Isolation and Engineering of Potent Anti-EBV Neutralizing Antibodies for the Treatment of MS
Abstract
Objectives and rationale for the proposed research project: Recent studies have provided compelling evidence that Epstein-Barr virus (EBV) infection predisposes people to developing MS, with EBV infection increasing the likelihood of developing MS by 32-fold. Although EBV infection is not the sole cause of MS, preventing EBV infection could substantially reduce the emergence of new MS cases. In addition, MS patients who have received anti-EBV T cell therapy have shown clinical improvement in clinical trials, indicating that anti-EBV therapeutic approaches may improve outcomes for current MS patients. In this proposal, we will develop a multi-pronged approach to targeting EBV for the treatment and prevention of MS. Our overall goal in this proposal is to develop novel neutralizing antibodies to two key viral protein targets, gHgL and gB, to block EBV infections and to suppress EBV reactivation in infected individuals. Both of these proteins are critically important for EBV infections and primary targets of the immune response, but highly potent antibodies are likely necessary to fully suppress EBV infection. The gB protein exists in an unstable form on the surface of the virus, making it challenging to develop as a vaccine or to use for the identification of neutralizing antibodies. However, we have engineered a stabilized version of the EBV gB protein, which is a key innovation that enables the proposed studies. The isolation of new anti-EBV antibodies and further stabilization of the EBV gB protein will also inform ongoing EBV vaccine design efforts. FY22 MSRP Focus Area(s): This research project will address the FY22 MSRP Focus Area Factors Contributing to or Associated with MS Etiology, Prodrome, Onset, and Disease Course by developing novel approaches to blocking primary and re-activated EBV infections. Applicability of the research to advance MS patient care: What types of patients could it potentially help and how? The promising results that have been observed with anti-EBV T cell therapy strongly indicate that targeting EBV in existing MS patients could have therapeutic benefit and potentially slow the course of the disease. Based on these and other preclinical studies, we believe that the anti-EBV neutralizing antibodies that we will develop in this proposal could similarly provide an important approach to the treatment of MS. Furthermore, our studies will provide an important foundation for the development of EBV vaccines. An EBV vaccine has the potential to prevent new MS cases by blocking primary EBV infections, although it remains to be established what percentage of MS cases would be prevented by this approach. What are the potential clinical applications, benefits, and risks? As indicated above, we believe that anti-EBV neutralizing antibodies could provide clinical benefit to existing MS patients. EBV establishes life-long latency in infected individuals and undergoes periodic reactivation and replication, which may lead to cross-reactive immune responses to normal tissues and the associated progression of MS disease. By suppressing EBV replication in infected MS patients, it may be possible to reduce the severity of disease. The benefits to this approach, if effective, would be to mitigate the role of EBV in triggering MS and the associated risks are likely to be low and similar to other antiviral antibody therapies used clinically. What is the projected time it may take to achieve a patient-related outcome? Anti-EBV antibody therapeutics, once validated in preclinical studies, would have to go through a development process prior to entering clinical trials. Once candidate antibodies have been identified and validated in the laboratory setting, these could potentially be moved into clinical trials within 2 to 3 years given sufficient financial resources. Although vaccines for SARS-CoV-2 were developed and approved within a year, the time frame for development of an EBV vaccin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310565
Entities
People
- Theodore Jardetzky
Organizations
- Stanford University
- United States Army