“Methods Of Treating Lupus Nephritis Using Interleukin-17 (Il-17) Antagonists” in Patent Application Approval Process (USPTO 20230009657): Patent Application
2023 JAN 27 (NewsRx) -- By a
This patent application has not been assigned to a company or institution.
The following quote was obtained by the news editors from the background information supplied by the inventors: “LN represents inflammation of the kidneys and is one of the organ-specific disease manifestations of Systemic Lupus Erythematosus (SLE) (Waldman and Madaio (2005) Lupus 14(1):19-24). LN is a chronic inflammatory disease characterized by auto-antibody production and other distinct immunological abnormalities (Gurevitz et al. (2013) Consult Pharm 28: 110-21). It is categorized histologically into six classes by the
“The pathogenesis of LN is complex and involves both the innate and adaptive immune system, various cytokines and tissue, and immune cells. Intra-renal inflammation is maintained via local cytokine and chemokine production and by cells of the innate immune system, such as neutrophils, that are attracted into the glomerulus and interstitium. Targeting local release of pro-inflammatory cytokines by blocking individual cytokines, may enhance treatment efficacy in autoimmunity without increasing systemic immunosuppression. (Allam (2008) Curr Opin Rheumatol; 20(5):538-44; Yu et al. (2017) Nat Rev Nephrol; 13(8):483-95).
“Despite recent advances in treatment for several autoimmune diseases, there is still no adequate treatment for LN. It remains a major cause of morbidity and mortality, with 22% of LN patients progressing to ESRD within 15 years (Faurschou et al. (2010)
“The American College of Rheumatology (ACR) Guidelines for Screening, Treatment, and Management of Lupus Nephritis have been published in 2012, and are recognized internationally (Hahn et al. (2012) Arthritis Care Res (Hoboken); 64:797-808].
“The guidelines are uniform in their recommendations for therapy for class III and IV LN and include a sequence of induction and maintenance phases. For patients with class III or IV proliferative glomerulonephritis, the ACR guidelines agree on induction therapy with mycophenolate mofetil (MMF) or i.v. cyclophosphamide (CYC), with or without initial pulses of i.v. methylprednisolone. With current induction regimens, <60% of class III to V patients achieve a complete response (Appel et al. (2009) J Am Soc Nephrol. 20: 1103-1112). Among those who attain a complete renal response (CRR) with current standard-of-care (SoC), nearly half of the patients had a relapse. The rate of relapse in these patients was 5 to 15 per 100 patient-years (Grootscholtenet al. (2006) Nephrol Dial Transplant 21:1465-1469).
“Patients with class V lupus nephritis are typically treated with antiproteinuric and antihypertensive medications and can receive corticosteroids and immunosuppressive therapy as required depending on the presence of persistent nephrotic proteinuria.
“Several histological features affect treatment decisions and prognosis. For example, patients with high “activity” (A) lesions are typically treated with immunosuppression, whereas those with “chronic” (C) lesions may not receive immunosuppressive therapy because of a poorer response prognosis (Hiramatsu et al. (2008) Rheumatology (Oxford) 47:702-07].
“Medical treatment of LN with the current SoC achieves a satisfactory renal response only in about half of the patients, and carries a significant burden with respect to safety. Non-responders to the current induction and maintenance therapies have the worst outcomes. Among patients with class IV LN, about 40% developing ESRD at 15 years (Tektonidou et al. (2016) Arthritis Rheumatol. 68(6):1432-41). Thus, despite the aggressive nature of SoC treatment, only up to 40% of patients achieve a CRR after 1 year (
“Given the severity of the condition and the lack of approved therapy, there is a high unmet medical need for safe and effective long-term therapies (i.e., stand alone or as add-on therapies) for the treatment of LN.”
