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CN-121985952-A - Precise immunosuppression for preventing and treating graft-versus-host disease

CN121985952ACN 121985952 ACN121985952 ACN 121985952ACN-121985952-A

Abstract

The present invention relates to a composition, preferably a pharmaceutical composition for preventing and/or treating graft versus host disease (GvHD), a combination of inhibitors for preventing and/or treating GvHD, stem cells comprising said composition or inhibitors, a method of manufacturing said pharmaceutical composition, and a method of preventing and/or treating a subject suspected to suffer from or developing GvHD.

Inventors

  • Reka Halazti
  • Anastasia Kramer

Assignees

  • 蒂宾根大学医学院

Dates

Publication Date
20260505
Application Date
20241010
Priority Date
20231011

Claims (15)

  1. 1. A pharmaceutical composition for preventing and/or treating graft versus host disease (GvHD) comprising an inhibitor of RA-associated nucleoprotein (RAN).
  2. 2. The pharmaceutical composition of claim 1, further comprising an inhibitor of Aurora kinase a (AURKA).
  3. 3. The pharmaceutical composition of claim 1 or 2, further comprising an inhibitor of the hemipteran gene protein homolog (WAPL).
  4. 4. The pharmaceutical composition of any one of the preceding claims, further comprising an inhibitor of kinesin family member 15 (KIF 15).
  5. 5. The pharmaceutical composition according to any of the preceding claims, wherein the inhibitor is selected from the group consisting of RNA interference (RNAi) molecules, including small interfering RNAs (siRNA), micrornas (miRNA), short hairpin RNAs (shRNA), piwi-interacting RNAs (piRNA) and trans-acting siRNA (tasiRNA), antisense oligonucleotides (ASO), small molecules.
  6. 6. The pharmaceutical composition according to claim 5, wherein the RNA interference (RNAi) molecule, preferably siRNA, targets a target selected from the group consisting of RAN, AURKA, WAPL and KIF15.
  7. 7. The pharmaceutical composition of claim 5 or 6, wherein the RNAi molecule comprises a chemically modified nucleotide.
  8. 8. The pharmaceutical composition of claim 7, wherein the chemical modification is 2 '-O-methyl and/or 2' fluoro.
  9. 9. The pharmaceutical composition of any one of claims 5-8, wherein the RNAi molecule comprises nucleotides linked by phosphorothioates.
  10. 10. An inhibitor of RA-associated nucleoprotein (RAN) for use in the prevention and/or treatment of graft versus host disease (GvHD).
  11. 11. The inhibitor of claim 10, further comprising an inhibitor of Aurora kinase a (AURKA) and/or an inhibitor of the hemipteran gene protein homolog (WAPL) and/or an inhibitor of kinesin family member 15 (KIF 15).
  12. 12. A stem cell composition, preferably a stem cell graft, comprising a composition according to any one of claims 1-9 and/or an inhibitor according to claim 10 or 11.
  13. 13. A lymphocyte composition, preferably a lymphocyte graft, comprising a composition according to any one of claims 1-9 and/or an inhibitor according to claim 10 or 11.
  14. 14. A method of manufacturing a pharmaceutical composition for the prevention and/or treatment of graft versus host disease (GvHD), comprising formulating the inhibitor of claim 10 or 11 into a pharmaceutically acceptable carrier.
  15. 15. A method of preventing and/or treating a subject suspected of having or developing graft versus host disease (GvHD) or having GvHD, comprising administering to the subject a pharmaceutical composition according to any one of claims 1-9 and/or an inhibitor according to claim 10 or 11 and/or a stem cell composition according to claim 12 and/or a lymphocyte composition according to claim 13.

