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The Infinitesimal Engines of Biologics

by | Aug 9, 2023 | Drug Manufacturing

Although all drugs restore or improve our health, the methods used to manufacture them vary greatly. Small molecule drugs are chemically synthesized; the production of biologics revolves around cells. Pharmaceutical scientists “program” cells to make proteins by transferring the genes that code for them into the cell line used for production.

ONCE UPON A BACTERIA…

Back in the days of disco and polyester; two California scientists discovered two phenomena that ushered in the biotech age. Stanley Cohen of Stanford University (Palo Alto, CA) and Herbert Boyer of the University of California, San Francisco, found out that: 

1) It’s possible to transfer genes for human proteins into bacterial cells, and 

2) the recipient bacteria can “read” the gene and translate it into the protein.

Cohen and Boyer realized that human genes could serve as recipes for bacteria to make human proteins. Venture Capitalist Robert Swanson convinced Boyer that the technology was commercially viable. 

Together, they founded Genentech (South San Francisco, CA) in 1976. The company’s first product, human insulin, was manufactured in E. coli bacteria. The Food and Drug Administration approved this first-ever biologic drug in 1982. Other human protein therapeutics produced in E. coli include human growth hormone, interferon, and parathyroid hormone.

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HAMSTERS AND OVARIES AND BACTERIA—OH MY!

Biologics production in E. coli proved highly successful. However, to grow, the biotech industry needed other cellular vessels. That’s because E. coli successfully produces only those human proteins with a relatively simple structure.

Drug scientists tried to make larger and more complex proteins with E. coli. However, they found that the resulting proteins lacked the correct structure and critical post-translational modifications—chemical and physical changes made to a protein by cellular enzymes after the protein is produced by the cell. Bacterial cells lack the enzymes required to make those changes.

Enter the humble Chinese hamster ovary (CHO) cell. These cells were already commonly used to produce human proteins for drug discovery research. Consequently, they made an obvious choice for biomanufacturing complex proteins such as antibodies and enzymes. The first biologic drug produced in CHO cells was Activase (Genentech), which came on the market in 1987. Activase is an enzyme that dissolves blood clots. Today, CHO cells provide the platform for about 70% of biologic drugs.

Why use CHO cells and not a human cell line? Pharmaceutical companies actually prefer to employ non-human mammalian cells. That’s because viruses that infect hamsters are unlikely to infect human cells. Yet as mammalian cells, CHO cells can produce complex human proteins. These cells can also grow in suspension. Because they don’t need to attach themselves to a solid surface such as the bottom of a tissue culture flask, it’s possible to grow thousands of liters of CHO cells in enormous vats.

ON BEYOND HAMSTER CELLS

Like in any area of biopharma, innovation still occurs in cell line development, despite the workhorse CHO cell.   Here’s just one of the more recent cell lines that may prove more efficient than CHO:

Dyadic International (Jupiter, FL) has bred the C1 cell line from the Myceliophthora thermophile fungus. These cells have been used to produce industrial enzymes since the 1990s. In fact, Dyadic started producing enzymes for the stonewashed jeans that have gone in and out of fashion for decades. 

In recent years, the company turned its attention to perfecting the cell line for biopharmaceuticals. In the words of CEO Mark Emalfarb, the company has gone “from jeans to genes.”   

C1 cells can now correctly produce a wide range of human therapeutic proteins, including monoclonal antibodies, which have long been the exclusive domain of CHO cells. 

This cell line potentially offers significant savings in time and money. The cells grow faster than CHO, doubling in two hours versus twenty hours. Moreover, their growth media costs far less than that used for CHO cells. Emalfarb estimates a savings of five to 10 times that of what it takes to use CHO cells. Further, the amount of protein produced per liter of cells is much higher for C1 cells than for CHO cells, according to Dyadic’s website. 

The company worked from 2015 to 2020 with the Zoonotic Anticipation and Preparedness Initiative (ZAPI), a European Union project, to facilitate fast and effective responses to new infectious diseases. The idea was that using C1 cells could expedite the production of proteins for drugs or vaccines. In 2020, Dyadic announced that the Israel Institute for Biological Research selected it to help develop treatments and vaccines for the current coronavirus, COVID-19. This collaboration of Dyadic and the Israel Institute for Biological Research resulted in the “DYAI-100” COVID-19 Vaccine in 2022. 

Whether bacterial, hamster, or fungal, the humble cell is the foundation for manufacturing today’s groundbreaking new therapies. Over the next several years, expect to see new and improved cell lines making biologic production even faster and more cost-effective.

CONCLUSION

The world of biopharmaceuticals has witnessed astounding innovations since the inception of biotech. The journey of identifying efficient cellular factories continues from bacteria to hamsters to fungi. These minute engines of life have been instrumental in producing lifesaving drugs and revolutionary therapies. As technology and science continue to meld, we stand on the cusp of even more groundbreaking discoveries. The potential of new and improved cell lines to revolutionize biologic production offers hope for quicker, more cost-effective, and more efficient therapeutic solutions in the future.

FREQUENTLY ASKED QUESTIONS

1. WHAT DIFFERENTIATES SMALL MOLECULE DRUGS FROM BIOLOGICS?

Small molecule drugs are chemically synthesized, while biologics are manufactured using living cells that are programmed to produce specific proteins.

2. HOW DID GENENTECH REVOLUTIONIZE THE BIOTECH INDUSTRY?

Genentech, co-founded by Boyer and Swanson, commercialized the process of using bacteria to produce human proteins by introducing genes that code for them. Their first product was human insulin, marking the first-ever biologic drug.

3. WHY ARE CHINESE HAMSTER OVARY (CHO) CELLS COMMONLY USED IN BIOMANUFACTURING?

CHO cells can produce complex human proteins, grow in suspension, and as non-human mammalian cells, they present a reduced risk of viral infection that might affect humans.

4. HOW DO C1 CELLS DIFFER FROM CHO CELLS IN BIOPHARMACEUTICAL PRODUCTION?

C1 cells, derived from a fungus, grow significantly faster than CHO cells, offer cost savings, and produce a larger amount of protein per liter. They also show potential in producing a wider range of therapeutic proteins.

5. WHAT IS THE SIGNIFICANCE OF DYADIC’S WORK WITH THE ZOONOTIC ANTICIPATION AND PREPAREDNESS INITIATIVE?

The collaboration aimed to provide rapid responses to new infectious diseases by using C1 cells to speed up the production of proteins for drugs or vaccines. Their efforts resulted in the “DYAI-100” COVID-19 Vaccine in 2022.

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