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CN-121987779-A - Application of interferon receptor 1 monoclonal antibody in preparation of medicines for treating neuromyelitis Optica (OPYNAMIC) spectrum diseases and pharmaceutical composition

CN121987779ACN 121987779 ACN121987779 ACN 121987779ACN-121987779-A

Abstract

The invention relates to the field of biological medicine, and relates to application of an interferon receptor 1 monoclonal antibody in preparation of a medicament for treating neuromyelitis optica (NGUF) spectrum diseases and a pharmaceutical composition. The antibody reduces inflammatory and demyelinating injuries of the central nervous system by inhibiting abnormal activation of a type I interferon signal pathway, down regulating the expression of an interferon-stimulated gene, and regulating immune response. The method comprises the steps of using humanized IFNAR1 monoclonal antibody singly, combining the humanized IFNAR1 monoclonal antibody with a B cell targeting drug to cooperatively inhibit B cell activation and antibody secretion, constructing a bispecific antibody targeting IFNAR1 and transferrin receptor, enhancing the ability of the drug to cross the blood brain barrier, and improving the concentration of the drug in the brain. In vivo and in vitro experiments prove that the treatment scheme can effectively reduce the lesion volume of the NMOSD model and improve the nerve function, and provides a new accurate treatment strategy for AQP4 antibody positive patients.

Inventors

  • ZHANG CHAO
  • SHI FUDONG
  • ZHANG TIANXIANG
  • HUA FEI
  • ZHOU JUN
  • SHAO NAIYUAN
  • LIAN XUEGAN
  • GAO XUE
  • YUAN LONGFENG

Assignees

  • 常州市第一人民医院
  • 天津医科大学总医院

Dates

Publication Date
20260508
Application Date
20260212

Claims (10)

  1. 1. An application of humanized interferon receptor 1 (IFNAR 1) monoclonal antibody in preparing medicament for treating neuromyelitis Optica (OPYNATIS) pedigree diseases, Wherein the medicament is for modulating abnormal activation of type I interferon signaling associated with neuromyelitis optica spectrum disorders.
  2. 2. The use according to claim 1, characterized in that, The abnormal activation state of type I interferon signal is manifested by an elevated expression level of at least one interferon-stimulating gene, The interferon stimulating gene is selected from at least one of ISG15, ISG20, IFIT1, IFIT2, IFIT3, IFI44L, IFITM2, IFITM3, MX1 and OAS 1.
  3. 3. The use according to claim 1 or 2, characterized in that, The abnormal activation state of type I interferon signals is further characterized by an increased proportion of chemokine receptor positive T cells, Wherein the chemokine receptor is selected from at least one of CCR5, CCR6 and CXCR 3; and/or, the humanized IFNAR1 monoclonal antibody is anilurab (Anifrolumab) or an antibody fragment thereof having IFNAR1 antigen binding activity.
  4. 4. The use according to claim 1 to 3, characterized in that, The neuromyelitis optica lineage disease is an aquaporin 4 antibody positive neuromyelitis optica lineage disease.
  5. 5. The use according to any one of claims 1 to 4, characterized in that, The medicament is used for selectively inhibiting the migration of pathogenic T cells associated with neuromyelitis optica lineage diseases to the central nervous system.
  6. 6. The use according to claim 5, characterized in that, The pathogenic T cells comprise Th17 cells and/or Th1 cells, And said inhibition of migration is associated with reduced expression of CCR5, CCR6 and/or CXCR3 in said T cells.
  7. 7. A pharmaceutical composition comprising a humanized interferon receptor 1 (IFNAR 1) monoclonal antibody and a pharmaceutically acceptable carrier or excipient, Wherein the pharmaceutical composition is configured for modulating abnormal activation of type I interferon signaling associated with neuromyelitis optica spectrum disorders.
  8. 8. A pharmaceutical composition configured for modulating an abnormal activation state of type I interferon signaling associated with neuromyelitis optica spectrum disease; Characterized in that the pharmaceutical composition comprises: (1) An interferon receptor 1 (IFNAR 1) monoclonal antibody, and (2) B cell targeted immunomodulatory drugs.
  9. 9. A pharmaceutical kit, comprising: (a) A first container comprising a humanized interferon receptor 1 (IFNAR 1) monoclonal antibody, and (B) The instructions for use are provided in the description, Wherein the instructions for use indicate that the humanized IFNAR1 monoclonal antibody is useful for modulating abnormal activation of type I interferon signaling associated with neuromyelitis optica spectrum disease.
  10. 10. A targeted drug for the preparation of a medicament for the treatment of neuromyelitis optica spectrum diseases, said targeted drug comprising an antibody or antigen binding fragment thereof capable of specifically binding to interferon receptor 1 and having central nervous system targeted delivery capability; the targeted drug is a bispecific antibody, the bispecific antibody comprises: (a) An antibody domain that binds to interferon receptor 1, and (B) An antibody domain that binds to a transferrin receptor; The targeted drug is configured for modulating abnormal activation of type I interferon signaling associated with neuromyelitis optica spectrum diseases.