In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors’ summary information for this patent application: “IL-17A and Th17 cells may play roles in the pathogenesis of LN, contributing to the glomerular injury and the persistence of inflammation and renal damage (Zhang et al. (2009) J Immunol. 183(5):3160-9; Crispin et al. (2008) J Immunol. 181:8761-66). High levels of IL-17 predict poor histopathological outcome after immunosuppressive therapy in patients with LN (Zickert et al. (2015) BMC Immunol. 16:7). A subset of T-cells infiltrate the kidneys of patients with LN and represent the major source for IL-17 (Crispin et al. (2008), supra). IL-17 has a potential to induce the production of additional inflammatory cytokines and chemokines and to promote recruitment of inflammatory cells such as monocytes and neutrophils to inflamed organs. Higher levels of glomerular IL-17 and IL-23 expression are observed in renal biopsies from class IV LN patients as compared with those from minimal change nephropathy patients and normal controls. Both glomerular IL-17 and IL-23 expression levels positively correlate with renal histological activity index for LN patients (Chen et al. (2012) Lupus 21:1385). The urinary expression of Th17-related genes, including ILI 7 and IL23, is increased and associated with the activity of LN (Kwan et al. (2009) Rheumatology (Oxford) 48(12):1491-7).
“Secukinumab (see, e.g., WO2006/013107 and WO2007/117749) has a very high affinity for IL-17, i.e., a KD of about 100-200 pM and an IC50 for in vitro neutralization of the biological activity of about 0.67 nM human IL-17A of about 0.4 nM. Thus, secukinumab inhibits antigen at a molar ratio of about 1:1. This high binding affinity makes the secukinumab antibody particularly suitable for therapeutic applications. Furthermore, secukinumab has a long half-life, i.e., about 4 weeks, which allows for prolonged periods between administration, an exceptional property when treating chronic life-long disorders, such as LN.
“A recent case study reports the successful treatment of a patient with coexisting SLE and axials spondyloarthritis using 150 mg secukinumab weekly for 4/52 weeks, followed by monthly administration thereafter (Ecclestone et al. (2019) Abst. 109; Rheumatology, 58:3, kez108.017) However, urinalysis was normal in this patient, suggesting the patient did not have LN. A case study of a patient having refractory LN (refractory to both MMF and cyclophosphamide therapy) and concomitant psoriasis vulgaris suggests that treatment with secukinumab may have contributed to the improvement in renal function and decrease in urine protein levels in this patient (Satoh et al. (2018) Lupus 27(7):1202-06). The patient in Satoh et al. was treated with initial doses of 300 mg secukinumab, followed by later monthly doses of 150 mg secukinumab. The total length of secukinumab treatment is not reported in Satoh et al., and hence the long-term safety of the secukinumab regimen used by the clinicians in Satoh et al. cannot be assessed.
“We have now devised novel treatments for LN patients (in particular, LN patients already receiving standard-of-care [SoC] LN treatments, e.g., patients receiving MMF [or CYC] with or without corticosteroids) with IL-17 antagonists, e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab, that are safe, effective and provide sustained responses for patients. Importantly, because current SoC treatments for LN have strong immunosuppressive effects, any add-on therapy must maintain a favorable risk/benefit profile. Hence, these novel treatments satisfy a long-felt need of clinicians and patients for a safe, sustained, and effective therapy (particularly an add-on therapy) for LN.
“Disclosed herein are methods of treating LN, comprising subcutaneously (SC) administering to a patient in need thereof a dose of about 150 mg (e.g., 150 mg) of an IL-17 antibody, or an antigen-binding fragment thereof (e.g., secukinumab), weekly during weeks 0, 1, 2, 3, and 4, and thereafter administering a SC dose of about 150 mg (e.g., 150 mg) of the IL-17 antibody, or an antigen-binding fragment thereof (e.g., secukinumab) every four weeks.
“Disclosed herein are methods of treating LN, comprising subcutaneously (SC) administering to a patient in need thereof a dose of about 300 mg (e.g., 300 mg) of an IL-17 antibody, or an antigen-binding fragment thereof (e.g., secukinumab), weekly during weeks 0, 1, 2, 3, and 4, and thereafter administering a SC dose of about 300 mg (e.g., 300 mg) of the IL-17 antibody, or an antigen-binding fragment thereof (e.g., secukinumab) every four weeks.
