Periodic Reporting for period 1 - AcTaferon (Revitalizing the clinical potential of type I IFNs in fighting influenza A virus infections with AcTaferon.)
Période du rapport: 2017-05-01 au 2018-12-31
The flu, caused by seasonal influenza epidemics and occasional pandemics, remains a serious health threat associated with substantial morbidity, mortality and economic loss due to sickness leave. Direct-acting antivirals (DAAs) that inhibit virus replication, and prophylactic vaccines are currently the most effective antiviral strategies. However, the emergence of numerous DAA- and vaccine-resistant virus strains presses the need to develop improved drugs against different influenza variants and subtypes.
AcTaferons (Activity by Targeting interferons) are a novel class of engineered interferons that maximally take advantage of a sophisticated, natural defense system that evolutionary arose to combat viral infections. Cells infected with a virus naturally produce the alarm signal type I interferon (IFN), which upon binding to the IFN receptor on infected and neighbouring cells activates an antiviral response that interferes with the viral replication and spread throughout the body. IFN binding on immune cells further stimulates our immune system to fight the infection. Based on their antiviral and immunostimulatory effects, type I interferons were believed to be the miracle drug to tackle viruses. However, clinical IFN applications remained limited as IFN drugs cause severe side effects due to unwanted IFN binding to IFN receptors present all over the body, resulting in widespread, aspecific action of the drug. AcTaferon circumvents these side effects by selective targeting of IFN to specific cell types. AcTaferon remains inactive “en route” through the body and unveils its antiviral activity only on specific target cells. This project aims to generate virus-targeted AcTaferons (O1) and to evaluate the prophylactic and therapeutic potential of virus- and immune cell-targeted AcTaferons to restrict influenza infection in vitro (O2 and O3) and in vivo (O4).
AcTaferons (Activity by Targeting interferons) are a novel class of engineered interferons that maximally take advantage of a sophisticated, natural defense system that evolutionary arose to combat viral infections. Cells infected with a virus naturally produce the alarm signal type I interferon (IFN), which upon binding to the IFN receptor on infected and neighbouring cells activates an antiviral response that interferes with the viral replication and spread throughout the body. IFN binding on immune cells further stimulates our immune system to fight the infection. Based on their antiviral and immunostimulatory effects, type I interferons were believed to be the miracle drug to tackle viruses. However, clinical IFN applications remained limited as IFN drugs cause severe side effects due to unwanted IFN binding to IFN receptors present all over the body, resulting in widespread, aspecific action of the drug. AcTaferon circumvents these side effects by selective targeting of IFN to specific cell types. AcTaferon remains inactive “en route” through the body and unveils its antiviral activity only on specific target cells. This project aims to generate virus-targeted AcTaferons (O1) and to evaluate the prophylactic and therapeutic potential of virus- and immune cell-targeted AcTaferons to restrict influenza infection in vitro (O2 and O3) and in vivo (O4).
Several virus-targeted AcTaferons were successfully generated, optimized and extensively evaluated in vitro (O1). Their selective antiviral signalling and effect observed in vitro (O2, O3) creates prospects for further in vivo evaluation of their prophylactic and therapeutic potential (O4). Preliminary in vivo results were obtained and more in-depth analysis is foreseen.
The obtained results will be exploited by the joint consortium of the three collaborating partners (CNRS, VIB and Orionis Biosciences), helped by their respective technology transfer and innovation departments and disseminated through publication in a peer-reviewed international journal. To increase access to scientific information, online publication of research results after peer-review will be pursued in full respect of international copyright law. This will be enabled via self-archiving of published work or via open access publishing under the conditions permitted by the journal. Following submission to a journal, results will be further communicated by participation to an international meeting of the IFN community.
The obtained results will be exploited by the joint consortium of the three collaborating partners (CNRS, VIB and Orionis Biosciences), helped by their respective technology transfer and innovation departments and disseminated through publication in a peer-reviewed international journal. To increase access to scientific information, online publication of research results after peer-review will be pursued in full respect of international copyright law. This will be enabled via self-archiving of published work or via open access publishing under the conditions permitted by the journal. Following submission to a journal, results will be further communicated by participation to an international meeting of the IFN community.
Selective targeting of antiviral IFN activity using AcTaferons is expected to improve the anti-viral defense either by reinforcing direct antiviral activity, boosting the immune response or both.
AcTaferons have many innovative, improved characteristics compared to conventional (targeted) IFN formulations currently used to treat patients suffering from viral infections. AcTaferons (1) show little topological constraints, (2) function with various targeting moieties, (3) function at physiological levels of the targeted surface marker such as on primary cells, (4) exhibit much lower systemic “background” activity, (5) have a superior targeting efficiency, (6) are expected to display a superior pharmacokinetic behavior as they avoid uptake by non-targeted cells, thus assuring a better in vivo bio-distribution and (7) are easily produced at low cost and hence readily available. Taken together, they represent a new type of very promising therapeutic drugs to fight infectious diseases.
AcTaferons have many innovative, improved characteristics compared to conventional (targeted) IFN formulations currently used to treat patients suffering from viral infections. AcTaferons (1) show little topological constraints, (2) function with various targeting moieties, (3) function at physiological levels of the targeted surface marker such as on primary cells, (4) exhibit much lower systemic “background” activity, (5) have a superior targeting efficiency, (6) are expected to display a superior pharmacokinetic behavior as they avoid uptake by non-targeted cells, thus assuring a better in vivo bio-distribution and (7) are easily produced at low cost and hence readily available. Taken together, they represent a new type of very promising therapeutic drugs to fight infectious diseases.