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EP-4739706-A1 - METHODS OF TREATING OR PREVENTING A COMPLICATION OF SICKLE CELL DISEASE

EP4739706A1EP 4739706 A1EP4739706 A1EP 4739706A1EP-4739706-A1

Abstract

The present disclosure relates to methods for treating or preventing or delaying progression or reducing or inhibiting or hindering development of a complication associated with sickle cell disease in a subject suffering from sickle cell disease, the method comprising administering to the subject a compound that inhibits granulocyte colony stimulating factor (G-CSF) signaling and/or G-CSF activity.

Inventors

  • LINDQVIST, Lisa Margareta
  • GILLE, ANDREAS
  • ROSSATO, Paolo
  • BRECHMANN, Markus
  • BELCHER, John Davis
  • VERCELLOTTI, GREGORY M.

Assignees

  • CSL Innovation Pty Ltd

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1. A method for treating or preventing or delaying progression or reducing or inhibiting or hindering development of a complication associated with sickle cell disease in a subject suffering from sickle cell disease, the method comprising administering to the subject a compound that inhibits granulocyte colony stimulating factor (G-CSF) signaling and/or G-CSF activity.
  2. 2. The method of claim 1, wherein the compound reduces and/or prevents and/or inhibits neutrophil activation, neutrophil extracellular trap (NET) activation and/or endothelial cell activation.
  3. 3. The method of claims 1 or 2, wherein the complication associated with sickle cell disease affects the cardiovascular system, central nervous system, dental system, endocrine system, gallbladder and/or pancreas, gastrointestinal system, genitourinary system, hematopoietic system, hepatic system, immune system, ophthalmic system, pulmonary system, renal system, reproductive system, skin and/or spleen.
  4. 4. The method of any one of claims 1 to 3, wherein the complication associated with sickle cell disease is selected from the group consisting of fatigue, dyspnea, syncope, relative systolic hypertension, myocardial infarction, acute myocardial infarction, tissue infarction, sickle cardiomyopathy, left ventricular hypertrophy, diastolic dysfunction, heart failure with preserved ejection fraction, iron-induced cardiomyopathy and dysrhythmias, endothelial dysfunction/autonomic dysfunction, prolonged QT interval, pulmonary hypertension, headache, infarctive stroke, hemorrhagic stroke, ischemic stroke, aneurysm, ruptured aneurysm, moyamoya syndrome, silent cerebral infarct, sino- venous thrombosis, ischemia-reperfusion injury, chronic headache, neurocognitive disorders due to silent cerebral infarcts/overt cerebrovascular accidents or strokes, intraparenchymal hemorrhage, subarachnoid hemorrhage, intraventricular hemorrhage, chronic anemia, anemia crisis, poor executive functioning, memory deficits, increased cerebral blood flow, blood transfusion requirement, organ damage, pain medicine requirement, vasculopathy, cerebral vasculopathy, microvascular stasis, vaso-occlusion, vaso-occlusive crisis (VOC), vascular stasis, venous stasis, moyamoya syndrome, cerebral aneurysm, dental abscess, dental crown fracture, dental pulp fracture, dental caries, gingivitis, cracked teeth, early dental loss, misaligned dentition, pain around menses, pregnancy, menopause, growth hormone deficiency, hypogonadism, disturbances in cortisol levels, delayed puberty, premature menopause, cholelithiasis, cholecystitis, common bile duct obstruction, acute pancreatitis, chronic gallbladder sludge, dyspepsia, chronic cholecystitis, chronic pancreatitis, mesenteric infarcts, chronic abdominal pain, constipation, irritable bowel syndrome, gastroesophageal reflux disease (GERD), increased abdominal girth due to shortened trunk and barrel chest (sickle-habitus), priapism, enuresis, hematuria, menses-induced vaso-occlusive episode, erectile (sexual) dysfunction, postcoital pain, enuresis/nocturia, hematuria, acute anemia, aplastic crisis, sequestration crises, splenic sequestration crisis, hyperhemolytic crisis, functional asplenia, indirect hyperbilirubinemia, scleral icterus, hemostatic activation, chronic hemolysis, chronic anemia, extramedullary hematopoiesis, leukocytosis, thrombocytosis, splenomegaly, hypersplenism, conjunctival pallor, scleral icterus, hemostatic activation, thrombophilia, hyperbilirubinemia, hepatic sequestration, hepatitis, acute intrahepatic cholelithiasis/cholestasis, acute and/or chronic renal failure, transaminitis, hepatic failure, hepatomegaly, hepatic congestion/chronic congestive hepatopathy, hepatic sequestration, portal hypertension, nephropathy, bacteremia/sepsis, iron overload, meningitis, hepatitis, osteomyelitis, pyelonephritis, influenza, osteomyelitis, hepatitis, dental abscesses, gingivitis, leg ulcer super infection, retinal detachment, retinal artery occlusion, vitreous hemorrhage, peripheral retinal ischemia, macular infarction, sickle retinopathy (proliferative and nonproliferative), maculopathy, chest syndrome, acute chest syndrome, pneumonia, pulmonary fat embolism syndrome, airway hyperreactivity, atelectasis from hypoventilation, pulmonary embolism, chronic lung disease, chronic hypoxemia/hypoxia, nocturnal hypoxemia, chronic pulmonary embolism, acute kidney injury (recurrent), hematuria, papillary necrosis, hypertension, thromboemboli, glomerular hyperfiltration, proteinuria/microalbuminuria, hyposthenuria, chronic kidney disease, end-stage renal disease, renal tubular acidosis, renal osteodystrophy, spontaneous abortion/miscarriages, intrauterine growth retardation, early fetal demise, pre- and post-eclampsia, severe dilutional anemia, other maternal-fetal complications, low sperm counts/poor sperm function, post-pregnancy chronic pain, leg ulcers, varicosity, acute splenic sequestration, acute splenic infarction, splenic abscesses, traumatic spleen rupture, functional asplenia or hyposplenia due to auto-infarction of spleen leading to increased risk for infection with encapsulated organisms, splenic infarction, hypersplenism, pain crisis and combinations thereof.
