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EP-4739333-A1 - TGF-SS INHIBITION AND ENGINEERED T-CELLS FOR THE TREATMENT OF COVID-19 SEQUELAE AND VIRUS-INDUCED HYPERINFLAMMATION

EP4739333A1EP 4739333 A1EP4739333 A1EP 4739333A1EP-4739333-A1

Abstract

The invention relates in one aspect to a TGF-β inhibitor for use in the treatment of virus-induced hyperinflammation or (post-)COVID-19 infection symptoms or sequelae, wherein the patient is suffering from or experiencing elevated (above-normal) expression, excretion and/or blood levels of transforming growth factor-β (TGF-β) and/or interferon. The invention relates also to a TGF-β inhibitor for use in the treatment of COVID-19-induced hyperinflammation or (post-)COVID-19 symptoms or sequelae or Long-COVID-19. In another aspect the invention relates to a method for stimulating T cells and to a T-cell for the use in the treatment of virus reactivation and/or SARS- CoV-2-induced hyperinflammation.

Inventors

  • Mashreghi, Mir-Farzin
  • Kallinich, Tilmann
  • Durek, Pawel
  • Goetzke, Carl-Christoph

Assignees

  • Deutsches Rheuma-Forschungszentrum Berlin

Dates

Publication Date
20260513
Application Date
20240705

Claims (15)

  1. 1 . A TGF-p inhibitor for use in the treatment of virus-induced hyperinflammation or (post-) COVID-19 symptoms or sequelae, wherein the patient is suffering from or experiencing elevated (above-normal) expression, excretion and/or blood levels of transforming growth factor-p (TGF-P).
  2. 2. The TGF-p inhibitor for use according to claim 1 , wherein the virus-induced hyperinflammation is associated with, or induced by a COVID-19 infection.
  3. 3. The TGF-p inhibitor for use according to any one of claims 1 or 2, wherein the virus- induced hyperinflammation is a severe acute hyperinflammatory shock or a multisystem inflammatory syndrome.
  4. 4. The TGF-p inhibitor for use according to any one of the preceding claims, wherein the sequelae of COVID-19 comprise the reactivation of viruses in the subject, preferably the reactivation of human Herpesviridae (HHV1-8).
  5. 5. The TGF-p inhibitor for use according to any one of claims 2-4, wherein the COVID-19- induced hyperinflammation is a multisystem inflammatory syndrome in children (MIS-C).
  6. 6. The TGF-p inhibitor for use according to any one of claims 2-5, wherein the patient suffering from COVID-19 induced hyperinflammation is a child, preferably wherein the patient is younger than 21 years of age, more preferably younger than 16 years of age.
  7. 7. The TGF-p inhibitor for use according to any one of the preceding claims, wherein the (post-)COVID-19 symptoms or sequelae are Long-COVID-19, (post-)COVID-19-infection symptoms and/or the reactivation of Herpesviridae in the subject.
  8. 8. The TGF-p inhibitor for use according to any one of the preceding claims, wherein the TGF-p inhibitor is a chemical or pharmaceutical compound, preferably a small molecule compound.
  9. 9. The TGF-p inhibitor for use according to any of the preceding claims, wherein the TGF- p inhibitor is an inhibitor of a transforming growth factor-p receptor (TGF-pR), a SMAD inhibitor and/or an inhibitor of MAP-kinases.
  10. 10. The TGF-p inhibitor for use according to any of the preceding claims, wherein the TGF-B inhibitor is an antibody against TGF-p-1 and/or TGF-p-2 and/or TGF-p-3.
  11. 11. A TGF-p inhibitor for use in the treatment of the reactivation of a virus in a patient, wherein the patient is suffering from or experiencing elevated (above-normal) expression, excretion and/or blood levels of transforming growth factor-p (TGF-beta).
  12. 12. The TGF-p inhibitor for use according to the preceding claim, wherein the reactivation of the virus in a patient is associated with or induced by a COVID-19 infection.
  13. 13. The TGF-p inhibitor for use according to the preceding claim, wherein the virus is a human herpes virus (Herpesviridae / HHV1-8).
  14. 14. A T-cell for the use in the treatment of virus reactivation and/or SARS-CoV-2-induced hyperinflammation, (long-term) symptoms and/or sequelae, wherein the T-cell is treated and/or genetically engineered to be non-sensitive to TGF-p and/or immunosuppression, and wherein the T cell preferably expresses CD4 and/or CD8.
  15. 15. A method for stimulating T cells comprising the steps of a. Providing a population of T cells, b. Optionally incubating the T cells with a TGF- p inhibitor and/or genetically engineering the T cells to be resistant or insensitive to TGF-p stimulation, c. Providing a population of antigen-presenting cells, d. Incubating the population of antigen-presenting cells with viral particles or parts thereof, e. Stimulating the population of T cells, comprising co-culturing the population of T cells with the population of antigen-presenting cells provided in step c.

