University of Toronto researcher Sachdev Sidhu and his collaborators
are engineering antibody molecules that can neutralize the novel
coronavirus in the body before it invades cells.
The investigator at the Donnelly Centre for Molecular and
Biomolecular Research is part of a team that recently received federal
funding support through a second round of emergency COVID-19 funding
from the Canadian Institutes for Health Research.
Sidhu already leads a different team that received support in the
first round of federal funding. The goal of that project is to design
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 Sidhu, who is a
professor of molecular genetics in the Faculty of Medicine.
The latest funded project, headed by U of T Professor James Rini of
the departments 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. To take one
existing example: Neutralizing antibodies are used to treat rabies,
which is also caused by a virus.
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 will also 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 a technology called 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, in which tiny bacterial viruses called phages
are instructed to create vast libraries of diverse antibodies, the team
will select the antibodies that can kill the virus in human cells before
testing them on mice and, eventually, patients. Experiments on mice
could start within three to six months, Sidhu says.
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 and provide an additional route
to the development of a therapeutic.
Given the global spread of the virus, it’s possible that it will
become endemic and circulate in the population like seasonal flu. And,
like the flu, it could mutate into new strains that will evade acquired
immunity and the vaccines that are being developed. By generating a
panel of different antibodies, the researchers aim to stay one step
ahead of the virus.
“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.”
https://medicalxpress.com/news/2020-04-antibodies-neutralize-coronavirus-invades-cells.html
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