Low-dose pegylated interferon alfa-2a to reduce systemic inflammation after surgical or medical interventions

Abstract

A composition comprising pegylated interferon alfa-2a is provided for use at low subcutaneous dosage to attenuate the systemic inflammatory stress response and improve recovery after surgical or medical interventions.

Description

[0001] Low-dose pegylated interferon alfa-2a to reduce systemic inflammation after surgical or medical interventions

[0002] Field of the invention

[0003] The present invention reduces the systemic inflammatory stress response in patients undergoing surgical or medical interventions, the stress response being reflected by increased levels of markers of local and systemic inflammation and poor patient-reported outcomes. As such, it is relevant to any medical or surgical intervention leading to an intervention-related stress response as indicated by increased levels of systemic inflammatory markers.

[0004] Background of the invention

[0005] Complications after surgical or medical interventions is a huge global challenge in terms of both patient morbidity and mortality, as well as healthcare resource utilization and costs. Surgery-related complications encompass a broad spectrum of adverse events that can occur during, but more often after, surgical procedures. These complications may range from minor issues such as surgical site infections and wound dehiscence to more severe outcomes including organ dysfunction, sepsis, and even death. The incidence and severity of complications vary depending on factors such as the type of surgery, patient characteristics, and the quality of perioperative care. It is estimated that postoperative death is the third leading cause of death globally.

[0006] Complications arising from surgery can have profound implications for patient outcomes and quality of life. They may prolong hospital stays, necessitate additional medical interventions, and contribute to physical discomfort and psychological distress. In severe cases, complications can lead to longterm disability, impaired functional status, and reduced life expectancy. Furthermore, surgery- related complications impose a considerable burden on healthcare systems, consuming resources and diverting attention from other patient needs. The systemic inflammatory stress response triggered by surgical interventions is closely linked to the development of postoperative complications. Surgical trauma initiates a cascade of inflammatory pathways involving the release of pro-inflammatory cytokines, activation of immune cells, and disruption of homeostatic mechanisms. While this acute inflammatory response is essential for tissue repair and healing, dysregulation of the inflammatory cascade can exacerbate tissue damage, promote oxidative stress, and contribute to organ dysfunction. Mounting evidence suggests that the intensity and duration of the systemic inflammatory response following surgery correlate with the likelihood of complications. Excessive inflammation may compromise tissue perfusion, impair wound healing, and increase the susceptibility to infections. Moreover, systemic inflammation can exacerbate pre-existing comorbidities and predispose patients to cardiovascular events, respiratory complications, and other adverse outcomes.

[0007] Understanding the role of the systemic inflammatory stress response in surgery-related complications has significant clinical implications. Strategies aimed at modulating inflammation perioperatively have the potential to mitigate the risk of complications and improve patient outcomes. Pharmacological agents targeting specific inflammatory pathways, such as cytokine inhibitors and immunomodulatory agents, represent promising avenues for intervention. By attenuating the systemic inflammatory response, these interventions may reduce the incidence of postoperative complications, shorten and improve recovery, and enhance the overall safety and efficacy of surgical procedures.

[0008] Thus, surgery-related complications pose a substantial global health burden, impacting patient wellbeing and healthcare systems worldwide. The systemic inflammatory stress response serves as a critical determinant of postoperative outcomes, influencing the incidence, severity, and progression of complications. Recognizing the link between inflammation and surgical morbidity underscores the importance of developing targeted interventions to mitigate inflammation and optimize perioperative care. By addressing the underlying inflammatory pathways, novel therapeutic approaches have the potential to revolutionize surgical practice, enhance patient safety, and improve healthcare delivery on a global scale. One promising avenue of research could involve the use of interferons, a class of signaling proteins that play crucial roles in modulating immune responses in infectious viral diseases and in cancers.

[0009] Interferons

[0010] Interferons, including interferon alfa (I NFa), have immune-modulatory properties that make them potential candidates for mitigating the systemic inflammatory stress response induced by surgical interventions. These proteins exert their effects by binding to specific cell surface receptors and triggering intracellular signaling pathways that regulate the expression of genes involved in immune function and inflammation. Pegylated INFa-2a, a modified form of interferon alfa-2a conjugated with polyethylene glycol, has shown enhanced pharmacokinetic properties and prolonged biological activity compared to native INFa-2a. This makes pegylated INFa-2a an attractive candidate for therapeutic interventions aimed at modulating the inflammatory response in various clinical setings.

