UCLA researchers at the Departments of Medicine and Microbiology Immunology and Molecular Genetics have developed a novel bispecific antibody-based immunotherapy strategy for the treatment of Cytomegalovirus infections.
BACKGROUND:
The human cytomegalovirus (CMV) is a widespread virus estimated to infect 60% of American adults and nearly 100% of the population in some parts of the world. Most infections in healthy individuals are lifelong and immunologically contained and therefore asymptomatic. However, immunocompromised individuals and those perinatally infected can develop severe infections that can result in high morbidity and mortality rates due to organ damage. FDA-approved drugs are available to treat CMV infections but come with major limitations. For instance, foscarnet and cidofovir pose a high risk of nephrotoxicity. For all currently used drugs, there is also growing concern of viral resistance mutations developing in CMV strains reducing their therapeutic efficacy. A new class of immunotherapies are being developed for the use against CMV. Immune cells responsible for controlling CMV infection are CD8+ T lymphocytes (CTLs). Anti-CMV antibodies and autologous immunotherapy using CMV-specific CTLs have limited efficacy or labor intensive and technically challenging to mass produce. Thus, there is a strong need for safe and effective therapeutics against CMV.
INNOVATION:
Researchers at UCLA have developed a novel therapeutic strategy to treat CMV infections utilizing a T cell redirecting bispecific antibody (TRBA). This entails an antibody-based molecule with binding domains against cell surface viral antigen and a CD3 antigen found on CTLs. The bispecific antibody will crosslink CTLs to target cells to induce killing of CMV-infected cells. Researchers identified a viral surface protein expressed abundantly in CMV-infected cells in the early stage of the viral life cycle. The variable chains of the antiviral antigen and anti-CD3 antibodies were used to form the TRBA, bispecific against a CMV-infected cell and immune cells responsible for curtailing CMV infections. In vitro studies confirm the TRBA’s ability to recruit CD8 T cells and antiviral activity against CMV-infected cells with majority clearance as early as 6 hours.
POTENTIAL APPLICATIONS:
- Immunotherapy against human cytomegalovirus infection
ADVANTAGES:
- Longer in vivo half lives compared to single chain antibodies (so-called “BiTEs” or bi-specific T cell engagers)
- Increased affinity due to the use of two binding sites against each specificity per molecule (as compared to BiTEs that have one binding site each)
- Antibody-based therapeutic that accomplishes the same effect as chimeric antigen-receptor T cell gene therapy
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)