CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of Finnish Patent Application No. 20186041 filed on Dec. 4, 2018, the disclosure of which is incorporated herein in its entirety by reference.

The present application includes a Sequence Listing filed in electronic format. The Sequence Listing is entitled “3100-120_AP107638US.txt” created on Mar. 6, 2020, and is 2 bytes in size. The information in the electronic format of the Sequence Listing is part of the present application and is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a method for determining a patient's responsiveness to the therapy comprising administration of type I interferon in order to make the decision to treat a patient with type I interferon and use of specific single nucleotide polymorphism as a marker for determining patient's responsiveness to said therapy. The present invention relates also use of type I interferons to treat patients having specified single nucleotide polymorphism.

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details the practice, are incorporated by reference.

Type I interferons (interferon alpha and beta among others) are our first line of defence in infections (Levy et. al., 2003). As a counter measure to acute insults type I interferons enhance cell membrane and vascular integrity. Vascular leakage is an important feature in sepsis; severe respiratory viral infections, such as MERS, SARS and influenza; viral hemorrhagic fever, such as Ebola; systemic inflammatory response syndrome (SIRS) and ischemia-reperfusion injuries brought forth by major trauma or cardiovascular surgery. Type I interferons have the ability to up-regulate CD73, a molecule which yields anti-inflammatory adenosine (Jalkanen and Salmi, 2006). CD73 derived adenosine enhances endothelial barrier function and leads to the prevention of vascular leakage, the predominant pathophysiological event in acute organ injury (Kiss et. al., 2007), namely acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and multi-organ failure (MOF). Vascular leakage in acute lung injury (ARDS) allows plasma exudation into the alveolar space leading to potentially life-threatening hypoxaemia. Interferon beta-1a has been shown to reduce the impact of ARDS by reducing vascular leakage (Bellingan et. al., 2014).

As with all protein-based biopharmaceuticals, one major obstacle that must be overcome in the use of type I interferons, such as interferon alpha or beta as a therapeutic agent is its bioactivity in an individual and exerting its anticipated effects. Genetic difference in molecular pathways threaten polypeptide activity and efficacy in pharmaceuticals. Some of these changes are known to lead to the loss or reduction of the pharmaceutical bioactivity of the protein of interest. When small amounts of hormone peptides are administered, it is also crucial that the patient is responsive to the treatment.

Type I interferons are also widely used in the treatment of multiple sclerosis (MS), but over 50% of patients do not respond to the treatment. The reason for this is unknown (Mahurkar et. al. 2016). As MS is usually a slowly progressive disease it takes in average up to 2 years to clinically determine if an MS patient is responsive to treatment or not. Means to pre-determine if a patient is responsive to interferon treatment or not are desperately needed both in MS, and also in life threating acute conditions, such as in ARDS and/or conditions associated with vascular leakage and organ dysfunction, were type I interferon could be used to enhance vascular integrity and prevent acute organ failure.

SUMMARY OF THE INVENTION

It is an object of the present invention to reduce or even eliminate the above-mentioned problems appearing in prior art.

An object of the present invention is to provide a method to make a clinical decision to treat a patient with type I interferon, and to predict an outcome and response in a disease and/or disorder requiring pharmacological intervention with type I interferon. One object is to provide a marker for use in predicting patents' responsiveness to a therapy comprising an administration of type I interferons.

By having a predictive test about the treatment response, the doctor can easily and efficiently optimize the care of the patient. Therefore, an object of the present invention is to provide a combination of a genetic test and pharmacological intervention with type I interferon to help physicians in their decision making.

Further, an object of the present invention is to provide a treatment with pharmacological intervention based on patient selection. Especially, an object of the present invention is to provide a treatment method with type I interferons to specifically identified patient group, i.e. personalized therapy.

In order to achieve among others the objects presented above, the invention is characterized by what is presented in the enclosed independent claims. Some preferred embodiments of the invention will be described in the other claims.

The embodiments and advantages mentioned in this text relate, where applicable, both to the methods and to the uses according to the invention, even though it is not always specifically mentioned.

A typical method according to the present invention is used to determine a patient's responsiveness to a therapy comprising administration of type I interferon and optionally concomitant administration of a corticosteroid, the method comprisingobtaining a sample from a patient,determining the presence or absence of single nucleotide polymorphism (SNP) rs9984273 (C/T) in subunit 2 of the interferon alpha and beta receptor (IFNAR2) in chromosome 21 from the sample obtained from the patient, andclassifying the patient on the grounds of the presence or absence of said SNP, whereini) the presence of said SNP indicates responsiveness to the therapy, which comprises an administration of type I interferon to said patient with or without concomitant administration of corticosteroids, orii) the absence of said SNP indicates non-responsiveness to the therapy with concomitant administration of corticosteroids and modest responsiveness to said therapy without concomitant administration of corticosteroids.