[0011] However, there is no prior evidence to support the efficacy of interferons, including pegylated interferons, in atenuating systemic inflammation related to surgical or medical interventions nor in reducing the incidence of postoperative complications in experimental models or clinical studies.

[0012] The current state of the art in reducing the surgery-related inflammatory stress response includes the use of corticosteroids immediately before, during or immediately after surgery.

[0013] Corticosteroids, commonly used for their anti-inflammatory and immunosuppressive properties, have long been a mainstay in perioperative care to mitigate the systemic inflammatory response associated with surgery. However, recent evidence suggests that the immunomodulatory effects of corticosteroids may have unintended consequences on oncological outcomes in patients undergoing cancer surgery. Of concern is the potential for corticosteroids to promote cancer progression and metastasis. In light of these concerns, it is relevant to explore alternative strategies for perioperative immunomodulation that minimize the risks of cancer progression and may even be beneficial in patients with cancer undergoing surgery. The present invention represents a significant advance in the field of perioperative medicine by leveraging the unique properties of pegylated INFa-2a to mitigate the systemic inflammatory stress response following surgery.

[0014] Summary of the invention

[0015] We have surprisingly found the invention that pegylated INFa-2a even in a low dose and only administered twice before surgery, exhibits a remarkable capacity to diminish the systemic inflammatory stress response following surgery for colon cancer and improve short term recovery. This reduction is evidenced by significant decreases in C-reactive protein (CRP) levels and neutrophil counts observed in the blood after surgery and quicker resolution of recovery in the early period after surgery. This finding suggests a potential therapeutic avenue for mitigating the risk of postoperative complications and facilitating an improved recovery process for patients undergoing surgery. By attenuating the systemic inflammatory stress response associated with surgery and by improving recovery in the early days after surgery, pegylated INFa-2a offer benefits beyond its conventional applications, paving the way for further exploration into its role in enhancing surgical outcomes and patient well-being. It is evident that the subcutaneous administration of low-dose pegylated INFa-2a will attenuate the systemic inflammatory stress response to any surgical or medical intervention that gives rise to such a response.

[0016] According to an embodiment, the invention concerns a composition comprising interferon, for use in the treatment of an inflammatory reaction, wherein said composition is for administration before a surgical or medical intervention that is expected to produce said inflammatory reaction.

[0017] According to an embodiment, the invention concerns a composition comprising pegylated interferon alfa-2a, for use in the treatment of an inflammatory reaction, wherein said composition is for subcutaneous administration before a surgical or medical intervention that is expected to produce said inflammatory reaction.

[0018] An inflammatory reaction may be defined as an inflammatory stress response, such as an inflammatory response to a surgical intervention. Such a response may result in increased levels of systemic inflammatory markers, such as elevated levels of CRP and / or neutrophil counts. An inflammatory reaction may be a surgical stress response, and / or an inflammatory response to a surgical or medical intervention. Said inflammatory reaction may also be an inflammatory process or inflammatory event.

[0019] In an embodiment, said inflammatory reaction is an acute inflammatory response.

[0020] An improved recovery may be defined by patient reported outcomes measures such as Quality of Recovery Questionnaire 15 or by other patient reported outcome measures.

[0021] A treatment may be a therapeutic treatment that require some intervention on the body or body part to be treated which cause a therapeutic effect, for example to attenuate an inflammatory response. Both prophylactic treatment, curative methods, improved recovery and attenuating an inflammatory response are covered by the word treatment, since they are directed to the maintenance or restoration of health.

[0022] According to an embodiment, the invention concerns the composition, wherein said interferon is interferon alfa.

[0023] According to an embodiment, the invention concerns the composition, wherein said interferon is interferon alfa-2a.

[0024] According to an embodiment, the invention concerns the composition, wherein said interferon is pegylated.

[0025] According to an embodiment, the invention concerns the composition, wherein said interferon is pegylated interferon alfa-2a.

[0026] According to an embodiment, the invention concerns the composition, wherein said interferon is pegylated with bis-monomethoxy polyethylene glycol. According to an embodiment, the invention concerns the composition, wherein said interferon is peginterferon alfa-2a, wherein said peginterferon alfa-2a is a covalent conjugate of the protein interferon alfa-2a produced by recombinant DNA technology in Escherichia coli with bis- [monomethoxy polyethylene glycol].

