Compounds and compositions for use in stem cell transplantation

Abstract

The invention relates to a Matriptase-2 (MT2) inhibitor, TMPRSS6 inhibitor, Ferroportin blocker, or hepcidin enhancer. In particular, the invention relates to the use of compounds capable of reducing at least one of systemic iron level, Transferrin saturation (Tsat), non-transferrin-bound iron (NTBI), and labile plasma iron (LPI). This may take place by inhibiting the expression of a target gene, wherein the target gene may be Transmembrane protease, serine 6 (TMPRSS6). Further, the invention relates to compositions comprising said compound and to methods for using such compounds and / or compositions. The uses may comprise therapeutic uses such as for reduction or iron overload and the prevention of iron related toxicity before, during or after chemotherapeutic conditioning, stem cell transplantation and engraftment.

Description

CN Title: Compounds and Compositions for Use in Stem Cell Transplantation CN Abstract: This invention relates to inhibitors of membrane-type serine protease-2 (MT2), TMPRSS6 inhibitors, iron transporter blockers, or hepcidin enhancers. In particular, this invention relates to the use of compounds capable of reducing at least one of systemic iron levels, transferrin saturation (Tsat), non-transferrin-bound iron (NTBI), and unstable plasma iron (LPI). This can be achieved by inhibiting the expression of a target gene, wherein the target gene may be transmembrane serine protease 6 (TMPRSS6). Furthermore, this invention relates to compositions comprising said compounds, and methods of using such compounds and / or compositions. Uses may include therapeutic uses, such as for reducing iron overload and preventing iron-related toxicity before, during, or after chemotherapy pretreatment, stem cell transplantation, and engraftment. Abstract

Claims

Claims1 . A therapeutic agent for use in the treatment of an iron metabolism disease or condition wherein the therapeutic agent comprises an inhibitor selected from:(g) a TMPRSS6 inhibitor;(h) a MT2 inhibitor; or(i) a Ferroportin inhibitor, and wherein the treatment comprises cell implantation, explantation, or transplantation.

2. A therapeutic agent for use according to claim 1 , wherein the agent is selected from:(i) an antibody or antigen-binding fragment thereof, or a variant, fusion, or derivative of said antibody or antigen-binding fragment, or a fusion of said variant or derivative thereof;(ii) antibody mimic (for example, based on non-antibody scaffolds); (hepcidin mimetic) selected from the group consisting of affibody, tetranectin, adnectin (monobody), anticalin, DARPin (ankyrin), avimer, iMab, microbody, peptide aptamer, Kunitz domain, and affilin(iii) RNA aptamer;(iv) small molecule;(v) CovX-body; or(vi) nucleic acid; wherein (i) or (ii) may be selected from the group consisting of affibody, tetranectin, adnectin, monobody, anticalin, DARPin, ankyrin, avimer, iMab, microbody, peptide aptamer, Kunitz domain, aflilin, and any combination thereof.

3. A therapeutic agent for use according to claim 2, wherein the nucleic acid comprises at least one duplex region that comprises at least a portion of a first strand and at least a portion of a second strand that is at least partially complementary to the portion of the first strand, wherein said first strand is at least partially complementary to at least a portion of RNA transcribed from the TMPRSS6 gene and is capable of inhibiting expression of TMPRSS6.

4. A therapeutic agent for use according to any one of claims 2 or 3, wherein one or more nucleotides on the first and / or second strand are modified, to form modified nucleotides.

5. A therapeutic agent for use according to any one of claims 2 to 4, wherein the nucleic acid is conjugated to a ligand, optionally at the 5’ end of the second strand.

6. A therapeutic agent for use according to claim 5, wherein the ligand comprises (i) one or more N-acetyl galactosamine (GalNAc) moieties and derivatives thereof, and (ii) a linker, wherein the linker conjugates the GalNAc moieties to the nucleic acid.

7. A therapeutic agent for use according to any one of claims 5 or 6, wherein the linker is a bivalent, trivalent, or tetravalent branched structure.

8. A therapeutic agent for use according to any one of claims 2 to 7, wherein the nucleic acid is any of the mentioned in Tables 1 , 2, 3, 4, or 5.