“Disclosed herein are also methods of treating LN, comprising intravenously (IV) administering to a patient in need thereof a dose of about 4 mg/kg-about 9 mg/kg (preferably about 6 mg/kg) of an IL-17 antibody, or an antigen-binding fragment thereof (e.g., secukinumab) once during week 0, and thereafter administering an IV dose of about 2-about 4 mg/kg (preferably about 3 mg/kg) of the IL-17 antibody, or an antigen-binding fragment thereof (e.g., secukinumab) every 4 weeks (monthly), beginning during week 4.
“In some embodiments of the disclosed uses, methods and kits, the IL-17 antagonist is an IL-17 antibody or antigen-binding fragment thereof. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of human IL-17 comprising
“In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is a human or humanized antibody. In preferred embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.
“In preferred embodiments, the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is subcutaneously (SC) administered at a dose of 150 mg or 300 mg. In other embodiments, the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is intravenously (IV) administered at a dose of 6 mg/kg or 3 mg/kg.”
There is additional summary information. Please visit full patent to read further.”
The claims supplied by the inventors are:
“1. A method of treating lupus nephritis (LN), comprising subcutaneously (SC) administering to a patient in need thereof a dose of about 150 mg of an IL-17 antibody, or an antigen-binding fragment thereof, weekly during weeks 0, 1, 2, 3, and 4, and every four weeks thereafter, wherein the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin variable heavy (VH) domain comprising the amino acid sequence set forth as SEQ ID NO:8 and an immunoglobulin variable light (VL) domain comprising the amino acid sequence set forth as SEQ ID NO:10; ii) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or iii) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.
“2. A method of treating lupus nephritis (LN), comprising subcutaneously (SC) administering to a patient in need thereof a dose of about 300 mg of an IL-17 antibody, or an antigen-binding fragment thereof, weekly during weeks 0, 1, 2, 3, and 4, and every four weeks thereafter, wherein the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin variable heavy (VH) domain comprising the amino acid sequence set forth as SEQ ID NO:8 and an immunoglobulin variable light (VL) domain comprising the amino acid sequence set forth as SEQ ID NO:10; ii) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or iii) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.
“3. A method of treating LN, comprising intravenously (IV) administering to a patient in need thereof a dose of about 4 mg/kg-about 9 mg/kg (preferably about 6 mg/kg) of an IL-17 antibody, or an antigen-binding fragment thereof, once during week 0, and thereafter administering an IV dose of about 2 mg/kg-about 4 mg/kg (preferably about 3 mg/kg) of the IL-17 antibody, or an antigen-binding fragment thereof every four weeks, beginning during week four, wherein the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin variable heavy (VH) domain comprising the amino acid sequence set forth as SEQ ID NO:8 and an immunoglobulin variable light (VL) domain comprising the amino acid sequence set forth as SEQ ID NO:10; ii) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or iii) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.
“4. The method according to any of claims 1-3, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising
“5. The method according to any of the above claims, wherein prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient was administered mycophenolic acid (MPA) or cyclophosphamide (CYC), and, optionally at least one steroid.
“6. The method according to claim 5, wherein prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the LN was inadequately controlled by the prior treatment with MPA or CYC, and, optionally the at least one steroid.
“7. The method according to any of the above claims, wherein during treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient is concomitantly administered MPA or CYC, and, optionally at least one steroid.
“8. The method according to claim 7, wherein during treatment with the IL-17 antibody or antigen-binding fragment thereof, the dose of MPA or CYC administered to the patient is reduced, and wherein the patient does not experience a flare as a result of said reduction.
“9. The method according to claim 7 or 8, wherein during treatment with the IL-17 antibody or antigen-binding fragment thereof, the dose of the at least one steroid administered to the patient is reduced using a taper regimen, and wherein the patient does not experience a flare as a result of said reduction.