[0027] According to an embodiment, the invention concerns the composition, wherein said inflammatory reaction is a systemic inflammatory reaction, such as a systemic inflammatory stress response.

[0028] According to an embodiment, the invention concerns the composition, wherein said composition is for subcutaneous administration.

[0029] According to an embodiment, the invention concerns the composition for use in the treatment of the inflammatory reaction in a patient undergoing major surgery.

[0030] Major surgery involves complex procedures with significant manipulation of organs or tissues, typically requiring general anesthesia, extended hospitalization, and longer recovery times and with a high risk of mortality. Examples could include open-heart surgery, organ transplant, brain surgery, joint replacement, spinal fusion, major cancer surgeries, abdominal surgery, thoracic surgery, amputation, and hysterectomy.

[0031] Minor surgery involves simpler, less invasive procedures, often performed with local or regional anesthesia, requiring minimal or no hospitalization, and featuring shorter recovery periods and low risk of mortality. Examples could include removal of skin lesions, cataract surgery, biopsies, appendectomy, hernia repair, tonsillectomy, arthroscopy, dilation and curettage (D&C), vasectomy, and carpal tunnel release.

[0032] According to an embodiment, the invention concerns the composition for use in the treatment of the inflammatory reaction in a patient undergoing surgery for cancer, such as colon cancer. According to an embodiment, the invention concerns the composition for use in the treatment of the inflammatory reaction in a patient undergoing minor surgery including a minimally invasive intervention, such as endoscopic, endobronchial or endovascular interventions.

[0033] According to an embodiment, the invention concerns the composition for use in the treatment of the inflammatory reaction in a patient undergoing a medical intervention.

[0034] According to an embodiment, the invention concerns the composition, wherein said administration is a single subcutaneous dose in the range of 22.5 microgram to 90 microgram, such as 22.5 microgram, 45 microgram or 90 microgram.

[0035] According to an embodiment, the invention concerns the composition, wherein said administration is a continuous subcutaneous infusion at a rate corresponding to giving a dose in the range of 0.5 microgram per hour to 2 microgram per hour, such as 0.5 microgram per hour, 1 microgram per hour or 2 microgram per hour.

[0036] According to an embodiment, the invention concerns the composition, wherein said administration is more than one single dose in the range of 22.5 microgram to 90 microgram, such as 22.5 microgram, 45 microgram or 90 microgram, wherein said composition is administered during periods of up to 4 weeks before and after the intervention, a single dose being given during the intervention.

[0037] According to an embodiment, the invention concerns a use of the composition in a treatment of an inflammatory reaction.

[0038] Brief description of the drawings

[0039] Figure 1. Boxplot of plasma CRP levels (mg / L) on postoperative day 1 (POD1). Interferon alfa = Pegylated INFa-2a. Figure 2. Boxplot of plasma CRP levels (mg / L) on postoperative day 2 (POD2). Interferon alfa = Pegylated INFa-2a.

[0040] Detailed description of the invention

[0041] Pegylated INFa-2a

[0042] Interferon alfa (INFa) is a cytokine normally produced by virus-infected cells and various immune cells (e.g., antigen-presenting cells such as dendritic cells) in response to viral infections. Secreted INFa binds to the INFa receptor (IFNAR) which activates and promotes the autophosphorylation of the receptor-associated kinases (Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2). The autophosphorylation of JAK1 and TYK2 activates the STAT1 and STAT2 proteins which form a heterodimer. The heterodimer of STAT1 and STAT2 form a complex (ISG factor 3) with INF regulatory factor 9 (IRF9). This complex promotes the transcription of INF stimulated genes (ISGs) through translocation to the nucleus. The ISGs are involved in viral and pathogen detection, immune modulation, apoptosis, cell attraction and cell adhesion. The immune modulating effects of ISGs are related to interleukin 12 (IL-12), tumor necrosis factor alfa (TNFa) and INFy. Under normal physiological circumstances, INFa inhibits the replication of viral proteins and upregulates the expression of the major histocompatibility complex (MHC) I. These changes enhance the antigen presentation to lymphocytes including CD8 cytotoxic T cells which are responsible for antiviral and antitumoral responses. Thus, INFa is an important promoter of the adaptive immune responses.

