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Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / NEUMANN Emmanuelle

Presentation of the Fender’s team

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

Team Members :
- Marie-Claire Dagher (CR-CNRS)
- Emilie Stermann (Engineer-CNRS)
- Marc André Hograindleur (IE-CNRS)
- Solène Besson (PhD 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
Adenoviral (Ad) vectors are excellent candidates for vaccination and gene therapy. However, the efficacy of current vectors, mainly derived from Ad5, is limited by pre-existing natural immunity against serotype 5 in most individuals and by the absence of its receptor (CAR) in target cells. Group B adenoviruses such as Ad3, Ad7, Ad11 and Ad14 are an interesting alternative because they use another attachment receptor, desmoglein 2 (DSG2), a transmembrane protein, present in desmosomes of many tissues and overexpressed in some epithelial cancers.

In collaboration with Prof. Lieber’s group, we showed that the interaction of Ad3 (or the dodecahedra of the adenovirus) with its receptor promoted the entry of anti-cancer drugs into tumours (Wang et al., Nat Med 2011, Beyer et al, Cancer Res. 2011). We then demonstrated through biochemical studies that the interaction between the Ad3 fiber and the DSG2 receptor was based on a novel mechanism that had never been reported to date (Vassal-Stermann et al., Sci Rep 2018). More recently, we have characterized accurately this unusual binding mode by resolving the atomic structure of Ad3 in complex with DSG2 using cryo electron microscopy (Vassal-Stermann et al Nat Commun 2019 ).

Collaboration : A. Lieber (Univ. Washington, USA) ; K. Benihoud (Univ. Paris-Sud) ; Financements : ANR PRC 2019-2022 ANR-18-CE11-0001-01 Ces derniers résultats ont fait l'objet de nombreuses communications Les defis du CEA 231 Octobre 2018 ; EMBL 2018 Annual Report p23 ; IBS Actualités n°54 Mars 2019 ; INSB Actualités Mars 2019 ; ESRF Spotlight on Science ; PSB et al Scientific Highlights ; Instruct ERIC
Figure 1 : Atomic structure of the trimeric fiber of adenovirus serotype 3 (Ad3) in complex with DSG2 cell receptor (orange)
Vassal-Stermann E, Effantin G, Zubieta C, Burmeister W, Iseni F, Wang H, Lieber A, Schoehn G, Fender P. CryoEM structure of adenovirus type 3 fibre with desmoglein 2 shows an unusual mode of receptor engagement. Nat Commun. 2019 Mar 12 ;10(1):1181. doi : 10.1038/s41467-019-09220-y

Understanding these fundamental processes should now allow us to develop effective viral "re-targeting" strategies to transform Ad3-based vectors into selective agents.

Collaboration : A. Lieber (Univ. Washington, USA) ; K. Benihoud (Univ. Paris-Sud) ;

Grants : ANR PRC 2019-2022 ANR-18-CE11-0001-01

These latter results have been the subject of numerous communications
Les defis du CEA 231 Octobre 2018 ; EMBL 2018 Annual Report p23 ; IBS Actualités n°54 Mars 2019 ;
INSB Actualités Mars 2019 ; ESRF Spotlight on Science ; PSB et al Scientific Highlights ;
Instruct ERIC

Topic 2 : Development of a patented polyvalent vaccine platform derived from the dodecahedron of human serotype 3 adenovirus.
Although vaccination is exceptionally powerful to combat infectious diseases (smallpox eradication, polio control), serious threats still exist, as evidenced by epidemics caused by Zika or Chikungunya viruses. These viral pathogens are transmitted by the bite of the tiger mosquito, which has recently spread throughout the world as these vector mosquitoes move geographically to the poles due to climate change. The need for vaccine technology to adapt quickly and simply to threats is therefore necessary.

Our team is working on an adenovirus protein (Ad3) that spontaneously self-assembles by 60 to give a particularly stable particle even without refrigeration similar to a virus but not infectious. A cryo electron microscopy study showed that this particle has a very flexible quasi-spherical surface. Engineering of this adenoviral protein was then carried out to customarily replace these exposed regions with those from other pathogens. Proof of principle was established by expressing a pseudo-adenoviral particle displaying neutralizing epitopes of the Chikungunya virus. These chimeric neo-particles Adenovirus/Chikungunya neo-particles have shown promising results in animal studies as shown both by their drainage to the lymph nodes and the humoral response produced against the epitopes of the Chikungunya virus covering the particle (Vragniau et al., Science Advances 2019). This easy-to-use vaccine technology, based on a single particle that can be modified by synthetic biology, has been patented by the CNRS and EMBL) and could eventually be used to fight many other infectious diseases (ADDomer Patent)
In addition to infectious diseases, our process will also be studied for applications in immuno-oncology. With the development of anti-cancer immunotherapies called "immune chekpoint inhibitor" (ICI) such as PD1, PD-L1, CTLA4, a new field of application is opening up to induce immune-stimulation against cancer neo-antigenes. Our objective is to enable more patients to become good responders to these innovative therapies by stimulating their immune systems strongly and specifically against these cancer targets.

Collaboration : I Berger and F Garzoni (University of Bristol)
Financing : Ongoing request to the FINOVI and Oncostarter Foundation


Figure 2 : From adenovirus dodecahedron to the engineered vaccinal particle. The Ad3 penton base spontaneously assembles by five then dodecamerises (X12) to form a quasi-spherical 30nm non-infectious particle. By a rapid and simple engineering, the display of epitopes from other pathogens (red and blue) can be done on this scaffold for vaccine purpose.

Publications

Vassal-Stermann E, Effantin G, Zubieta C, Burmeister W, Iseni F, Wang H, Lieber A, Schoehn G, Fender P.(2019). CryoEM structure of adenovirus type 3 fibre with desmoglein 2 shows an unusual mode of receptor engagement. Nat Commun. Mar 12 ;10(1):1181. doi : 10.1038/s41467-019-09220-y.

Publication list