  5. 5. A method for treating or preventing or delaying progression or reducing or inhibiting or hindering development of a vasculopathy associated with sickle cell disease in a subject suffering from sickle cell disease, the method comprising administering to the subject a compound that inhibits granulocyte colony stimulating factor (G-CSF) signaling and/or G-CSF activity.
  6. 6. The method of claim 5, wherein the vasculopathy is associated with vasoocclusion or hemolysis-endothelial dysfunction.
  7. 7. The method of claim 6, wherein the subject has or is suffering from a complication of the vaso-occlusion.
  8. 8. The method of claim 7, wherein the complication of the vaso-occlusion is a vasoocclusive crisis, acute chest syndrome, osteonecrosis, progressive retinopathy, chronic renal failure, pulmonary hypertension, priapism, splenic sequestration and/or stroke.
  9. 9. A method of treating or preventing or delaying progression or reducing or inhibiting or hindering development of a vaso-occlusive crisis and/or acute chest syndrome in a subject suffering from sickle cell disease, the method comprising administering to the subject a compound that inhibits granulocyte colony stimulating factor (G-CSF) signaling and/or G-CSF activity.
  10. 10. The method of any one of claims 1 to 9, wherein the subject has or is suffering from pain associated with vaso-occlusive crisis and/or pain associated with acute chest syndrome.
  11. 11. The method of any one of claims 1 to 10, wherein the sickle cell disease is selected from the group consisting of sickle cell anemia (HbSS), hemoglobin sickle cell disease (HbSC), hemoglobin sickle-beta-thalassemia (Hb S beta-thalassemia), sickle cell- hemoglobin D disease (HbSD), sickle cell-hemoglobin E disease (HbSE) and sickle cell- hemoglobin O disease (HbSO).
  12. 12. The method of any one of claims 1 to 11, wherein the method reduces and/or prevents and/or inhibits: (i) neutrophil adhesion to endothelial cells and transmigration; (ii) neutrophil-platelet aggregate formation; (iii) neutrophil extracellular trap (NET) formation; (iv) reactive oxygen species formation; (v) von Willebrand factor secretion from endothelial cells; (vi) neutrophil activation; (vii) neutrophil extracellular trap (NET) activation; and/or (viii) endothelial cell activation.
  13. 13. The method of any one of claims 1 to 12, wherein the compound that inhibits G- CSF signaling and/or G-CSF activity is administered in an amount sufficient to have one or more of the following effects: (i) reduce or prevent an increase in percent vascular stasis; (ii) reduce or prevent an increase in blood flow; (iii) reduce or inhibit expression of E-selectin on endothelial cells; (iv) reduce or inhibit expression of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells; (v) reduce or inhibit expression of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells; (vi) reduce or inhibit expression of P-selectin on endothelial cells; (vii) increase or upregulate expression of heme-oxygenase- 1 (HO- 1 ) on endothelial cells; (viii) increase or upregulate expression of NF-E2-related factor 2 (NRF2) on endothelial cells; (ix) reduce or prevent an increase in neutrophil infiltration and/or accumulation in the subject’s liver.
  14. 14. The method of any one of claims 1 to 13, wherein the compound that inhibits G- CSF signaling and/or G-CSF activity binds to G-CSF or G-CSF receptor (G-CSFR).
  15. 15. The method of claim 14, wherein the compound that inhibits G-CSF signaling is a protein comprising an antibody variable region that binds to or specifically binds to G- CSF or G-CSFR and neutralizes G-CSF signaling.
  16. 16. The method of claim 15, wherein the compound that inhibits G-CSF signaling is a protein comprising a Fv.
  17. 17. The method of claim 16, wherein the protein is selected from the group consisting of: (i) a single chain Fv fragment (scFv); (ii) a dimeric scFv (di-scFv); (iii) a diabody; (iv) a triabody; (v) a tetrabody; (vi) a Fab; (vii) a F(ab’)2; (viii) a Fv; (ix) one of (i) to (ix) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and/or CH3; (x) one of (i) to (ix) linked to albumin or a functional fragment or variants thereof or a protein that binds to albumin; and (xi) an antibody.
  18. 18. The method of any one of claims 15 to 17, wherein the protein comprises an antibody variable region that binds to or specifically binds to G-CSFR.
  19. 19. The method of any one of claims 15 to 18, wherein the protein comprises an antibody variable region that binds to or specifically binds to G-CSFR and competitively inhibits the binding of antibody C1.2G comprising a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 4 and a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 to G-CSFR.
  20. 20. The method of any one of claims 15 to 19, wherein the protein binds to an epitope comprising residues within one or two or three or four regions selected from 111-115, 170-176, 218-234 and/or 286-300 of SEQ ID NO: 1.