9. The therapeutic agent for use according to any one of statements 1 to 8, wherein the nucleic acid is EU401 or EU402.

10. A pharmaceutical composition for use in the treatment of an iron metabolism disease or condition, the pharmaceutical composition comprising an effective amount of the therapeutic agent as defined in any of the preceding claims, further comprising a pharmaceutically acceptable diluent, carrier, or excipient.

11. The pharmaceutical composition for use of claim 10, adapted for delivery by a route selected from the group comprising: intravenous, intramuscular, subcutaneous, intraarticular, pulmonary, intranasal, intraocular, and intrathecal.

12. The pharmaceutical composition for use of claims 10-11 , wherein the delivery route is selected from the group comprising: intravenous, intramuscular, subcutaneous, intraarticular, pulmonary, intranasal, intraocular, and intrathecal.

13. The therapeutic agent for use or the pharmaceutical composition for use of any of the preceding claims, wherein the disease or condition is a) non-malignant, wherein the non-malignant disease or condition is selected from the group consisting of severe aplastic anemia, hemoglobinopathies, like thalassemias and / or sickle cell disease, aplastic anemia, fanconi anemia, Wiskott Aldrich Syndrome, Hurlers Syndrome, familial haemophagocytic lymphohistiocytosis (FHL), chronic granulomatous disease (CGD), Kostmanns syndrome, Severe immunodeficiency syndrome, severe combined immune deficiency syndrome, or autoimmune disorders such as SLE, Multiple sclerosis, IBD, Crohn’s Disease, Sjorgen’s syndrome, vasculitis, Lupus, MyastheniaGravis, Wegener’s disease, malignant infantile osteopetrosis, mucoplysaccharidosis, paroxysmal nocturnal hemoglobinuria, pyruvate kinase deficiency, inborn errors of metabolisms, and / or other immunodeficiencies or autoimmune diseases; or b) wherein the disease is malignant, wherein the malignant disease or condition is selected from the group consisting of myelodysplastic syndromes (MDS), leukaemia (e.g., acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and other leukemias (such as hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia and adult T-cell leukemia), lymphoma (e.g., Precursor T-cell leukemia / lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia / lymphoma, MALT lymphoma, solid tumors (e.g. renal, hepatic and pancreatic cancer), Mycosis fungoides, Peripheral T-cell lymphoma not otherwise specified, Nodular sclerosis form of Hodgkin lymphoma, Mixed- cellularity subtype of Hodgkin lymphoma, multiple myeloma, neuroblastoma, Ewing sarcoma, and glioma.

14. A therapeutic agent for use or the pharmaceutical composition for use of any of the preceding claims, wherein the treatment comprises or consists of the step of:(a) inhibiting TMPRSS6,(b) inhibiting MT2,(c) blocking ferroportin, or(c) increasing hepcidin wherein the systemic iron level, NTBI, transferrin saturation, labile plasma iron, and / or eLPI level are decreased.

15. A therapeutic agent for use or the pharmaceutical composition for use of any of the preceding claims, wherein the treatment further comprises co-administration of one or more chemotherapeutic agent, radiotherapy, and / or immunotherapy.

16. A therapeutic agent for use or the pharmaceutical composition for use of any of the preceding claims, wherein the cell explantation, implantation, or transplantation treatment comprises hematopoietic stem cell transplantation (HSCT), optionallywherein the therapeutic agent or the pharmaceutical composition is administered to the subject in need thereof prior to, during, or after conditioning for HSCT, or wherein the agent is administered to the subject in need thereof prior to, during, or after receiving HSCT.

17. A therapeutic agent or the pharmaceutical composition for use of claim 16, wherein the agent is capable of preventing and / or reducing graft-versus-host disease (GVHD) and / or graft-versus-leukemia (GVL), and optionally further improves HSCT efficacy, including improvement of engraftment, improvement of overall survival, reduction of non-relapse mortality, reduction of infections and idiopathic pneumonia syndrome, and / or reduction of HSC-T related morbidities, like sinusoidal obstruction syndrome, and chronic liver disease.

18. A method of treating an iron metabolism disease or condition in a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition or the therapeutic agent defined in any of the preceding claims, wherein the treatment comprises cell explantation, implantation, or transplantation.

19. Use of a therapeutic agent or a pharmaceutical composition according to the preceding claims for the manufacture of a medicament for the treatment of an iron metabolism disease or condition, wherein the treatment comprises cell explantation, implantation, or transplantation.

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