[0043] Pegylated INFa-2a is a modified form of interferon alfa-2a conjugated with polyethylene glycol. The molecule shows enhanced pharmacokinetic properties and prolonged biological activity compared to native interferon alfa-2a. Pegylation increases the size of the molecule, which makes it circulate longer in the bloodstream, results in a slower rate of clearance from the body and thereby extends the half-life of the drug and reducing the frequency of dosing required. Pegylation also enhances the stability of the drug, making it more resistant to degradation by enzymes leading to improved bioavailability and therefore a more consistent and predictable therapeutic effect. Finally pegylation can also reduce immunogenicity and thereby reduce the potentially side effects associated with its use. Dosing of pegylated INFa-2a

[0044] In Example 1 below, a low dose of pegylated INFa-2a, administered twice prior to surgery within a 10-day window, was effective in attenuating the systemic inflammatory stress response to surgery. The innovatory use of pegylated INFa-2a extends beyond this specific low-dose regimen and can be expected to have an effect on the post-intervention systemic inflammatory stress response using other dosing regimens including those involving doses of 22.5, 45, or 90 micrograms per single subcutaneous administration. This nuanced dosing strategy offers flexibility by providing a range of dosage options to attenuate the post-intervention systemic inflammatory stress response in various situations and hereby create improved outcomes.

[0045] In addition, as a regimen of repeated fixed doses can reduce the post-intervention systemic inflammatory response, opting for dosage by continuous subcutaneous infusion can sustain therapeutic levels of INFa-2a in the bloodstream, thereby maintaining a consistent suppression of the inflammatory response over an extended period. This approach not only minimizes fluctuations in drug concentration but also offers the advantage of improved patient compliance and convenience.

[0046] Diverse dosing strategies should be considered by the treating clinician according to the specific circumstances affecting the patient and the planned intervention. These include extended periods of administration of the composition both before and after surgery. By extending the dosing duration for up to four weeks before or after surgery, the full therapeutic potential of pegylated INFa-2a in attenuating the post-intervention systemic inflammatory response. Whether administered by continuous subcutaneous infusion or through repeated subcutaneous doses, these extended regimens offer several advantages. First, prolonged exposure to INFa-2a may lead to a more pronounced suppression of the inflammatory response, potentially reducing the risk of postoperative complications and expediting the recovery process. In addition, the post-intervention administration of pegylated INFa-2a can facilitate swift resolution of inflammation, promoting tissue healing and reducing recovery time. Pegylated IN Fa-2 a in current clinical practice

[0047] Due to its antiviral and anti-neoplastic effects, pegylated INFa-2a is currently used in the treatment of chronic hepatitis B (HBV) and C (HBC) and chronic myeloid leukemia (CIVIL). In chronic HBV infection, INFa is used as a single treatment modality or in combination with other antiviral medications to suppress viral replication, reduce virally mediated liver inflammation, and thereby prevent disease progression. INFa stimulates the production of antiviral cytokines and enhances the activity of natural killer cells and cytotoxic T lymphocytes, which target and eliminate HBV-infected hepatocytes. Additionally, INFa may induce direct antiviral effects by inhibiting viral RNA transcription and protein synthesis. In HCV infections, INFa enhances the host immune response against HCV, leading to viral clearance and suppression of viral mediated liver inflammation. Additionally, INFa may exert direct antiviral effects by inhibiting HCV replication and protein synthesis.

[0048] In chronic myeloid leukemia (CIVIL), pegylated INFa-2a inhibits proliferation, induces apoptosis, and modulates the bone marrow microenvironment. Additionally, INFa enhances the antitumor immune response by activating cytotoxic T cells and natural killer cells, which target and eliminate leukemic cells. INFa has also been used in the treatment of renal cell carcinoma (RCC) and malignant melanoma. Pegylated INFa-2a has historically been used as a cytokine-based immunotherapy for advanced RCC. INFa exerts its antitumor effects through multiple mechanisms, including inhibition of angiogenesis, stimulation of immune responses, and direct antiproliferative effects on tumor cells.

[0049] Clinical trials have also demonstrated a modest improvement in relapse-free survival with adjuvant INFa therapy compared to observation alone, particularly in patients with intermediate to high-risk malignant melanoma.

