Visualisation
of SARS-CoV-2 virus with nanobodies (purple) attaching to the virus ‘spike’
protein. Courtesy: Dr Drew Berry in collaboration with Associate Professor
Wai-Hong Tham.
WEHI
researchers are studying 'nanobodies' – tiny immune proteins made by alpacas—in
a bid to understand whether they might be effective in blocking SARS-CoV-2, the
virus that causes COVID-19.
Alpacas
produce unique antibodies—called nanobodies—that can bind very specifically to
a protein. The research team are developing nanobodies specific for the
SARS-CoV-2 'spike' protein, which sticks out from the surface of the virus and
allows the virus to bind and enter human cells.
The team
hopes that developing nanobodies against the 'spike' protein could be an
important step towards new antibody-based 'biologics' therapies to treat
COVID-19.
This
nanobody program against COVID-19 is part of a consortium-led effort that
brings together the expertise of Victorian and Australian academic and industry
leaders in infectious diseases and antibody therapeutics at WEHI, the Doherty
Institute, CSL, Affinity Bio, CSIRO, the Burnet Institute and the Kirby
Institute.
Nanobodies—the
building blocks for antibody-based therapies
Antibodies
are key infection-fighting proteins in our immune system. An important aspect
of antibodies is that they bind tightly and specifically to another protein,
said Associate Professor Wai-Hong Tham, who is leading the research at WEHI.
"Antibody-based
therapies—or 'biologics'—utilize this property of antibodies, harnessing an
antibody that binds specifically to a protein involved in disease. In our case,
we are looking to develop a therapy that binds to the SARS-CoV-2 virus' 'spike'
protein, which it uses to get into human cells. These antibodies could prevent
the virus binding to the human receptor called ACE2—stopping the COVID-19
infection cycle," she said.
A quirk of
the alpaca immune system makes alpaca antibodies a key resource in this
project.
"Alpacas
make unique antibodies, which are smaller than conventional antibodies.
Conventional antibodies are composed of two immunoglobin—heavy chains and light
chains—whereas alpacas make the majority of antibodies that lack the light
chains. Nanobodies are laboratory-made antibody fragments of the heavy chain
only domain that recognizes foreign proteins. These bind really specifically to
their target protein and are more stable than other antibodies," Associate
Professor Tham said.
To
generate nanobodies against SARS-CoV-2, a group of alpacas in regional Victoria
are being immunized with a synthetic, non-infectious, part of the SARS-CoV-2
'spike' protein.
"The
synthetic 'spike' protein is not infectious and does not cause the alpacas to
develop disease—but it allows the alpacas to develop nanobodies,"
Associate Professor Tham said.
"We
can then extract the gene sequences encoding the nanobodies and use this to
produce millions of types of nanobodies in the laboratory and then select the
ones that bind to the 'spike' protein."
"We
are now comparing these nanobodies to discover which are the most effective at
binding the 'spike' protein and blocking the virus from entering cells. These
antibodies could enable the development of new treatments against
COVID-19."
ANSTO's
Australian Synchrotron was a critical resource in the project, allowing the
research team to map which parts of the 'spike' protein the nanobodies bound to
and how this impacted the virus' ability to bind to its human receptor.
Using
antibody therapies to treat COVID-19
Antibody
therapies are already in clinical use for diseases such as cancer, inflammatory
and autoimmune conditions.
They can
be used both to prevent and treat disease and are particularly useful in older
people or those who are immunocompromised, who may not be able to mount a
robust immune response to a vaccine.
Associate
Professor Tham said antibody-based therapies differed from vaccines.
"Vaccines
elicit an immune response to produce antibodies, whereas antibody-based
therapies deliver the effective antibodies directly. While this means the
antibody-based therapies start working straight away, they would not provide
long-term protection. In contrast, a vaccine takes some time to build
protective immunity, but this immunity can last for months, years or
decades."
The
research is at an early stage, but the team are hopeful it will help in the
fight against COVID-19.
"We
are in the early stages of this research and there are a number of steps that
need to take place in developing the therapies, as well as clinical trials,
before this treatment could be used in humans. But we are hopeful antibody-based
therapies could offer one potential solution to COVID-19 and could be used
alongside other treatment methods to combat this global pandemic,"
Associate Professor Tham said.
"While
we are not sure yet when these treatments for COVID-19 will be available to the
public, we are working as hard as we can to make these safely available as soon
as possible. I have never seen groups of people mobilizing scientifically in
such a passionate and collaborative way."