Description

Precise immunosuppression for preventing and treating graft-versus-host disease Technical Field The present invention relates to a composition, preferably a pharmaceutical composition for preventing and/or treating graft versus host disease (GvHD), a combination of inhibitors for preventing and/or treating GvHD, a stem cell and lymphocyte composition comprising said composition or inhibitors, a method of manufacturing said pharmaceutical composition, and a method of preventing and/or treating a subject suspected to suffer from or developing GvHD. The present invention relates to the field of molecular immunology. Background Graft versus host disease (GvHD) is a disease caused by bone marrow donation or hematopoietic stem cell transplantation. In particular, gvHD is a serious side effect of allogeneic stem cell transplantation. Allogeneic T cells are effectors of Hematopoietic Stem Cell Transplantation (HSCT), deliver powerful anti-tumor (GvT) effects, providing anti-infective (GvI) effects, but sometimes also result in serious and even fatal side effects, gvHD. GvHD occurs when immune cells of a donor repel new environment and begin to attack healthy host tissue. Allogeneic stem cell transplantation is the only cure for many leukemias and lymphomas and non-malignant hematological diseases (e.g., aplastic anemia). The mortality rate of GvHD is as high as 50%. The quality of life of the remaining patients is also severely limited by GvHD. Current drugs used to treat GvHD also interfere with the graft versus leukemia (GvL) and graft versus infection (GvI) effects expected from allogeneic stem cell transplantation. They damage allogeneic T cells, leading to recurrence of underlying disease, severe infection, and sepsis. This is associated with a very poor prognosis. There is currently no selective treatment for GvHD, as no intracellular biological pathway has been found to be able to selectively lead to GvHD without affecting GvT and GvI. In this context, there is an urgent need for a precise therapy that inhibits only GvH in T cells, does not affect the GvL and GvI functions of T cells, and as little as possible inhibits the activity and function of other cells. It is therefore an object of the present invention to provide an active agent and a composition to avoid or at least reduce the drawbacks of existing GvHD therapeutic agents. In particular, the present invention aims to provide a composition with which the selective pathogenic properties of allogeneic T cells can be eliminated or reduced, but with which GvL and GvI functions are at least largely retained. Disclosure of Invention The problem to be solved by the present invention is solved by a composition comprising an inhibitor of RA-associated nucleoprotein (RAs-related Nuclear protein, RAN) for the prevention and/or treatment of graft versus host disease (GvHD), in particular by a pharmaceutical composition comprising said inhibitor. The inventors have unexpectedly found that selective and specific prevention and treatment of GvHD can be achieved by inhibiting RA-associated nucleoprotein (RAN) without negatively affecting graft versus leukemia (GvL) and graft versus infection (GvI) by screening for a large number of potential targets. It is particularly worth mentioning that the effect observed by the inventors is synergistic, i.e. the combination of the two inhibitors produces an effect that is stronger than the sum of the individual effects of the inhibitors. These findings were surprising and unexpected. Ran (RA-associated nucleoprotein), also known as GTP-binding nucleoprotein Ran, is a protein encoded by the Ran gene (Entrez: 5901) in humans. Ran is a small protein of 25 kDa, involved in the transport of cells into and out of the nucleus during cell intervals, and also involved in mitosis. It is a member of the Ras superfamily. Ran is a small G protein that is critical for the transport of RNA and proteins through the nuclear pore complex (translocation). Ran proteins are also involved in DNA synthesis and regulation of cell cycle progression, as Ran gene mutations have been found to disrupt DNA synthesis. There is no report on inhibiting RAN to prevent or combat the occurrence of GvHD. According to the present invention, an "inhibitor" refers to a compound or molecule that ultimately reduces the activity of a target. Such inhibition may be achieved in essentially any manner, for example, by reducing expression (e.g., transcription, translation, synthesis), reducing stability or quantity of a target or gene, gene transcript or gene product, or other activity reduction. Thus, inhibitors may simultaneously inhibit the coding molecule, thereby reducing or eliminating the production of the encoded product (i.e., protein) at all. However, inhibitors may also inhibit the encoded product (i.e., protein) itself. Thus, the inhibitor may be used in any form, e.g., a chemically defined substance (e.g., a small molecule), an inhibitory nucleic acid molecule