“10. The method according to any of the above claims, wherein the patient does not have concomitant plaque-type psoriasis.
“11. The method according to any of the above claims, wherein the patient has active LN.
“12. The method according to any of the above claims, wherein the patient has
“13. The method according to claim 12, wherein the ISN/RPS Class III IN is not Class III(C).
“14. The method according to claim 12, wherein the ISN/RPS Class
“15. The method according to any of the above claims, wherein the patient has features of ISN/RPS Class
“16. The method according to any of the above claims, wherein said patient achieves a complete renal response (CRR) after one year of treatment
“17. The method according to any of the above claims, wherein said patient achieves a partial renal response (PRR) after one year of treatment.
“18. The method according to any of the above claims, wherein the patient is additionally administered at least one LN agent selected from the group consisting of rituximab, ocrelizumab, abatacept, azathioprine, a calcineurin inhibitor, cyclosporine A, tacrolimus, cyclophosphamide, mycophenolic acid, voclosporin, belimumab, ustekinumab, iguratimod, anifrolumab, BI655064, CFZ533, and combinations thereof.
“19. The method according to any of the above claims, wherein the patient is an adult.
“20. The method according to any of the above claims, wherein the IL-17 antibody or antigen-binding fragment thereof is disposed in a pharmaceutical formulation, wherein said pharmaceutical formulation further comprises a buffer and a stabilizer.
“21. The method according to claim 20, wherein the pharmaceutical formulation is a liquid pharmaceutical formulation.
“22. The method according to claim 20, wherein the pharmaceutical formulation is a lyophilized pharmaceutical formulation.
“23. The method according to any of claims 20-22, wherein the pharmaceutical formulation is disposed within at least one pre-filled syringe, at least one vial, at least one injection pen, or at least one autoinjector.
“24. The method according to claim 23, wherein the at least one pre-filled syringe, at least one vial, at least one injection pen, or at least one autoinjector is disposed within a kit, and wherein said kit further comprises instructions for use.
“25. The method according to any of claim 2 or 4-24, wherein the dose of the IL-17 antibody or antigen-binding fragment thereof is 300 mg, which is administered to the patient as a single subcutaneous administration in a total volume of 2 milliliters (mL) from a formulation comprising 150 mg/ml of the IL-17 antibody or antigen-binding fragment thereof, wherein the pharmacological exposure of the patient to the IL-17 antibody or antigen-binding fragment is equivalent to the pharmacological exposure of the patient to the IL-17 antibody or antigen-binding fragment thereof using two separate subcutaneous administrations of a total volume of 1 ml each of the same formulation.
“26. The method according to any of claim 2 or 4-24, wherein the dose of the IL-17 antibody or antigen-binding fragment thereof administered to the patient is 300 mg, which is administered as two separate subcutaneous administrations in a volume of 1 mL each from a formulation comprising 150 mg/ml of the IL-17 antibody or antigen-binding fragment
“27. The method according to any of the above claims, wherein the IL-17 antibody or antigen-binding fragment thereof has a Tmax of about 7-8 days.
“28. The method according to any of the above claims, wherein the IL-17 antibody or antigen-binding fragment thereof has an absolute bioavailablilty of about 60%-about 80%.
“29. The method according to any of the above claims, wherein the IL-17 antibody or antigen-binding fragment thereof is a human monoclonal antibody.
“30. The method according to any of the above claims, wherein the IL-17 antibody or antigen-binding fragment thereof is of the IgG1/kappa isotype.
“31. The method according to any of the above claims, wherein, when said method is used to treat a population of patients having LN, at least 50% of said patients achieve a daily steroid dose of ≤10 mg/day following a steroid tapering regimen during treatment with the IL-17 antibody or antigen-binding fragment thereof.”
There are additional claims. Please visit full patent to read further.
URL and more information on this patent application, see: HUEBER, Wolfgang; MPOFU, Shephard; PRICOP, Luminita. Methods Of Treating Lupus Nephritis Using Interleukin-17 (Il-17) Antagonists.
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