UCLA researchers in the Department of Microbiology Immunology and Molecular Genetics have created a novel T cell redirecting bispecific antibody (TRBA) for treatment of cytomegalovirus (CMV) infection.
BACKGROUND: The human cytomegalovirus (CMV) has a seroprevalence of about 60% in the USA and nearly 100% of the population in some parts of the world. Infections in healthy individuals are lifelong and typically immunologically contained and asymptomatic. However, immunocompromised individuals and perinatally infected individuals can develop severe disseminated infections with high morbidity and mortality. Currently available drug treatments face barriers such as risks for nephrotoxicity/hematopoietic toxicity and viral resistance. However, proof-of-concept immunotherapy trials with expanded autologous CMV-specific CD8+ T cells have shown they are necessary and sufficient to clear and contain disseminated CMV infection. However, this strategy is highly labor intensive and not feasible for widespread adoption. Thus, alternative immunotherapy options are sorely needed for treatment of disseminated CMV infection, which has orphan disease status with the FDA.\
INNOVATION: Researchers at UCLA have developed a novel therapeutic strategy to treat disseminated CMV infection utilizing T cell redirecting bi-specific antibody (TRBA). This entails an antibody-based molecule with binding domains against a CMV cell surface antigen (expressed early in the viral life cycle) and human CD3 found on T cells including CTLs. The TRBA crosslinks T cells/CTLs to CMV-infected cells to induce killing of the latter. While currently FDA-approved TRBAs consist of two linked single chain antibodies (termed “BiTEs”), this novel design has two binding sites for each target antigen, which is a key advantage for overall potency, and a heavy chain constant region for longer half-life and additional antibody effector functions. Preclinical studies show successful demonstration of this TRBA directing T cells to destroy CMV-infected target cells.
POTENTIAL APPLICATIONS:
- Immunotherapy against disseminated human cytomegalovirus infection
- Use in immunocompromised patients, such as solid organ or bone marrow transplantation patients
- Use in congenital CMV as an adjunct to drug treatment
ADVANTAGES:
Compared to the current FDA approved TRBAs that are both BiTEs:
- Longer in vivo half-life
- Additional antibody innate immune effector function via inclusion of the Fc domain
- Greater affinity due to two binding sites per targeted antigen
DEVELOPMENT-TO-DATE: Validation of concept shown in human cells infected with CMV
Related Papers (from the inventors only): Chiuppesi et al, J Virol. 2015 Dec;89(23):11884-98 (PMID 26378171)
Keywords: Human cytomegalovirus (CMV), Viral infection, CD8+ T cells, Lymphocytes, Bispecific antibodies, T cell redirecting bispecific antibody (TRBA), Immunotherapies, Anti-CD3 antibodies, BiTEs, Congenital CMV infection, Immunocompromised hosts, Transplantation patients