[0050] Surgical Stress Response (SSR)

[0051] A surgical stress response may be defined as the predictable, primarily sterile, damage-associated molecular pattern ( DAM P)-d riven host program initiated by surgical tissue injury and anaesthesia, comprising a coordinated neuroendocrine (activation of the hypothalamic-pituitary-adrenal axis and sympatho-adrenal system), autonomic (shift toward sympathetic dominance), metabolic (transient insulin resistance, hyperglycemia, lipolysis, and proteolysis), and innate / adaptive immune response (acute-phase reaction and transient immune redistribution). The response is evidenced by one or more of: elevated cortisol and / or catecholamines, hyperglycemia or reduced insulin sensitivity, reduced heart-rate variability, elevated CRP, neutrophilia and increased NLR, complement activation, changes in chemokines / endothelial factors, Thl->Th2 skewing with reduced NK-cell activity, altered yST-cells, and altered T-cell clonality, often accompanied by a transient deterioration in patient-reported recovery (e.g., QoR-15). By definition it arises without clinical or microbiological evidence of infection and without infection-related organ dysfunction.

[0052] The Surgical Stress Response (SSR) is initiated by sterile surgical injury (mainly DAM P-d riven) and anesthesia, is time-locked to the procedure, and is characterized by HPA and sympatho-adrenal activation with transient insulin resistance and catabolism; innate immune activation is accompanied by predictable lymphocyte redistribution (e.g., Thl->Th2 skewing, NK suppression). In contrast, sepsis requires suspected or proven infection (PAMP-driven) and is defined by infection-related organ dysfunction; its inflammatory and cardiovascular profile is dominated by pathogen-mediated dysregulation and microcirculatory / vasoplegic changes. Accordingly, the SSR is identified in its immediate absence of clinical or microbiological evidence of infection and without infection-related organ dysfunction, whereas sepsis (including postoperative sepsis) is excluded by these criteria.

[0053] Examples

[0054] Example 1

[0055] Prospective randomized trial of low-dose s.c. pegylated INFa-2a in patients scheduled for elective surgery for colon cancer

[0056] 18 adult patients (aged 50 to 86 years) were randomized to receive subcutaneous injections of either 45 pg of pegylated INFa-2a or placebo twice in a period of 10 days before surgery, the first dose being given around 10 days before surgery and the second dose on the day of surgery. The active and placebo groups consisted of 9 patients each, 7 women and 2 men in the active group, and 4 women and 5 men in the placebo group.

[0057] The patients in the active group receiving subcutaneous pegylated INFa-2a reacted with local inflammatory reaction at the injection site, several of the patients experiencing chills and transient systemic discomfort lasting for minutes to hours. The systemic inflammatory stress response was assessed by measurement of plasma CRP and by white blood cell counts including neutrophils and lymphocytes the day after and two days after surgery.

[0058] Of the patients receiving pegylated INFa-2a, 5 patients had a local reaction at the injection site and / or had a mild systemic response. Statistical significance was assessed using the Mann-Whitney U-test. The active group had significantly lower plasma CRP levels after surgery with a median of 35 mg / L (range 4 to 70) on postoperative day 1 (p-value 0.007775). The plasma CRP level was near- significantly lower with a median of 40 mg / L (range 8 to 216) on postoperative day 2 (p-value 0.05031). Compared to the placebo group that had higher CRP levels on both day 1 and 2 after surgery with a median of 81 mg / L (range 52 to 117) on postoperative day 1 and 121 mg / L (range 79 to 233) on postoperative day 2 (Figures 1 and 2).

[0059] For the neutrophil count the same pattern was seen with a mean value of 8.8 and 6.4 109 / L the first and second day after surgery in the active group versus 10.4 and 8.7 109 / L in the placebo group respectively. The statistical significance was assessed with Welch Two Sample t-test. The neutrophil count in the active group was significantly lower on postoperative day 2 compared to the placebo group (p-value 0.04385).

[0060] The minimal clinically significant improvement in Quality of Recovery Score 15 (QoR-15 represents a scale going from 30 to 150 with higher numbers indicating improved recovery) is 8. Quality of recovery, measured by the QoR-15 was improved from day one after surgery to day 2 after surgery going from a score of 102 to 116 in the interferon group and going from 110 to 96 in the placebo group. In 20 patients, with ten patients in the interferon group compared with 10 patients in the placebo group, the number of patients having an improvement in their score from day 1 to day to was 9 in the interferon group and 4 in the placebo group (P=0.057).

