In Development: Neutralizing antibodies and medicines that block viral replication

Researchers at the University of Toronto’s Donnelly Centre are working on two key projects in the battle against COVID-19: developing neutralizing antibodies to help boost patient immunity to the virus, and designing antiviral medicines that block viral replication. “With our two funded projects, we are working to develop molecules that can target the virus both inside human cells and on the outside to prevent it from getting in,” says Sachdev Sidhu, who is a professor of molecular genetics in the Faculty of Medicine. 

The latest funded project – headed by James Rini, University of Toronto professor of molecular genetics and biochemistry – aims to produce antibodies that can effectively neutralize the virus before it causes damage. Such antibodies are naturally produced by the body in response to infection, but researchers hope to reduce the duration and severity of the disease by boosting the immune system with injected antibodies. 

The research team recently received federal funding support through a second round of emergency COVID-19 funding from the Canadian Institutes for Health Research. 

Other teams in Canada, as well as in the U.K. and U.S., are looking to infuse COVID-19 survivors’ blood plasma containing antibodies into patients to aid their recovery. Plasma transfusion, however, is fraught with challenges, including variability in efficacy between different donors and risk of disease transmission. Synthetic antibodies, on the other hand, represent a defined drug in terms of molecular content, efficacy and dosing regimen.

Rini has previously helped to determine how antibodies bind to and inactivate the SARS virus, the coronavirus that caused the outbreak in Asia more than 15 years ago. Also on the team is Alan Cochrane, a professor in the department of molecular genetics and an HIV virologist with expertise in viral RNA processing.

The antibodies will be engineered to block the so-called S-protein that forms spikes on the virus’s surface. The spikes lock on to a protein called ACE2 on the surface of human cells to gain entry. Coating viral particles with synthetic antibodies should prevent the spikes from binding to ACE2.

Sidhu and Rini also will engineer antibodies that bind ACE2 to make it inaccessible to the virus. This type of engineered immunity surpasses the capacity of the body’s natural immune system since antibodies that react against self-proteins have been filtered out. If successful, the approach may obviate worries about viral mutations that can render drugs ineffective to new emerging viral strains because the host protein ACE2 does not change over time.

Sidhu’s team has advanced phage display to rapidly create and select human antibodies with desired biological properties, including blocking the virus’s spike protein. Over the last decade, his team has created hundreds of antibodies with therapeutic potential – some of which are in clinical development through spin-off companies and large pharmaceutical firms.

The group has demonstrated success with both approaches for inhibiting viral entry, having developed neutralizing antibodies that target the Ebola virus as well as antibodies that target the human host receptor of hantavirus or hepatitis C. Moreover, other research has shown that antibodies targeting SARS, a related virus whose genetic material is over 80 percent identical to the one causing COVID-19, can clear infection in cells and mice.

Using phage display, the team will select the antibodies that can kill the virus in human cells before testing them on mice and, eventually, patients. In addition to creating antibodies tailored to the new virus from scratch, the researchers will also modify existing SARS-blocking antibodies so that they attack COVID-19.

“Our advances in antibody engineering technologies and access to the complete genomes of the COVID-19 virus and its relatives provides us with an opportunity to create tailored therapeutic antibodies at a scale and speed that was not possible even a few years ago,” says Sidhu. “Ultimately, we aim to optimize methods to the point where the evolution of new drugs will keep pace with the evolution of the virus itself, providing new and effective drugs in response to new outbreaks.”

–information provided by the University of Toronto 

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