to mAbs for therapeutic applications. The characterization of these antibodies provides a comprehensive understanding of how mAbs work in cancer.MethodsIn depth biocuration taking advantage of the abundant literature data as well as amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, allowed to define a standardized and consistent description of the MOA of mAbs targeting immune checkpoints in cancer therapy.ResultsA fine description and a standardized graphical representation of the MOA of selected mAbs are integrated within IMGT/mAb-DB highlighting two main mechanisms in cancer immunotherapy, either Blocking or Agonist. In both cases, the mAbs enhance cytotoxic T lymphocyte (CTL)-mediated anti-tumor immune response (Immunostimulant effect) against tumor cells. On the one hand, mAbs targeting co-inhibitory receptors may have a functional Fc region to increase anti-tumor activity by effector properties that deplete Treg cells (Fc-effector function effect) or may have limited FcγR binding to prevent Teff cells depletion and reduce adverse events. On the other hand, agonist mAbs targeting co-stimulatory receptors may bind to FcγRs, resulting in antibody crosslinking (FcγR crosslinking effect) and substantial agonism.ConclusionIn IMGT/mAb-DB, mAbs for cancer therapy are characterized by their chains, domains and sequence and by several therapeutic metadata, including their MOA. MOAs were recently included as a search criterion to query the database. IMGT® is continuing standardized work to describe the MOA of mAbs targeting additional immune checkpoints and novel molecules in cancer therapy, as well as expanding this study to other clinical domains.

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Integrated continuous biomanufacturing on pilot scale for acid-sensitive monoclonal antibodies.

Publications

Integrated continuous biomanufacturing on pilot scale for acid-sensitive monoclonal antibodies.

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