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State-of-the-Art Technology Facilitates Protein Manufacturing

Published: May 15 ,2020

News summary
Today let me introduce a successful case related to this topic- how Leto Laboratories Co., Ltd. develops and manufactures ACE2, a recombinant protein, with BioAccord system of Waters. This system has been used for virus research, development and quality control of vaccines, diagnostic reagents and therapeutic medications in many world-renowned research institutions and firms.

About ACE2

Angiotensin-converting enzyme 2 (ACE2) is reported to be the doorway through which the coronavirus causes COVID-19, therefore, current research is focusing on ACE2 as a biological target when making screening for drug discovery and in the search for therapeutics, while drugs made of human recombinant ACE2 (hrACE2) extracellular domain might come to clinical use ahead of all those stopping virus’ invasion, such as neutralizing proteins, interferons, cell therapy etc. It has high specificity and desired safety, and is likely to prevent respiratory distress and cytokine storms. Hence, hrACE2 will probably become a specific drug against all viruses (including SARS-CoV and SARS-CoV-2) that use ACE2 receptor as a doorway to get into human cells.

Develop scale-up process for hrACE2 production at the earliest possible time

A core competency in life sciences is manufacturing proteins, and Leto Laboratories as a technology- driven company is specialized in the design, development, manufacturing and industrialization of them. At the beginning of the pandemic outbreak, its scientist team had started the research and validation on hrACE2. They checked the feasibility and defined the structure design of the protein drug, expedited generating a stable, high-expression cell line with independent IPR for hrACE2, and quickly built a complete quality control system and methodology for purification process allowing scale-up manufacturing. Now Leto Laboratories has produced the first-generation hrACE2 with high purity, quality and activity (dimer as functional protein).

Its scientists also predicted that, HrACE2 might be given to patients with early infections, especially asymptomatic infections, in a form of spray to nasopharynx or intravenous injection, after reading the articles having been published so far. They think severe cases should use hrACE2 at appropriate dose by IV, which can not only relieve respiratory distress by increasing the concentration of surfactant Protein D but also reduce cytokine storm by decreasing the concentration of IL-6.

(Note: Results from phase II clinical trials of hrACE2 https://www.ncbi.nlm.nih.gov/pubmed/28877748)

Figure 1. Some of the QC results of hrACE2 produced by Leto Laboratories

A recent article published on Cell (available online), Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2, by Karolinska Institute, the Swedish National Veterinary Institute, and the Barcelona Institute of Science and Technology (BIST), validates the prediction of Leto Laboratories, who’s now intensively working on the design and production of second-generation hrACE2 for severe covid cases with a hope to provide it to each stage of the antiviral therapy.

Establish a quality control (QC) system with the help of BioAccord

Protein is pivotal in biological drugs and agents including diagnostic reagents for IVD, but it can impose great technological challenges. Since the day of its founding, Leto Laboratories has faced up to these challenges and begun its efforts in manufacturing recombinant protein, focusing on breaking the bottleneck issues in protein product development through its patented, innovative technology and unique manufacturing concept.

In this search for anti-covid-19 drugs, the BioAccord LC-MS System of Waters played a crucial role in analysis and QC. With its help, Leto Laboratories’ scientist team figured out the requirements to get high expression from the protein of interest in less than two weeks, and quickly built the QC methodology covering assessment of protein aggregates, purity control, and measurement of molecular weight after removing part of glycans.

BioAccord provides reliable results to help identify and monitor the critical quality attributes (CQA), to ensure batch consistency in scaled-up manufacturing of ACE2 with low levels of aggregation, high purity and accurate quality control. This, on the other hand, represents what an efficient and complete system Leto Laboratories has made for the platform-based protein analysis and quality assurance, and the capabilities it possesses to deal with emergency tasks.

Figure 2. An example of analytical QC testing for protein characterization on Leto Laboratories’ recombinant protein platform

Throughout the production process Leto Laboratories implements high-standard quality control. According to Ms. Zhang Qiulei from QC Center, the complexity of the glycosylated ACE2 purposed to fight against covid-19 poses quite a challenge to the analytical testing for QC. However, using the QC platform for protein characterization based on Waters ACQUITY UPLC H-Class/TUV/FLR and the BioAccord SmartMS-enabled LC-MS/UNIFI, Leto Labs is able to monitor the protein quality during the whole production process, including protein quantification, purity control, measurement of molecular weight, peptide mapping, analysis to post-translational modifications (PTMs), stability study, and release testing etc.

“Leto Laboratories had the BioAccord system ready as soon as it was launched to the market. It brought innovative changes and competitive edges to us. We can tell and decide if we should move on to the next step when the molecules were still at an early stage with the accurate data BioAccord provides, thus efficiency was secured and time could be won for the advancement and delivery of the project results.

This system can also help us to get started quickly, as our process and quality control colleagues don’t have to be experts on mass spectrometry to use it. With brief trainings, they can make reports meeting regulatory requirements, which, to a certain extent, makes our staffing flexible. Besides, the regulatory compliance design of the UNIFI is an important factor that we took into account, for our CMC design in the future should also achieve that.