Developing and manufacturing custom recombinant antibodies for R&D

insights from industryDr. Zhang Lin LinTechnical SpecialistSino Biological Europe

In this interview, Dr. Linlin Zhang, technical specialist for Sino Biological Europe, discusses how Sino is expanding its product offerings into the European market and outlines its process for developing and manufacturing custom recombinant antibodies for its clients.

Could you briefly introduce your background and role at Sino Biological?

I am currently a technical specialist at Sino Biological, Europe, based on my research background in protein structural biology. I completed my Ph.D. at the University of Lübeck in 2017, where I then stayed to study for my postdoc. Subsequently, I got promoted to project leader for a few years.

My research mainly focuses on developing small-molecule compounds based on structural biology by targeting nonstructural proteins of emerging or re-emerging viruses. For instance, the famous coronaviruses, enteroviruses and flaviviruses.

Last September, I joined Sino, taking charge of technical assistance at our sales and marketing department on recombinant protein and antibody products.

Could you share a little bit of the history of Sino Biological as a company with us?

Sino Biological, Inc.

Video credit: Sino Biological

Sino Biological was founded in 2007 in Beijing, China, after its founders realized the increasing demand for high-quality, fully active recombinant proteins for research and diagnostics development.

Our CEO, Dr. Liangzhi Xie (an MIT graduate), specializes in recombinant protein expression using mammalian cells. This focus is the core technique at our company.

The company also manages a team that specializes in antibody development. Based on the above facts, we successfully went public last year and raised 4.98 billion RMB during this initial public offering for the company’s continuous development.

In addition to business development in the Chinese market, Sino Biological has broadened its worldwide physical presence by establishing two subsidiaries in the United States and Europe.

As the only official data company in Europe, we are currently located in Frankfurt with our local sales and service team, including our product inventory division. Additionally, besides the domestic and overseas branches, a network of distributors supports our product sales distributors in the North American, European, and Asian markets.

Presently, Sino has 30 distributors, and our products are available in more than 90 countries. Furthermore, our products have been well distributed and are widely used.

What kind of product(s) does Sino Biological provide to its clients, and what are the main application fields for the products?

Sino Biological is an internationally leading reagent manufacturer and service provider. All of Sino’s products are independently developed and produced. These products include recombinant proteins, antibodies and cDNA clones.

Furthermore, Sino currently manufactures and sells more than 46,000 products in stock, including more than 6,000 recombinant proteins, of which 3,800 proteins expressed by human cells are close to nature’s structure and property. We also have a comprehensive collection of drug targets, cytokines and their receptors, FC receptor proteins and viral proteins among these products.

Similarly, we can provide 12,000 antibodies, including 4,600 monoclonal antibodies, and featured products covering a broad range, including primary antibodies, secondary antibodies, tag antibodies, neutralizing antibodies, control antibodies, etc. Additionally, these antibodies can be used in various areas, including ELISA, western blotting, immunofluorescence staining, immunohistochemistry, immunoprecipitation pursuit, viral infection, in vivo studies, etc.

Hence, all our products cover multiple research areas in the life sciences.

Sino Biological can also provide a one-stop-shop for research reagents and technical services for basic scientific research, including molecular biology, cell biology, immunology, developmental biology, stem cell research and innovative drug research and development.

Therefore, Sino Biological offers pharmaceutical companies and biotechnology firms preclinical product technology services for hundreds of monoclonal antibody drug candidates.

If clients have special or custom requirements for a product not in the catalog, do you also have a customized service? Also, can you tell us a bit about how that works? Finally, what kind of service do you provide, and what is the typical lead time for a customized product versus a catalog one?

We have excellent CRO services that attend to clients' recombinant production of proteins and antibody development. The complete service starts from gene cloning and synthesis to protein characterization. In Sino, we also have four main platforms for recombinant expression, including the mammalian cell system. This platform is in addition to the insect cell and yeast expression systems and particular expression systems, for instance, the E. coli expression system.

Sino Biological also provides recombinant antibody production services and a rich experience. We are committed to producing all the four subtypes of IgG and IgM in boosting pentameric and hexameric forms.

Similarly, we have a lot of experience producing different shapes of antibodies, such as the Fabs or scFvs, Fc-fusion proteins, chimeric antibodies, bispecific antibodies and circulating antibodies, in addition to a comprehensive animal immunization platform, antibody generation platform, screening platform and other safe platforms to identify the most suitable leads based on our antibody development services.