Description

Application of interferon receptor 1 monoclonal antibody in preparation of medicines for treating neuromyelitis Optica (OPYNAMIC) spectrum diseases and pharmaceutical composition Technical Field The invention relates to the technical field of biological medicines, in particular to application of an interferon receptor 1 monoclonal antibody in preparing a medicament for treating neuromyelitis optica (NMOSD) and a pharmaceutical composition thereof. Background The neuromyelitis optica (Neuromyelitis Optica Spectrum Disorders, NMOSD) is an autoimmune disease characterized by inflammation and demyelinating injury of the central nervous system, and is often manifested clinically as symptoms such as neuromyelitis optica, long-segment transverse myelitis. Studies have shown that autoantibodies against aquaporin 4 (Aquaporin-4, aqp 4) are present in most NMOSD patients and play an important role in the development and progression of the disease. Currently, clinical treatment of NMOSD relies mainly on broad spectrum immunosuppressive or immunomodulatory strategies, such as glucocorticoids, immunosuppressants, and biologicals targeting B cells or cytokines. Although the treatment means can alleviate disease activities to a certain extent, the problems of insufficient specificity of action targets, limited curative effect on partial patients, high safety risk in long-term use and the like are generally existed. Therefore, developing a more accurate therapeutic strategy for NMOSD immunopathology mechanism is still an important research direction in this field. In recent years, the role of type I interferon signaling pathways in autoimmune diseases has been of interest. Interferon Receptor 1 (Interferon Alpha/Beta Receptor 1, IFNAR 1) is a key component in the type I interferon signaling pathway, and its mediated signal transduction can trigger the expression change of various interferon-stimulated genes, so as to regulate the activation, migration and effector functions of immune cells. Zhang et al reported in ADVANCED SCIENCE that the type I interferon signaling pathway was responsible for neuromyelitis optica spectrum disorders, revealing that IFNAR 1-related signaling enhancement may promote NMOSD-related autoimmune responses, and through animal model and mechanism studies, that blocking this signaling pathway helps to reduce central nervous system inflammatory lesions. The document clarifies the pathogenic effect of IFNAR1 signals in NMOSD from the aspect of disease occurrence mechanism, and provides important theoretical basis for understanding the immunopathology of NMOSD. However, the above-mentioned researches are mainly focused on the explanation of the biological action and mechanism of the type I interferon signaling pathway in NMOSD, and have not yet involved the application of specific humanized IFNAR1 monoclonal antibodies in preparing medicines for treating diseases of neuromyelitis spectrum, and have not provided technical schemes for related pharmaceutical compositions, administration combinations or pharmaceutical kits, etc., which can be directly used for clinical transformation. Therefore, it is still necessary to further develop a technical scheme with definite drug forms and application modes based on the existing research so as to meet the actual requirements of treatment of neuromyelitis optica diseases. Disclosure of Invention The invention aims to provide a novel pharmaceutical application and related product form, which are used for relieving central nervous system inflammatory response related to diseases of the neuromyelitis optica spectrum through regulating and controlling immune signal pathways related to the diseases. In order to achieve the above purpose, the present invention proposes the following technical scheme: The invention provides an application of a humanized interferon receptor 1 (IFNAR 1) monoclonal antibody in preparing a medicament for treating neuromyelitis optica (NGS) spectrum diseases. The humanized IFNAR1 monoclonal antibodies modulate immune responses associated with neuromyelitis optica lineage disease by inhibiting activation of type I interferon signaling pathways, reducing abnormal expression of interferon-stimulated genes. In some embodiments, the humanized IFNAR1 monoclonal antibody may be selected from anilurumab (Anifrolumab) or an antibody fragment thereof having IFNAR1 antigen binding activity. In other embodiments, the medicament is suitable for patients with aquaporin 4 antibody positive neuromyelitis optica spectrum disorders. Furthermore, the technical scheme of the invention also relates to application of the humanized IFNAR1 monoclonal antibody in regulating and controlling immune cell functions, including inhibiting migration of pathogenic T cells to the central nervous system and inhibiting activation of B cells and antigen presentation functions. The pathogenic T cells may include Th17 cells and/or Th1 cells, the surfaces of which may express chem