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Institut de Biologie StructuraleGrenoble / France

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Presentation of the Fender’s team

Members
Team Leader : Pascal Fender (Research Director-CNRS)

Team Members :
- Emilie Stermann (Engineer-CNRS)
- Charles Vragniau (PhD student-UGA)

Adenovirus and therapeutic applications

Adenoviruses are non-enveloped, double-stranded linear DNA viruses which infect many animal species. In humans, about sixty serotypes are identified causing diseases such as conjunctivitis, pneunomia or gastroenteritis. Adenoviruses are also known to be the most widely used vector in gene therapy clinical trials in humans. (http://www.abedia.com/wiley/vectors.php).
Two capsid proteins of the adenovirus are responsible for the internalization of the virus : the fiber and the penton base. The fiber interacts with an attachment receptor such as CAR or desmoglein 2 (DSG2) identified by Professor Lieber’s group in Seattle in collaboration with our team (Wang et al., Nat Med 2011). The penton base interacts with integrins through an RGD sequence and triggers virus endocytosis. We have reported that some adenovirus serotypes such as Ad3 produced an excess of this pentameric protein that dodecamerizes (symmetrically assembles by12) to give rise to a non-infectious particle called the adenovirus dodecahedron.
The fiber and the penton base are the key actors of the two main subjects developed by our team.

Objectives of the team :
Bridge the gap between basic research and therapeutic applications

Topic 1 : Biochemical and structural study of the Desmoglein 2 receptor (DSG2) of human Adenoviruses and applications
DSG2 is the adenovirus receptor for serotypes such as Ad3, Ad7, Ad11 and Ad14 which are successfully used as oncolytic virus in clinical trials. DSG2 is a component of desmosomes overexpressed in some cancer types. In a collaboration with Professor Lieber’s group (Medical Genetic Dpt, Seattle), we have shown that the interaction of the Ad3 virus or penton-dodecahedra (Pt-Dd) has a facilitating effect for drugs approved in oncology such as monoclonal antibodies or Doxil (Wang et al., Nat Med 2011, Richter et al., Mol Ther 2013). Our team is interested in the molecular mechanisms of the interaction between the adenovirus fibers and the DSG2 receptor. We have just reported that this interaction was taking place according to a new mechanism that had never been reported to date (Stermann-Vassal et al., Sci Rep 2018 : https://www.nature.com/articles/s41598-018 -26 871-x).
We are currently solving the atomic structure of the complex between Ad3 fiber and DSG2 by X-ray crystallography and cryo-electron microscopy. This structure will enable us in the near future to design rationally a new generation of adenoviral vectors with modified tropism.

Topic 2 : Development of a patented polyvalent vaccine platform derived from the dodecahedron of human serotype 3 adenovirus.
The dodecahedron of Ad3 is a symmetrical particle (30 nm in diameter) made up of twelve homopentamers of the penton base. The final particle is composed of 60 identical monomers. We have solved the atomic structure of the dodecahedra which enabled us to identify flexible and surface-exposed regions of the particles that could be useful for the insertion of foreign epitopes of interest. Thanks to a genetic design of the the penton base, it is now possible to insert in a ‘plug and play’ manner these epitopes which are displayed to 60 copies per immunostimulatory particle. This vaccine platform named ADDomer, which can be produced on a large scale, was patented in 2016 (CNRS / EMBL). It has been tested with a neutralizing epitope of Chikungunya virus (Vragniau et al., in preparation) and currently we are developing particles in the field of immuno-oncology targeting melanoma.
More details on technology and intellectual property can be found on the following links :
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017167988
http://www.biovaria.org/technologies-details/multiepitopic-insertion-platform-addomer/
https://www.canceropole-clara.com/wp-content/uploads/2018/04/42_FENDER-Pascal.pdf

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