There are more than 300 million people in the world suffering from chronic hepatitis B, which is one of the first factors for liver cirrhosis and tumor. In patients affected by this chronic infection, immune system fails to eradicate the virus responsible for this disease, that survives and continues to reproduce in the liver cells.

Researchers at San Raffaele Hospital and San Raffaele University, thanks to this fruitful collaboration with the American start up Asher Biotherapeutics, tested for the first time in the world, in preclinical models, a molecule which is able to re-activate immune system against chronic hepatitis B.

The research – published today on the prestigious scientific journal Science Translational Medicine and headed by Professor Matteo Iannaccone, Director of the Immunology, Transplantation and Infective Diseased Division at IRCCS San Raffaele Hospital – and returned to Italy from USA that to Career Development Award of Amenise-Harvard Fountation – put the basis for future clinical development of possible immunotherapies for this serious pathology.

Hepatitis B virus and current therapies

Hepatitis B virus (HBV) is transmitted by contact with infected blood, sexually or from mother to child during childbirth. Contrary to what happens when an adult contracts the virus, over 90% of children infected from birth develop chronic hepatitis B. In patients suffering from this chronic infection immune system fails to eradicate the virus responsible for this disease, that survives and continues to reproduce in liver cells.

Nowadays there is a preventive vaccine for this disease, but patients affected by HBV cannot benefit from it. Scientific research is developing considerably in antiviral field, in which San Raffaele Hospital is an international point of reference.

The research of Matteo Iannaccone’s team, in collaboration with the Unit headed by Professor Luca Guidotti, scientific deputy director of the institute, contributed in these years to develop some of current antiviral that today are used to treat the disease in its chronic form.

How to awaken the immune system: the proposal of San Raffaele Hospital

What causes the ineffectiveness of the immune system and how could we awake its action? Researchers had already answered to this question in 2019 with a study published on Nature in which they demonstrated, through a molecular analysis realized thanks to intravital microscopy, that T-lymphocytes, cells of our immune system responsible for attacking HBV virus, cannot eradicate infection and they result dysfunctional since their activation.

Characterizing dysfunctional T-cells permitted to San Raffaele researchers to identify the most suitable and effective molecules able to awake these cells. Among those, interleukina-2, a messenger-molecule of immune system, a sort of immunotherapy, that has been already tested successfully both in vitro, on patient cells, and in animal models.

Interleukina-2, unfortunately, if administered systemically, lead to serious side effects: it increases the permeability of blood vessels and this causes a severe edema. This happens because molecule fails to reach its target only (t-cells), but they reach also Natural Killer cells (that induce toxicity) and on regulatory cells (that suppress the immune response).

The new study

The study, just published on Science Translational Medicine, develops a particular element already present in the 2019 research: thanks to the Asher Biotherapeutics company which produces interleukina-2, scientists have successfully tested this molecule, developing a “cis-targeting” approach: interleukina-2, conjugated with a specific antibody, is now able to reach t-cells only, activating them correctly against the disease.

“We have seen – on mouse models of disease – that, administering this type of immunotherapy, t-cells expand and increase their functions, i.e. they release cytokines that are able to inhibit viral replication and to eliminate infected cells, eradicating effectively the virus”, says Professor Matteo Iannaccone.

The study demonstrates, in preclinical models of hepatitis B and in the blood of healthy people, the safety, the low toxicity and therapeutic efficacy of this innovative approach.

“In addition to antiviral approaches, it is possible to think to a strategy of immunotherapy. The next step is to test this approach on men, combining it with antivirals”, concludes the researcher.

The research was granted by European Research Council (ERC), by AIRC Foundation for research on cancer, by Ministry of Health and by Ministry of University and Research.