Our experience covers not only classical mouse monoclonal antibody development using hybridoma but also single B cells based on antibody development platforms. Several services for developing antibodies against the specific post-translational modification, for instance, phosphorylation, and for generating anti-idiotypic antibodies are also provided.

Our customers are particularly interested in the fast lead time. Typically, using E. coli, we start from gene synthesis to delivery of the final product. The process usually takes approximately four to eight weeks. However, the insect cell expression system takes a little longer, around 10 weeks, because it has two integral virus package processes.

The antibody protein expression in mammalian cells also takes about six to eight weeks to complete because generating antibodies as the immunogen preparation can take a while. It can also take time to develop a sufficient immune response, after which they can be moved to the antibody selection process.

Alternatively, it commonly takes about four to six months to generate the number of monoclonal antibodies in our antibody generation service. However, we have a fast immunization reading system, which combines our unique immunization strategy and AR events to expedite this process, allowing us to finish a project in about three to four months.

We understand that time is sensitive when conducting research, and we try to work as quickly as possible.

Could you describe a typical workflow for the first few weeks of a customer project? Could you also share a success story or a case study of a particular project that went well?

Once our sales team receives a CRO inquiry from a client, our professional CRO team will extensively analyze the project to ensure that the client gets timely feedback. Then, after in-depth communication with the client, we will use our solid internal infrastructure to outline the details of the deliverables.

After the project assessment process has been completed, a standard service package is offered for cases with no conflicting data. However, if the project is more complex than a simple antibody expression or a normal protein expression, we provide some nonstandard service packages.

There are more procedures involved after this stage. First, we finalize the details of the project and identify the project’s scope so that we are clear on the specifics of the deliverables.

If the client is satisfied with our proposal, payment is issued in the form of a purchase. Other payment information is also confirmed, then we can begin the project.

Our client is typically notified once the project is initiated and upon each milestone as the project progresses. Finally, a shipment process with the invoice certificate of analysis is provided when the project is finished. We also offer a complete project report.

I will briefly discuss a project we conducted for a client who wanted to develop an antibody using the single B-cell sorting technique.

After sorting the B cell, we identified 380 antigen-specific B cells and generated about 142 sequence pairs. This protein also yielded 46 clones, among which 8 were better than the control antibodies. These were then made commercially available.

It took us about 26 days to complete the project, from immunization to antibody characterization. The B-cell sorting platform is an expedited method to generate customized antibodies.

As a leading manufacturer of biological agents, what would you say are the most cutting-edge products or platforms, or what are the particular technical strengths that make Sino Biological a leader in this field?

First, our independently developed cutting-edge products are widely used in infectious disease research, therapeutic antibodies, evaluation, immunodiagnostic, SC and vaccine development studies.

The viral protein bank also features an exclusive coronavirus catalog, a comprehensive collection of influenza antigens and many other hard-to-find viral proteins, such as the Zika virus, RSV, Ebola, etc., including over 1,000 antigens from 90 virus types, subtypes and 350 strains.

In particular, this catalog includes the recombinant spike protein of the wider type of SARS COVID 2 and the Omicron variant, which our company was the first to launch worldwide. Additionally, we have a Sino milling chip, a multiplex acid platform for high throughput. Therefore, serological studies continue to use many of our upper respiratory virus antigens.

Second, rapid monoclonal antibodies developed using our phage display and single B-cell platforms exhibit higher sensitivity and specificity than mouse monoclonal antibodies. These features reduce the need for antigen retrieval and pretreatments in some applications.

Additionally, rapid monoclonal antibodies can recognize more novel epitopes in a highly diverse range of B-cell lymphomas, useful for antigens with weak immunogenicity or those derived from rodents.

We also have experience producing antibodies of different shapes and formats, including bispecific, tri-specific and multivalent antibodies, nanobodies, antibody fragments, antibody fusion proteins, etc.

Sino Biological is now expanding into Europe with its Frankfurt office. How does the European market differ from the areas that the company has operated in globally? Where are you more established? Also, do Sino Biological Europe’s services differ from what it offers elsewhere?

The services and products we offer in the European market are similar to those in other global markets, both in product range and quality control criteria.

However, the European market does have some differences compared to our national market because it is uniquely characterized by its culture and regional factors, including logistics, customs, currency, etc. Therefore, we consider these factors. For example, here in Germany, we have our local sales and service team and a protein inventory department in the European subsidiary.

Although the products are delivered directly from Germany to our clients, saving them a lot of effort with importing procedures, we still have to deal with product export challenges in this market, such as aligning the Swiss and UK prices of different currencies, including the Euro, the British pound and more. Occasionally, we have included additional language services to bridge some of these gaps.

