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CN-121991210-A - Anti-Marburg virus humanized antibody A023 and application thereof

CN121991210ACN 121991210 ACN121991210 ACN 121991210ACN-121991210-A

Abstract

The invention discloses a Marburg virus-resistant humanized antibody A023 and application thereof. The nucleotide sequence of the heavy chain variable region of the Marv GP4 human antibody of the envelope glycoprotein of the Marv virus is shown as SEQ ID NO. 1, and the nucleotide sequence of the light chain variable region is shown as SEQ ID NO. 2. The humanized antibody can specifically recognize and bind MARV GP4, and can be used for diagnosis and treatment of Marburg virus MARV GP 4.

Inventors

  • CHEN ZHINAN
  • YANG XIANGMIN
  • LI LING
  • BIAN HUIJIE
  • ZHANG ZHENG
  • HUANG WAN

Assignees

  • 中国人民解放军空军军医大学

Dates

Publication Date
20260508
Application Date
20260205

Claims (7)

  1. 1. The anti-Marburg virus humanized antibody is characterized in that the antibody specifically binds to a MARV GP4 target molecule, and the nucleotide sequence of the MARV GP4 is shown as SEQ ID NO. 5 or the amino acid sequence of the MARV GP4 is shown as SEQ ID NO. 6.
  2. 2. The anti-marburg virus human antibody of claim 1, wherein the heavy chain variable region VH of the antibody has the complementarity determining regions HCDR1, HCDR2 and HCDR3 sequences GGTFSSYA, IIPILGIA and ARESYYYDSSGYYYYMDV, respectively; the sequences of the antigen complementarity determining regions LCDR1, LCDR2 and LCDR3 of the light chain variable region VL are QDIRRW, AAS and QQSNSFPLG, respectively.
  3. 3. The anti-marburg virus human antibody of claim 1, wherein the antibody specifically binds to MARV GP4 target molecule, the heavy chain variable region (VH) nucleotide sequence of the antibody is shown in SEQ ID No. 1 or the heavy chain variable region (VH) amino acid sequence is shown in SEQ ID No. 3; The nucleotide sequence of the light chain variable region (VL) is shown as SEQ ID NO. 2, or the amino acid sequence of the light chain variable region (VL) is shown as SEQ ID NO. 4.
  4. 4. The anti-marburg virus human antibody of claim 2 or 3, wherein the anti-MARV GP4 full length human antibody has a light chain (VL) constant region of kappa and a heavy chain (VH) constant region of IgG1.
  5. 5. Use of a human antibody against marburg virus according to any of claims 1-3 for the preparation of an anti-marburg virus medicament.
  6. 6. The use according to claim 5, wherein the medicament comprises a polypeptide medicament, an antibody conjugated medicament or a formulation for gene therapy.
  7. 7. Use of a human antibody against marburg virus according to any of claims 1-3 for the preparation of a diagnostic marburg virus kit.

Description

Anti-Marburg virus humanized antibody A023 and application thereof Technical Field The invention belongs to the technical field of antiviral infection treatment of novel antibody candidate medicines, and particularly relates to screening, identifying and preparing gene sequences of a Marburg virus (MARV) envelope glycoprotein 4 (GP 4) humanized antibody A023 and application of the Marburg virus candidate medicines in detection and treatment of Marburg virus diseases. Background Marburg virus (MARV, also known as green monkey virus), wherein the virion is polymorphic, branched or coiled, and coiled into U-shape, 6-shape or ring shape. The virus is a deadly virus, and is the first filovirus found in humans to cause Marburg hemorrhagic fever. The virus belongs to the family of filoviridae and is also derived from the same African Undaria and Kennel zone, and is a common disease [1,2] between human beings and other primates. Marburg virus is transmitted from animals to humans, but the source of the virus is not known. The highly pathogenic viral infection can cause Marburg virus disease (Marburg virus disease, MVD), and clinical characteristics include acute fever, bleeding tendency, multiple organ failure, etc., and the death rate can reach more than 50%. Since the first outbreak of germany and selveya in 1967, the malburg virus caused an epidemic a plurality of times in africa, and the high infectivity and rapid progress of the malburg virus constituted a serious threat to global public health. Marburg virus has become a global public threat [3] due to the severe symptoms and high mortality rate after onset. Marburg virus is a single-stranded negative-strand RNA virus whose genome encodes a variety of structural proteins, with glycoprotein GP being a critical surface protein for virus invasion into host cells, facilitating membrane fusion and cellular internalization processes by mediating binding of the virus to host receptors. The viral particles of the family filoviridae generally take on a filiform or rod-like morphology, the surface of which is enveloped by a lipid envelope, on which GP trimer spike proteins are embedded, these spikes playing a central role in the viral attachment and fusion process. Studies have shown that Marburg virus GP proteins can initiate viral invasion processes by interacting with receptor molecules on the surface of host cells (e.g., TIM-1 or AXL), with the GP4 subtype having important functions in viral pathogenicity and immune escape. Studies have shown that the structural proteins VP24, VP35, VP40, glycoprotein 4 (GP 4) of Marburg virus are all important proteins for virus assembly and infection function, wherein the surface of the Marv virus particle is covered with glycoprotein (Glycoprotein, GP), and GP4 is a key structural protein for virus invasion into host cells. GP4 may mediate binding of the virus to host cell receptors, promoting viral membrane fusion and invasion. Studies show that antibodies targeting GP4 can block the viral infection process, and have potential therapeutic value. Currently, no specific therapeutic drug is available for Marburg virus diseases, symptomatic treatment and supporting therapy are generally adopted, such as water, electrolyte and acid-base balance maintenance, blood coagulation function maintenance and the like, and development of a novel therapeutic strategy with strong targeting and high safety is needed for emergency prevention and treatment. The monoclonal antibody medicament has the advantages of high specificity, high affinity, small toxic and side effects, capability of mediating long-acting immune response and the like, and has broad prospect in the field of antiviral treatment. However, repeated injection of murine mcabs into humans can cause patients to elicit a response to human anti-murine antibodies (human anti mouse antibody, HAMA), develop systemic allergic and toxic responses and block the development of antibody efficacy. At present, the research and development of therapeutic antibodies against Marburg virus are still in an early stage, and few mouse-derived or chimeric antibodies have been reported to have a certain protection effect in animal models, but the clinical application of the antibodies still faces challenges of high immunogenicity, short half-life and the like [4,5]. Reference is made to: [1] A Asad, A Aamir, NE Qureshi, et al. Past and current advances in Marburg virus disease: a review. Infez Med, 2020, 28(3):332-345. [2] P Reynolds, A Marzi. Ebola and Marburg virus vaccines. Virus Genes, 2017, 53(4):501-515. [3] G Cuomo-Dannenburg, K McCain, R McCabe, et al. Marburg virus disease outbreaks, mathematical models, and disease parameters: a systematic review. Lancet Infect Dis, 2024, 24(5):e307-e317. [4] D Abelson, J Barajas, L Stuart, et al. Long-term Prophylaxis Against Aerosolized Marburg Virus in Nonhuman Primates With an Afucosylated Monoclonal Antibody. J Infect Dis, 2023, 228(Suppl 7):S701-S711. [5]