[0061] Collectively these effects represent a substantial attenuation of the postoperative systemic inflammatory response, which is expected to reduce the risk of complications and also improve recovery after surgery. The direct effects of pegylated INFa-2a on the tumor microenvironment and the improved earlier recovery that have already been described may in turn lead to improved longterm oncological outcomes such as a reduced risk of recurrence and improved survival.

[0062] Example 2

[0063] Patient receiving pegylated INFa-2a before surgery for colon cancer

[0064] A 50-year-old female without significant previous medical history was diagnosed with stage II colon cancer and scheduled for a surgical resection. The first perioperative subcutaneous administration of 45 microgram pegylated INFa-2a was administered by the nurse after the patient's visit at the outpatient clinic 9 days before surgery. The patient was admitted on the morning of surgery where she received the second dose of 45 microgram pegylated INFa-2a. The patient underwent laparoscopic resection of the sigmoid colon and experienced expedited recovery with minimal abdominal pain. She was discharged on postoperative day 2.

[0065] The improvement obtained by the treatment in the surgical stress and inflammatory response was reflected in the postoperative levels of CRP and the neutrophil counts. The patient had a normal CRP level (8 mg / L) on both postoperative days 1 and 2. A marginal increase in the neutrophil count was seen on postoperative day 1 (7.25 109 / L). This was normalized on the postoperative day 2 (4.41 109 / L). The patient's enhanced postoperative recovery was also reflected in the QoR-15 score, which increased from 102 to 131 from postoperative day 1 and day 2.

[0066] Example 3

[0067] Patient receiving pegylated INFa-2a before surgery for colon cancer

[0068] A 64-year-old female with a history of hypercholesterolemia was diagnosed with stage I colon cancer and scheduled for a surgical resection. The first perioperative subcutaneous administration of 45 microgram pegylated INFa-2a was administered by the nurse after the patient's visit at the outpatient clinic 9 days before surgery. The patient was admitted on the morning of surgery where she received the second dose of 45 microgram pegylated INFa-2a. The patient underwent laparoscopic left-sided hemicolectomy and experienced expedited recovery with no symptoms of nausea and minimal abdominal pain. She was discharged on postoperative day 3.

[0069] The substantial improvement obtained by the use of pegylated INFa-2a in the management of surgical stress and inflammatory response during the surgery was evident from the significantly low levels of CRP on the postoperative day 1 (35 mg / L) and postoperative day 2 (27 mg / L). This was also reflected in the neutrophil counts, where the count was 8.66 109 / L on the first day after surgery and normalized on the second postoperative day to 4.67 109 / L).

[0070] A notable increase in the patient's QoR-15 score from postoperative day 1 to postoperative day 2 with a rise from 85 to 116.

[0071] Example 4

[0072] Patient receiving placebo before surgery for colon cancer

[0073] A 62-year-old female with a history of hyperthyroidism was diagnosed with stage III colon cancer and scheduled for a surgical resection. The first perioperative subcutaneous administration of placebo (saline) was administered by the nurse after the visit at the outpatient clinic 9 days before surgery. The patient was admitted on the morning of surgery when she received the second dose placebo. The patient underwent laparoscopic right-sided hemicolectomy. In the days after surgery, the patient experienced abdominal pain and nausea. The increased postoperative systemic inflammation was revealed by the high levels of CRP and neutrophil counts on day 1 and day 2 after surgery. The patient had a CRP level of 89 mg / L and neutrophil count of 9.23 109 / L on postoperative day 1. On postoperative day 2, the CRP level rose to 172 mg / L and the neutrophil count was 8.56 109 / L.

[0074] The impact of postoperative inflammation on recovery was evident in a low QoR-15 score of 23 on postoperative day 1, with a substantial increase on day 2, rising to 85.

[0075] Embodiments

[0076] In an embodiment of the invention, pegylated INFa-2a is administered at a dose in the range of 22.5 microgram to 90 microgram subcutaneously on two occasions before any surgical or medical intervention that is expected to result in a systemic inflammatory stress response due to the intervention planned.

[0077] In a further embodiment of the invention, pegylated INFa-2a is administered at a dose in the range of 22.5 microgram to 90 microgram subcutaneously on one occasion before any urgent or emergent surgical or medical intervention that is expected to result in a systemic inflammatory stress response due to the intervention planned.