You mentioned the COVID-19 pandemic, and how Sino has supported research efforts by providing antibodies for scientists developing vaccines and other treatments. How has the pandemic imparted the way Sino Biological operates internally? Furthermore, has that changed its workflow or how colleagues work in the office or the laboratory?

Sino Biological has been a front-line worker, delivering rapid responses against public health crises, such as the famous COVID-19 pandemic. Moreover, being the first company to express the SARS-CoV-2 spike protein and its variants means that our SARS-CoV-2 products are well accepted and distributed globally.

Additionally, as a leading manufacturer in recombinant proteins, Sino Biological has been recognized for its highly comprehensive recombinant protein production and antibody development platforms, even before the COVID-19 pandemic.

Specifically, we use this platform to develop reagents against different infectious diseases known to affect humans. As a result, we have an extensive collection of recombinant proteins from SARS-CoV-1 and other coronaviruses, influenza viruses, HIV, Ebola and others in our recombinant viral protein bank.

This platform has allowed us to familiarize ourselves with the process and develop techniques to prepare us for future pandemics better.

When the COVID-19 pandemic began, a significant part of our research and development and our production capacity was quickly switched to the development and production of SARS-CoV-2 reagents. This shift supported the industrial, academic and community efforts in stopping the pandemic. As a result, we developed a wider range of proteins.

Subsequently, we are constantly trying to create a panel of recombinant protein variants. For example, when working with the SARS-CoV-2 variants, we built a template for the SARS-CoV-2 spike protein and segments of the spike protein, meaning that whenever a variant or variants are encountered, we can quickly produce these recombinant proteins and supply them worldwide.

We have also developed a range of stock antibodies that can be deployed quickly for immunological assay development once a familiar or existing virus arises. For instance, COVID-19 was similar to the SARS-CoV-2 outbreak that occurred around a decade ago. Hence, the SARS antibodies were useful at the beginning of the pandemic to develop a rapid serological assay and support the companies working in vaccine development.

Notably, these companies used these antibodies as detection reagents, resulting in the encouraging results observed during that period. Therefore, this process favors vaccine efficacy. Furthermore, we are constantly developing specific antibodies targeting the spine or other relevant proteins of SARS-CoV-2 and its variants to ensure that we offer timely and high-quality services to our clients.

However, customers are beginning to require significant quantities of proteins, meaning that the platform’s capacity is stretched. Nevertheless, we have a high throughput common antibody expression platform with which we aim to create recombinant antibody libraries for clients. Due to these efforts, long-term collaboration has been established with many vaccine and rapid test developers. Meanwhile, a flexible infrastructure has also been maintained to allow the continuous provision of non-COVID-19 products and services.

We are ready to switch entirely to normal production when the virus is under control, and the pandemic ends

The information and opinions provided by speakers as well as Sino Biological employees during podcast series are solely of their own and Sino Biological assumes no responsibility or liability for this content.

About Dr. Zhang

Dr. Zhang is a technical specialist at Sino Biological Europe.Her research experience spans academia and industry. Dr. Zhang worked as a project leader in the University of Lübeck before she joined Sino Biological Europe. Her research interests fall into the fields of protein structural biology, antiviral therapy, and virus-host interaction mechanisms. A highlight of her scientific career was determination of the crystal structure of the unliganded main protease of SARS-CoV-2, as well as its complex with an alpha-ketoamide peptidomimetic compound named 13b (Zhang et al., Science, 368, 409-412 (2020)).

 

About Sino Biological Inc.

Sino Biological is an international reagent supplier and service provider. The company specializes in recombinant protein production and antibody development. All of Sino Biological's products are independently developed and produced, including recombinant proteins, antibodies and cDNA clones. Sino Biological is the researchers' one-stop technical services shop for the advanced technology platforms they need to make advancements. In addition, Sino Biological offers pharmaceutical companies and biotechnology firms pre-clinical production technology services for hundreds of monoclonal antibody drug candidates.

Sino Biological's core business

Sino Biological is committed to providing high-quality recombinant protein and antibody reagents and to being a one-stop technical services shop for life science researchers around the world. All of our products are independently developed and produced. In addition, we offer pharmaceutical companies and biotechnology firms pre-clinical production technology services for hundreds of monoclonal antibody drug candidates. Our product quality control indicators meet rigorous requirements for clinical use samples. It takes only a few weeks for us to produce 1 to 30 grams of purified monoclonal antibody from gene sequencing.


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