Research Group Prevention and Immunomodulation

Projects

Development of a safe and efficient vaccine to EBV

A safe and efficient vaccine for EBV is not available so far despite the fact that the virus is a substantial burden to human health and associated with various human diseases. In fact, EBV is the first human tumor virus identified and contributes to about 200,000 cases of cancer worldwide any year. We are working on a vaccine based on virus-like particles (VLPs) that mimic the structure of the virus while lacking its infection competence. This means, EBV-VLPs contain various viral proteins and packaged RNAs but are devoid of the viral DNA genome. Additionally, we produce VLPs in a dedicated cell line that harbors an modified EBV helper genome from which critical genes that are associated with tumor genesis, have been genetically deleted (see figure). Thus, even in the very rare case that the helper genome is illegitimately packaged into VLPs, this particle will never have the potential to growth-transform an infected cell. Collectively, we believe that our VLP-based vaccine would help to relieve the disease burden caused by EBV.

Figure: AGV. VLPs are produced in a dedicated human cell carrying a genetically attenuated EBV genome that lacks genes with oncogenic potential (yellow circles) and the signals mandatory for packaging of the genome into nascent viral particles (red circle).

Figure: AGV. VLPs are produced in a dedicated human cell carrying a genetically attenuated EBV genome that lacks genes with oncogenic potential (yellow circles) and the signals mandatory for packaging of the genome into nascent viral particles (red circle).

Function of packaged transduced viral RNAs

Although it is decisive for the fate of the virus in infected B cells, the very earliest phase of infection is only incompletely understood. It is now well described that the herpes viruses, which are charaterized by a large DNA genome, also package RNA molecules into their virions which they transduce into target cells upon infection. We could recently demonstrate that, in the case of EBV, these transduced viral RNAs (termed tvRNAs) shape the earliest phase of infection. One the one hand, tvRNAs activate the infected cell, on the other hand they protect them from elimination through the immune system. Several other functions of tvRNA are yet to be discovered but it is clear, that altogether, they substantially enhance the infection efficacy and persistency. Our results make us believe that tvRNAs are central to the biology of EBV so that we are currently pursuing a project aiming at a better understanding of their relevance and function. In particular, we would like to learn

• how tvRNAs are selected for packaging into nascent viral particles.
• how tvRNAs are released from EBV particles in newly infected cells and where they become immediately translated.
• about the relevance of tvRNAs for the persistence of EBV in vivo.

Figure: AGV. EBV particles consists of a membrane spiked with viral glycoproteins, a capsid harboring the viral DNA genome, and a compartmen, termed 'tegument' of unknown function. We have shown recently that these particles also contain viral RNA molecule

Figure: AGV. EBV particles consists of a membrane spiked with viral glycoproteins, a capsid harboring the viral DNA genome, and a compartmen, termed 'tegument' of unknown function. We have shown recently that these particles also contain viral RNA molecule

Generation of new tumor-specific monoclonal antibodies

Monoclonal antibodies are established as key therapeutic modalities for various diseases including cancer. A prerequisite for the clinical application of therapeutic antibodies is their specificity for diseased tissues like tumors. Optimally, they selectively recognize, and bind to, tumor cells whilst sparing normal tissues. However, the identification of so called tumor-specific antigens and the development of tumor-specific antibodies is challenging, owing to the fact that cancer cells are very much similar to normal cells they derive from.

Together with Dr. Elisabeth Kremmer from the Institute of Molecular Immunology at the Helmholtz Center, we have established a new 'reverse screening' immunization platform technology that allows us to generate numerous antibodies that recognize, and bind to, native proteins on the surface of vital tumor cells – a prerequisite for an accessibility by therapeutic antibodies. This technology helped us generating the first inhibiting antibody to human carbonic anhydrase XII (CA12), a key enzyme for tumor growth under conditions when oxygen is scarce (which is almost always the case in solid tumors). This CA12 antibody* inhibits tumor cell growth both in vitro and in a small animal model. We are currently looking for opportunities to apply the antibody in a clinical setting. In our portfolio, we have also a number of other tumor-specific antibodies which are currently under investigation.

Figure: AGV. Immunocompromised NSG mice carrying a human tumor were either treated with the CA12-specific antibody ('treated') or with an isotype antibody ('control') over 52 days. The CA12 antibody retarded the growth of the tumor by 65%. *patent pending

Figure: AGV. Immunocompromised NSG mice carrying a human tumor were either treated with the CA12-specific antibody ('treated') or with an isotype antibody ('control') over 52 days. The CA12 antibody retarded the growth of the tumor by 65%. *patent pending