The present invention concerns also use of a single nucleotide polymorphism (SNP) rs9984273 (C/T) and/or a SNP in linkage disequilibrium with the SNP rs9984273 (C/T), in subunit 2 of the interferon alpha and beta receptor (IFNAR2) in chromosome 21, for a marker for determining a patient's responsiveness to a therapy comprising administration of type I interferon and optionally concomitant administration of corticosteroids, i.e. said SNP can be used as a marker in a selection of patients to the treatment comprising type I interferon and optionally concomitant with a corticosteroid. In a preferred embodiment of the present invention, a single nucleotide polymorphism (SNP) rs9984273 (C/T) and/or a SNP in linkage disequilibrium with the SNP rs9984273 (C/T), in subunit 2 of the interferon alpha and beta receptor (IFNAR2) in chromosome 21 is used as a marker in a selection of patients to the treatment comprising type I interferon concomitant with a corticosteroid.

Further the present invention concerns a composition comprising type I interferon as an active ingredient for use in prevention and/or treatment of a disease or a disorder requiring or beneficiating from a pharmacological intervention with type I interferon in an individual, wherein said individual has a detected single nucleotide polymorphism (SNP) rs9984273 (C/T) and/or a detected SNP in linkage disequilibrium with the SNP rs9984273 (C/T), in subunit 2 of the interferon alpha and beta receptor (IFNAR2) in chromosome 21.

Now, it has been observed that the patients receiving type I interferon treatment and having single nucleotide polymorphism (SNP) rs9984273 (C/T) in subunit 2 of the interferon alpha and beta receptor (IFNAR2) had a significantly better outcome than did the patients receiving interferon treatment without said SNP rs9984273 (C/T). The results show that SNP rs9984273 (chr 21: chr position 34635065) marker associates with the response to type I interferon therapy. The sequence containing this polymorphic marker is a glucocorticoid receptor binding site in IFNAR2 gene. In the large-scale phase III randomized placebo-controlled study, it has been observed that patients having CT instead of TT in IFNAR2 are enriched among responders and they have also better survival in ARDS. Therefore, it has been observed that SNP rs9984273 (C/T) and/or a SNP in linkage disequilibrium with the SNP rs9984273 (C/T) in IFNAR2 can be as a marker to aid a clinical decision making to start or not to start pharmacological type I interferon intervention in a patient suffering a disease or a disorder requiring or beneficiating from an administration of type I interferon. This finding enables to personalize patient's treatment methods on the grounds of the presence or absence of SNP rs9984273 (C/T) in IFNAR2. The presence or absence of SNP rs9984273 (C/T) in IFNAR2 may be determined simply by using a specific genomic test and the result of the test may be utilized to estimate outcome and response in a disease or a disorder requiring intervention with type I interferon.

Further, it has been observed that concomitant corticosteroid uses with type I interferons, such as interferon alpha or interferon beta, does not affect the treatment response in the patients having SNP rs9984273 (C/T) in IFNAR2. In patients having SNP rs9984273 (C/T) in IFNAR2 has responsiveness to type I interferon, such as interferon alpha or interferon beta pharmacological intervention despite concomitant corticosteroid use. The presence of SNP rs9984273 (C/T) in IFNAR2 in patient provides a treatment method to up-regulate CD73 by using type I interferon despite concomitant corticosteroid use. The presence of SNP rs9984273 (C/T) in IFNAR2 in patient can also be used as a marker to aid a clinical decision making to start or not to start an administration of corticosteroids in a combination with type I interferon treatment.

According to one aspect of the present invention a combination of genetic test and type I interferon treatment can be used in the prevention and/or treatment of acute organ injuries (ARDS, AKI, SIRS and MOF) and severe viral infections. One such treatment is intravenous interferon beta-1a, which is considered to be beneficial e.g. in the treatment of acute organ injuries (ARDS, AKI, SIRS and MOF) and severe viral infections.

According to another aspect of the present invention, a combination of genetic test and type I interferon treatment can be used in the prevention and/or treatment of vascular-endothelial diseases in humans with sepsis, severe acute viral infections, humans undergoing major cardiovascular surgery leading to ischemia-reperfusion injury, and disease states referred to as AKI, ARDS, SIRS, MOF, as well as MS.

According to yet another aspect of the present invention, a combination of genetic test and type I interferon treatment can be used in the prevention and/or treatment of malignant diseases in humans comprising hairy cell leukaemia, malignant melanoma, follicular lymphoma, condylomata acuminate, AIDS related Kaposi's Sarcoma, chronic hepatitis C, acute hepatitis C, and chronic hepatitis B.

According to the present invention SNP rs9984273 (C/T) and/or a SNP in linkage disequilibrium with the SNP rs9984273 (C/T) in IFNAR2 can be used as prognostic biomarker in the above-mentioned conditions/diseases.

