Cryo-EM Advances Monoclonal Antibody Research

As pharmaceutical companies work to develop the next generation of drugs, they’re increasingly turning to biologics — or therapeutic agents manufactured in living systems such as microbe and animal cells. Indeed, 29 percent of drugs approved by the U.S. Food and Drug Administration in 2018 were biologics, and that percentage is expected to grow.

Monoclonal antibodies

One important type of biologics are monoclonal antibodies, which are immune system proteins created in the lab. Like the antibodies naturally produced by the human immune system, monoclonal antibodies recognize diseases such as viruses and cancer and help turn the body against them. With the ability to bind to very specific targets, they can be engineered to serve as substitute antibodies that restore, enhance, or mimic the immune system’s attack against a wide variety of diseases.

Compared to small molecule drugs, biologics are more effective and have fewer side effects, making them one of the most successful candidates for new drug development. As of December 2019, 79 therapeutic mAbs had been approved by the US FDA for a total of 97 indications. Today, monoclonal antibody therapies already exist for 3 of the top 25 R&D spend-indications. The global market for monoclonal antibody therapies was valued at $123 billion in 2019 (USD), with steady growth projected over the next several years.

As more pharmaceutical companies enter this highly competitive market, they are turning to cryo-electron microscopy (cryo-EM) to help accelerate their research. Unlike other drug discovery techniques such as X-ray diffraction or nuclear magnetic resonance spectroscopy, cryo-EM provides scientists the complete structural information needed, uncovers how these antibodies function in the body, and shows how they bond to antigens.

Antibody cryo EM

With the high-resolution data it generates, cryo-EM can help pharmaceutical companies improve the drug development process, from pinpointing effective therapies during drug discovery to improving quality control. As rational drug design gains steam, an increasing number of researchers are turning to cryo-EM to advance their monoclonal antibody research.

Monoclonal antibody research

A few recent examples:

A group up scientists at Novartis used cryo-EM to develop an antibody screen that examines human response to polyomaviruses. These viruses establish themselves as a dormant infection in the kidney during childhood but can re-activate in immune-compromised individuals and cause severe complications. Using cryo-EM, scientists isolated monoclonal antibodies that neutralize two of the virus subtypes (BK and JC), revealing a powerful way to inhibit polyomavirus infection in kidney transplant recipients and other immune-compromised patients. The findings provided insight into the humoral response to polyomavirus infection, which may ultimately lead to therapeutic approaches that limit the re-activation of these viruses in immuno-compromised patients.

Novartis scientists obtained a cryo-EM structure of a BK polyomavirus-like particle in complex with single chain antibody. Cryo-EM revealed a potent modality for inhibiting polyomavirus infection in kidney transplant recipients and other immune-compromised patients.

Using cryo-EM, a group of Amgen researchers determined the structure of the HER2-trastuzumab-pertuzumab complex. Trastuzumab and pertuzumab are monoclonal antibodies that bind to distinct subdomains of the extracellular domain of human epidermal growth factor receptor 2 (HER2), associated with more aggressive breast cancers, higher recurrence rates, and increased mortality. Although researchers had uncovered the individual crystal structures of HER2-trastuzumab and HER2-pertuzumab, detailed structural information on the HER2-trastuzumab-pertuzumab complex had been elusive. Solving the high-resolution structure of this entire complex with cryo-EM provides key insights into the design of a novel molecule that can bind to both antibodies within the complex and potentially have greater clinical efficacy.
Cryo-EM is also helping scientists at Humabs Biomed pave the way for using antibodies as a treatment for SARS-CoV-2, the newly emerged coronavirus responsible for the current COVID-19 pandemic. The S309 antibody potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-EM and binding assays, the researchers found that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. This research is paving the way for the use of S309 in antibody cocktails for patients who have either been exposed to COVID-19 or are at high risk of exposure.

These are just a few examples of how cryo-EM can help pharmaceutical companies develop the next generation of effective drugs. With the ability to visualize biologics at high resolution, scientists are poised to accelerate the drug development process, bringing to market new monoclonal antibody therapies that more efficiently neutralize some of the world’s deadliest diseases.

Visit our Cryo-EM in the Pharmaceutical Industry webpage to learn more about how other pharmaceutical companies are using cryo-EM to accelerate their drug discovery.

To find out how you can incorporate cryo-EM into your pharmaceutical research, please see our Bio-pharmaceutical Research with Electron Microscopy page.

Aleksander Stefanovic is a Senior Market Development Manager at Thermo Fisher Scientific.

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