Description

METHODS OF TREATING OR PREVENTING A COMPLICATION OF SICKLE CELL DISEASE RELATED APPLICATION DATA This application claims priority from US Patent Application No 63/511,983 filed on 5 July 2023 and entitled “Methods of treating or preventing a complication of sickle cell disease”, and US Patent Application No 63/635,186 filed on 17 April 2024 and entitled “Methods of treating or preventing a complication of sickle cell disease”. The entire contents of these applications are hereby incorporated by reference. SEQUENCE LISTING The present application is filed together with a Sequence Listing in electronic form. The entire contents of the Sequence Listing are hereby incorporated by reference. FIELD The present disclosure relates to methods for treating or preventing or delaying progression or reducing or inhibiting or hindering development of a complication associated with sickle cell disease in a subject suffering from sickle cell disease, the method comprising administering to the subject a compound that inhibits granulocyte colony stimulating factor (G-CSF) signaling and/or G-CSF activity. BACKGROUND Sickle cell disease (SCD) has a high prevalence and social impact worldwide. With about 300,000 babies born with SCD globally every year, SCD also has a high mortality within the first three years of birth. SCD refers to a group of inherited erythrocyte disorders caused by a mutation in both of an individual’s beta globin genes. Beta globin combines with alpha globin to form hemoglobin, required for blood oxygen transport. In SCD, beta globin mutations cause abnormal hemoglobin which polymerises to form hard, sticky red blood cells that are C- or sickle-shaped. The specific beta globin mutations inherited by an individual contribute to the severity of disease experienced. The most severe common SCD is sickle cell anaemia, caused by a homozygous glutamic acid-valine mutation in the sixth amino acid of the beta globin protein causing a mutant beta globin protein, HbS. Hemoglobin SC disease and HbS beta thalassemia are caused by compound heterozygous mutations of HbS together with either mutant beta globin HbC or a beta thalassemia gene respectively and are usually milder than sickle cell anaemia. Beta thalassemia has two forms, zero and plus; HbS betaO usually results in severe SCD disease, while HbS beta+ usually results in milder SCD disease. Other, rare forms of SCD exist, with variable severity, wherein an HbS gene is inherited together with a different hemoglobin mutation, for example HbD, HbE or HbO. Sickle cells are prone to hemolysis earlier than normal erythrocytes, resulting in a chronic depletion of red blood cells. Sickle cells are sometimes referred to as being “sticky” as they can also clog smaller blood vessels due to their rigidity and tendency to aggregate. In addition to shortened life expectancy, subjects with SCD suffer increased morbidity due to varied chronic and acute complications, including: acute chest syndrome, anaemia, aplastic crisis, avascular necrosis, blood clots, dactylitis, fever, hepatic crisis, hyperhemolytic crisis, infection, kidney disease, leg ulcers, liver disease, organ damage, pain crises, priapism, pulmonary hypertension, sleep-disordered breathing, splenic sequestration, stroke, proliferative retinopathy and vaso-occlusive crisis. Currently, there are five major approaches for the general management of SCD and its complications. These include (i) symptomatic management, (ii) supportive management, (iii) preventive management, (iv) abortive management, and (v) curative therapy. A blood and bone marrow transplant is the only cure for SCD, is only effective for some types of SCD and is only available where a closely matched donor can be found. In addition, in certain patients it carries a significant risk of complications, including death. Treatments to alleviate complications arising from SCD include pharmaceuticals that: prevent the C-shaped deformation of erythrocytes, reduce vaso-occlusion and pain crises, reduce or prevent multiple or complex complications, treat pain, and reduce the risk of infection; and/or transfusions. Currently approved therapies include hydroxyurea, Endari® (L-glutamine), Adakveo® (crizanlizumab-tmca) and Oxbryta® (voxelotor). The currently available treatments each have a number of side-effects, availability restrictions and/or limited efficacy for different patient groups. Accordingly, there remains a significant need for improved therapies for treating or reducing the severity or the development of complications associated with SCD. SUMMARY In producing the present invention, the inventors identified granulocyte colony stimulating factor (G-CSF) as a potential target for pharmacological intervention of complications associated with sickle cell disease. The inventors found that administering a compound that inhibits G-CSF binding to its receptor and/or inhibits G-CSF signaling successfully inhibited several measures of vaso-occlusion and vas