[0078] In a further embodiment of the invention, pegylated INFa-2a is administered in a repeated dose of up to 90 microgram subcutaneously during a period of up to 4 weeks before any elective surgical or medical intervention that is expected to result in a systemic inflammatory stress response due to the intervention planned.

[0079] In a further embodiment of the invention, pegylated INFa-2a is administered in a repeated dose of up to 90 microgram subcutaneously during a period of up to 4 weeks after surgery for any elective surgical or medical intervention that is expected to result in a systemic inflammatory stress response due to the intervention planned.

[0080] In a further embodiment of the invention, pegylated INFa-2a is administered as a continuous subcutaneous infusion at a total dose of up to maximum 180 microgram per week during a period of up to 4 weeks before or after any elective surgical or medical intervention that is expected to result in a systemic inflammatory stress response due to the intervention planned.

[0081] In a further embodiment of the invention, pegylated INFa-2a is administered as a continuous subcutaneous infusion at a total dose of up to 180 microgram per week during a period of up to 4 weeks after any urgent or emergency surgical or medical intervention that is expected to result in a systemic inflammatory stress response due to the intervention. In a further embodiment, the invention relates to a composition comprising interferon, for use in the treatment of an inflammatory reaction and the following recovery wherein said composition is for administration before a surgical intervention, or any medical intervention that can cause an inflammatory reaction, such as but not limited to endovascular-, endoscopic procedures, organ transplantation or thrombolysis, which is expected to produce said inflammatory reaction and a need for recovery.

[0082] In a further embodiment, the composition according to the invention is administered before a surgical or medical intervention. Said composition may be administered within 10 weeks before said surgical or medical intervention, within 9 weeks before, within 8 weeks before, within 7 weeks before, within 6 weeks before, within 5 weeks before or about within 4 weeks before, about 3 weeks before, about 2 weeks before, or about 1 week before.

[0083] In a further embodiment, the composition according to the invention does not comprise a steroid, such as a corticosteroid.

[0084] In a further embodiment, the composition according to the invention is not for use in the treatment of hepatitis.

[0085] In a further embodiment, the composition according to the invention is not for administration after said surgical or medical intervention.

[0086] In a further embodiment, said inflammatory reaction is an inflammatory reaction to a surgical or medical intervention. Said inflammatory reaction is not a reaction to a bacterial or viral infection, such as purulent sepsis. In an embodiment, the invention is related to reducing the natural response to surgery and / or a medical intervention.

[0087] In a further embodiment, the composition according to the invention, is for use in preventing relapse of medical condition, such as a tumor, such as a colorectal cancer. In a further embodiment, the composition according to the invention, is not for oral administration.

[0088] 5

Claims

Claims1. A composition comprising interferon for use in the treatment of an inflammatory reaction, wherein said composition is for administration before a surgical or medical intervention that is expected to produce said inflammatory reaction.

2. The composition of claim 1, wherein said interferon is interferon alfa.

3. The composition of claim 1-2, wherein said interferon is interferon alfa-2a.

4. The composition of claim 1-3, wherein said interferon is pegylated.

5. The composition of claim 1-4, wherein said interferon is pegylated interferon alfa-2a.

6. The composition of claim 1-5, wherein said interferon is pegylated with bis-monomethoxy polyethylene glycol.

7. The composition of claim 1-6, wherein said inflammatory reaction is a systemic inflammatory reaction, such as a systemic inflammatory stress response.

8. The composition of claim 1-7, wherein said treatment results in one or more of the following: reduced levels of C-reactive protein (CRP) levels, reduced neutrophil count, improved neutrophil-lymphocyte ratio (NLR), lower neutrophil-lymphocyte ratio (NLR), changes in the complement system, activation of the complement system, altered levels of chemokines, altered levels of endothelial factors, reduced levels of Th2-cells, normalized or increased levels of NK-cells, altered levels of y6 T-cells, altered levels of T-cell clonality (TCR) and / or improved QoR-15 score.

9. The composition of claim 1-8, wherein said composition is for subcutaneous administration.

10. The composition of claim 1-9 for use in the treatment of the inflammatory reaction in a patient undergoing surgery for cancer, such as colon cancer.

