DS0410 -

Development of innovative reagents targeting Mycobacterium tuberculosis – TARGIS

Submission summary

Tuberculosis (TB) is a contagious infectious disease that remains a major public health threat. Its etiologic agent is Mycobacterium tuberculosis (Mtb). The World Health Organization (WHO) reported that 9.6 million people developed TB in 2014 in different regions of the world including Europe. Furthermore, multi-drug resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) have emerged making the standard treatment virtually inefficient. Among the 480000 people who developed a MDR-TB, 190000 of them died in 2014. Although substantial progress has been made in tuberculosis drug development in the last decade, few novel drugs are in early clinical development phase and only two new drugs have been approved recently. Given the WHO ambitious goal to eradicate TB as a public health problem by 2050, imaging is a keystone for the diagnosis and treatment follow up, but no Mtb specific imaging tool is actually available. Thus, the lack of new drugs for more than forty years is dramatic and there is an emergency to develop new therapeutics and new imaging-based diagnostic tools.
Our project consists in the exploration of original approaches focused on the active targeting of Mtb by using a novel class of artificial affinity proteins, Affitins. Our aims are to minimize toxicity problems of novel compounds and emergence of drug resistance, as well as to develop TB specific and efficient imaging tools.
We have established Affitins as an innovative alternative to antibodies. Affitins are derived from archaeal extremophilic proteins from the Sac7d family and combine a number of favorable properties. With their molecular weight of 7 kDa (66 amino-acids), they are 20 times smaller than monoclonal antibodies, and their size is compatible with full chemical synthesis. Affitins are robust (temperature, pH, artificial gastric fluids, denaturants), easy to engineer, well expressed recombinantly in Escherichia coli, able to inhibit biological functions of targeted proteins either in vivo or in vitro. In vivo, they can target pathogenic cells without showing hepatic and renal retentions, and they show no immunogenicity after several intravenous injections in mice. Finally, they show a diffusion in mice much faster than that of monoclonal antibodies. All these properties validate Affitins as vector proteins suitable for in vivo usages in general, and for diagnosis and targeting applications in particular.
By using Affitins, TARGIS proposes to target exposed biomarkers, such as the extracellular region of PknB, a Ser/Thr kinase essential to survival of Mtb.
Through a joint effort of three teams with complementary expertise, the TARGIS consortium will produce previously identified anti-PASTA Affitins and will screen for new ones to diversify available Affitins for the program. In a first approach, these naked Affitins will be studied for their potential to interfere with Mtb growth in vitro. In a second innovative approach, Affitins will be coupled to a radionuclide to assess their potential to kill Mtb. Contrarily to a drug approach, it is expected that bacteria will have more difficulties to develop resistance mechanisms to radiations. Most promising Affitins will be also tested for their ability to reach Mtb in granuloma model and for their efficiency to inactivate Mtb in mice. Finally, Affitins will be evaluated as diagnostic tools as a radiotracer to perform imaging in mice using a positron emission tomography (PET) scan apparatus.
Outcome of our strategy has the potential to provide new route(s) to tackle both drug sensitive and drug-resistant Mtb infections, and should be transposable to other infection diseases. Furthermore, TARGIS should provide new tools, for example for specific PET imaging of Mtb, useful for diagnosis and for optimization of treatments.

Project coordinator

Monsieur Frédéric Pecorari (INSERM U892 - CNRS 6299 - Team 13)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

T5-INSERM INSERM U892 - CNRS 6299 - Team 5
T13-INSERM INSERM U892 - CNRS 6299 - Team 13
INSTITUT PASTEUR (BP)

Help of the ANR 466,840 euros
Beginning and duration of the scientific project: January 2017 - 48 Months

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