Nature Biotechnology: Prevents rejection of transplanted cells by tricking antibodies

A new approach could overcome the persistent barriers of cell transplantation and immunotherapy

Researchers at the University of California, San Francisco, have developed a novel, potentially life-saving way to prevent antibodies from triggering immune rejection in engineered therapy cells and transplanted cells
.

Antibody-mediated rejection, in contrast to chemical attacks initiated by immune cells, has proven particularly difficult to resolve, a factor
hindering the development of these treatments.

The new strategy, published in the Jan.
2, 2023 issue of Nature Biotechnology, uses a "bait" receptor to capture antibodies and remove them from the loop before they kill treatment cells, which are considered invading foreign substances
.
This approach may also be suitable for organ transplantation
.

"This antibody-mediated rejection response is really hard to overcome," says Julien I.
E.
Hoffman, M.
D.
, "so instead of trying to suppress the patient's immune system, we look for ways to alter the cells that the patient will receive to better keep them alive
.
" ”

Protects foreign friendly cells

The most famous cell therapy in the United States is chimeric antigen receptor (CAR-T) cell therapy
.
These CAR-T therapies are often used to treat specific forms of lymphoma, but using them against solid tumors has proven much more difficult
.

Until recently, most CAR-T therapies were performed using patients' own cells, but the long-term commercial viability of all types of cell therapies will rely on "allogeneic" cells — therapeutic cells
that are mass-produced from sources outside the patient.

Just like transplanted organs, the recipient's immune system may treat any foreign cells or tissues developed from them as foreign and reject them
, Deuse said.
"We've already gone through organ transplants, so we know what happens with cell transplants," said Deuse, a heart transplant surgeon who is no stranger to
the troubles caused by immune rejection.
"This problem is likely to become a serious barrier
to any type of allogeneic cell transplantation.
"

Clinical trials of allogeneic CAR-T therapies have worse outcomes than those from patient cells, and Deuse noted that immunotherapy requires additional challenges, and these free-floating cells are more vulnerable to immune attack
than cells in transplanted organs.

"We have to find better ways to protect these cells," he said
.

Deceive antibodies with decoys

Normally, when an antibody binds to a cell, it acts like a tag that calls on immune cells to bind to the antibody and initiates an efficient process
of destroying the labeled cell.
To stop this chain reaction, Deuse and his team devised a way to capture antibodies before they bind to cells, preventing the activation
of the immune response.

The researchers genetically engineered three types of cells — insulin-producing islet cells, thyroid cells, and CAR-T cells — so that the surface of each type produced and displayed large amounts of the CD64 protein
.

On these engineered cells, CD64 tightly binds to the antibodies responsible for this immune rejection, acting as a kind of bait, trapping the antibodies and binding them to the engineered cells so they don't activate immune cells
.

"We found that we can get high levels of these antibodies, which creates a very strong protection
against the therapeutic cells," Deuse said.
"This clearly demonstrates the concept of
this approach.
"

He said there is more work to be done
before this approach can be tested on therapeutic cells or transplanted cells.
While such cells are biologically complex, they are also expensive and difficult to manufacture
.

"I hope our concept can help develop universally available allogeneic cells
.
" This will make cell therapies cheaper and more accessible, making them
accessible to more patients.
”

Original:

Protection of cell therapeutics from antibody-mediated killing by CD64 overexpression