Engineered antibodies can direct T-cells to kill cytomegalovirus-infected cells

A UCLA research team has found a new way to prompt the immune system to kill cells infected with cytomegalovirus (CMV), a life-threatening infection that is particularly deadly in immunocompromised people.

They did this by engineering antibodies that direct the immune system’s T-cells to kill cells infected with the virus, which poses a danger for people such as those who have undergone organ transplants or who have AIDS. Infection with CMV can also lead to deafness in infants when the virus is transmitted from the mother during pregnancy.

The findings could pave an alternative way for treating infection without the current drugs, which are both expensive and often carry severe side effects, said study lead Dr. Otto Yang, professor of medicine in the division of infectious diseases and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA.

“This is a potentially new way to harness the immune system against this virus and could offer new opportunities to treat transplant patients or AIDS patients with life-threatening infection, or children with poorly controlled infection that puts them at risk for deafness,” Yang said.

The findings are published in the journal Science Advances.

CMV infection is a lifetime infection that is typically contained asymptomatically in infected persons who have healthy immune systems. There are drugs for prophylaxis and treatment of CMV infection, but these can lead to bone marrow suppression, kidney damage and other severe side effects, and viral resistance to these drugs can be an issue.

A process known as adoptive transfer of expanded patient-specific CMV-killing T-cells has proven the importance of T-cell immunity in controlling infection, and it is a potential therapeutic approach. But it is time consuming to apply, which limits it in cases of a life-threatening infection. The same holds true when using chimeric antigen receptors, also known as CAR-T therapy. A faster and more effective treatment is needed.

A new approach is to use what are known as T-cell redirecting bispecific antibodies (TRBAs). To date, these have been used as therapies against malignancies. But researchers have been eyeing TRBAs as a potential weapon against CMV. The UCLA team has devised TRBAs by engineering antibodies to act as a bridge connecting CD3-epsilon on CD8⁺T-cells (CTLs) to a viral protein on CMV-infected cells. This leads to the CTLs clustering around the infected cell and killing it.

“Hopefully, if there is commercial interest, these antibodies could be tested in clinical trials,” Yang said.