Description

TGF-p INHIBITION AND ENGINEERED T-CELLS FOR THE TREATMENT OF COVID-19 SEQUELAE AND VIRUS-INDUCED HYPERINFLAMMATION DESCRIPTION The invention lies in the field of biochemistry and medicine, particularly in the field of therapies of symptoms or sequelae of viral infections and virus-induced hyperinflammation, such as (post-)COVID-19 symptoms or sequelae. The present invention is directed in one aspect to the targeted intervention involving transforming growth factor-p (TGF-P) blockade for the management of virus-induced hyperinflammation, MIS- C and also other inflammatory (post-)COVID-19 symptoms or sequelae, also known as LONG- COVID-19. In embodiments beyond (post-)COVID-19 sequelae, therapies comprising the administration of autologous Epstein-Barr virus (EBV) or other Herpesviridae (HHV1-8)-specific T-cells engineered to be non-sensitive to TGF-p or immunosuppression can alleviate undesirable virus-induced hyperinflammation. BACKGROUND OF THE INVENTION At the beginning of the COVID-19 pandemic, children appeared to be only mildly affected by SARS-CoV-2 infections (Zhu, Wang et al. 2020). However, in April 2020, British paediatric intensive care physicians observed a cluster of patients with hyperinflammatory shock linked to a previous infection with SARS-CoV-2 (Riphagen, Gomez et al. 2020). Simultaneously, paediatricians in Bergamo documented a significant rise in cases of Kawasaki-like disease (Verdoni, Mazza et al. 2020). These patients had symptoms resembling both a toxic shock syndrome and Kawasaki-shock-syndrome, which usually started 4-8 weeks after infection with SARS-CoV-2 (Belot and Levy-Bruhl 2020). Untreated, this hyperinflammation involving multiple organs led to organ failure (Loomba, Villarreal et al. 2020). In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock (Riphagen, Gomez et al. 2020) termed multisystem inflammatory syndrome in children (MIS-C) within 4-8 weeks post-infection. MIS-C is characterised by oligoclonal T-cell expansion (Moreews, Le Gouge et al. 2021) and systemic hyperinflammation (Sacco, Castagnoli et al. 2022). The pathogenesis of multisystem inflammatory syndrome (MIS) and MIS-C remains elusive. Several studies were conducted, testing different hypotheses for the pathogenesis of MIS-C; despite these studies, the pathogenesis of MIS-C remains ill characterised. Some results point to impaired viral clearance and intestinal barrier dysfunction (Yonker, Gilboa et al. 2021), yet in animal models, fever alone can induce similar findings (Lambert 2004). Additionally, while autoantibody formation (Porritt, Binek et al. 2021 , Pfeifer, Thurner et al. 2022) has been described in some cases, specificity of auto-antibodies has not consistently been confirmed across different studies. For example, in one cohort, interleukin-1 receptor antagonist (IL-1 Ra) neutralising antibodies were found in 13 of 21 patients. This was accompanied by low levels of IL- 1 Ra (Pfeifer, Thurner et al. 2022), which could explain the widespread inflammation in these individuals. Others have raised the hypothesis of a superantigen-like immune reaction, as MIS-C is linked to a unique oligoclonal T-cell expansion, and/or activation associated with Vp21 .3 TCR+ CD4 and CD8 T-cells (Cheng, Zhang et al. 2020, Hoste, Roels et al. 2021 , Moreews, Le Gouge et al. 2021 , Porritt, Paschold et al. 2021). As of now, however, only structural models predict a superantigen-like region within the spike-protein, which could bind to VP21.3 TCR (Porritt, Paschold et al. 2021). More recently, autosomal recessive deficiencies in the OAS-RNAse L pathway were found in nearly 1% of affected children, highlighting the importance of monocyte activation in the development of MIS-C (Lee, Le Pen et al. 2023). Taken together, none of these hypotheses can explain the full set of disease features in all cases of MIS and MIS-C. In the prior art different treatments of COVID-induced symptoms and/or sequalae were described, such as OT-101 , artemisin, methylprednisolone or dexamethasone (e.g., WO 2022/251102, US 2023/201290, WO 2021/195088, Carvacho et al., 2021). However, previous studies could not reveal a successful treatment of COVID-19 associated symptoms, hyperinflammation and sequalae, particularly in younger patients and children. Therefore, especially treatments of COVID-induced symptoms and/or sequalae in younger patients and children are urgently needed. In light of the prior art there remains a significant need to provide novel means for the management of MIS-C, other inflammatory (post-)COVID-19 sequelae, including Long-COVID- 19, as well as undesirable virus-induced hyperinflammation and/or (herpes) virus reactivation, e.g., after COVID-19 infection. SUMMARY OF THE INVENTION The afore problem is solved by the features of the independent claims. Preferred embodiments of the present invention are provided by the dependent claims. The invention relates in one aspect to a T