11. The composition of claim 1-10 for use in the treatment of the inflammatory reaction in a patient undergoing minor surgery including a minimally invasive intervention, such as endoscopic, endobronchial or endovascular interventions.

12. The composition of claim 1-11 for use in the treatment of the inflammatory reaction in a patient undergoing a medical intervention.

13. The composition of claim 1-12, wherein said administration is a single subcutaneous dose in the range of 22.5 microgram to 90 microgram, such as 22.5 microgram, 45 microgram or 90 microgram.

14. The composition of claim 1-13, wherein said administration is a continuous subcutaneous infusion at a rate corresponding to giving a dose in the range of 0.5 microgram per hour to 2 microgram per hour, such as 0.5 microgram per hour, 1 microgram per hour or 2 microgram per hour.

15. The composition of claim 1-14, wherein said administration is more than one single dose in the range of 22.5 microgram to 90 microgram, such as 22.5 microgram, 45 microgram or 90 microgram, wherein said composition is administered during periods of up to 4 weeks before and after the intervention, a single dose being given during the intervention.

16. The composition of claim 1-15, wherein said medical intervention is a medical intervention that can cause an inflammatory reaction, such as endovascular procedures, endoscopic procedures, organ transplantation or thrombolysis.

17. The composition of claims 1-16, wherein said inflammatory reaction is a surgical stress response.

18. The composition of claims 1 - 17, wherein said inflammatory reaction is a result of a surgical intervention.

19. The composition of claims 1-18, wherein said inflammatory reaction is a surgical stress response, and wherein said surgical stress response is a systemic reaction to surgical tissue injury and / or anesthesia.

20. The composition of claims 1-19 for use in reducing recurrence of a surgically removed tumor.

21. The composition of claims 1-20, wherein said composition is not for use in the treatment of sepsis or an infection induced systemic inflammatory reaction.

22. The composition of claims 1-21, wherein said surgical stress response occurs in the absence of clinical or microbiological evidence of infection and / or without infection related organ dysfunction.

23. The composition of claims 17-22, wherein said surgical stress response is a systemic reaction characterized by one or more of the following, a. Increased levels of C-reactive protein (CRP), b. Increased neutrophil count, c. Increased neutrophil-lymphocyte ratio (NLR), d. Activation of the complement system, e. Altered levels of chemokines, f. Altered levels of endothelial factors, g. Increased levels of Th2-cells, h. Reduced levels of NK-cells, i. Altered levels of yST-cells, j. Altered levels of T-cell clonality (TCR) and / or k. Worsened QoR-15 score.

24. The composition of claims 1-23, wherein said composition comprises pegylated interferon alpha 2a for use in the treatment of a surgical stress response, wherein said composition isfor administration before a surgical intervention that is expected to produce said surgical stress response.

25. The composition of claims 1-24, wherein said surgical stress response is a primarily sterile, damage associated molecular pattern (DAMP) mediated systemic reaction to surgical tissue injury and / or anesthesia.

26. The composition of claims 17-25, wherein said surgical stress response is a primarily sterile, damage associated molecular pattern (DAMP) mediated systemic reaction to surgical tissue injury and / or anesthesia, characterized by activation of the hypothalamic-pituitary-adrenal axis and the sympatho adrenal system and by one or more of:(a) elevated plasma cortisol and / or catecholamines;(b) transient hyperglycemia and / or reduced insulin sensitivity;(c) reduced heart rate variability and / or increased sympathetic tone;(d) increased levels of C reactive protein (CRP);(e) increased neutrophil count and / or increased neutrophil to lymphocyte ratio (NLR);(f) activation of the complement system;(g) altered levels of chemokines;(h) altered levels of endothelial factors;(i) increased levels of Th2 cells;(j) reduced levels of NK cells;(k) altered levels of y6T cells;(l) altered T cell clonality (TCR); and / or(m) worsened QoR 15 score; wherein said surgical stress response occurs in the absence of clinical or microbiological evidence of infection and without infection related organ dysfunction.

27. The composition of claims 17-26, wherein said composition comprises pegylated interferon alfa 2a for use in attenuating said surgical stress response, wherein said composition is for subcutaneous administration before a surgical intervention that is expected to produce saidsurgical stress response, and wherein said composition is not for the treatment of sepsis or an infection induced systemic inflammatory responses.

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