Search

CN-121971598-A - Antibody medicine for preventing and treating sepsis related encephalopathy and application thereof

CN121971598ACN 121971598 ACN121971598 ACN 121971598ACN-121971598-A

Abstract

The invention relates to an antibody medicine for preventing and treating sepsis-related encephalopathy and application thereof, wherein the complementarity determining regions of the variable regions of the heavy chain and the light chain of the antibody and the full-length amino acid sequences are definite. The incidence rate and death rate of sepsis related encephalopathy are high, the existing treatment means are limited, and the core pathogenesis of sepsis is related to blood brain barrier injury and neuroinflammation. The A-FABP antibody 6H2 is combined with A-FABP through high affinity, so that the integrity of blood brain barrier is protected, neuronal apoptosis is inhibited, the symptom of sepsis-related encephalopathy is obviously improved, a breakthrough solution from symptomatic treatment to symptomatic treatment is provided for the disease, and the kit has important clinical application value.

Inventors

  • YANG SHILUN
  • FANG CHENG
  • LI CHUNYAN
  • CHEN YUKUN
  • XU CHONGLIN

Assignees

  • 中国科学院深圳先进技术研究院

Dates

Publication Date
20260505
Application Date
20251222

Claims (10)

  1. 1. The use of an A-FABP antibody 6H2 for the preparation of a medicament for the prevention and/or treatment of sepsis-related encephalopathy (SAE) or for the amelioration of sepsis-related encephalopathy symptoms or conditions, Wherein the amino acid sequence of the complementarity determining region 1 of the variable region of the A-FABP antibody 6H2 is shown as SEQ ID No. 3, the amino acid sequence of the complementarity determining region 2 of the heavy chain is shown as SEQ ID No. 4, and the amino acid sequence of the complementarity determining region 3 of the heavy chain is shown as SEQ ID No. 5, and/or The amino acid sequence of the light chain variable region complementarity determining region 1 is shown in SEQ ID No. 6, the amino acid sequence of the light chain variable region complementarity determining region 2 is shown in SEQ ID No. 7, and the amino acid sequence of the light chain variable region complementarity determining region 3 is shown in SEQ ID No. 8.
  2. 2. The use according to claim 1, wherein the sepsis-related encephalopathy is a decrease in blood brain barrier integrity and neuronal apoptosis.
  3. 3. The use according to claim 1, wherein the sepsis-associated brain disease symptom is fluctuation of consciousness level, somnolence or agitation, cognitive dysfunction, disorientation, abnormal eye movement, gaze paralysis, pupil light reflex, nystagmus, abnormal breathing rhythm, central breathing disorder, autonomic nerve dysfunction, abnormal sweating, flushing of skin or pallidum.
  4. 4. The use according to claim 1, wherein a is The amino acid sequence of the heavy chain variable region of FABP antibody 6H2 is shown as SEQ ID NO. 9, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO. 10.
  5. 5. Use according to claim 1, characterized in that the amino acid sequence of the heavy chain is shown in SEQ ID No.1 and the amino acid sequence of the light chain is shown in SEQ ID No. 2.
  6. 6. A method of treatment of sepsis-associated brain disease comprising administering to a subject a therapeutically effective amount of an A-FABP antibody 6H2, wherein the amino acid sequence of the variable region complementarity determining region 1 of the A-FABP antibody 6H2 is shown in SEQ ID No. 3, the amino acid sequence of the heavy chain variable region complementarity determining region 2 is shown in SEQ ID No.4, and the amino acid sequence of the heavy chain variable region complementarity determining region 3 is shown in SEQ ID No. 5, and/or The amino acid sequence of the light chain variable region complementarity determining region 1 is shown in SEQ ID No. 6, the amino acid sequence of the light chain variable region complementarity determining region 2 is shown in SEQ ID No. 7, and the amino acid sequence of the light chain variable region complementarity determining region 3 is shown in SEQ ID No. 8.
  7. 7. The method of treatment of claim 6, wherein the sepsis-related encephalopathy symptom or condition is decreased blood brain barrier integrity and neuronal apoptosis.
  8. 8. The method of treatment of claim 6, wherein a The amino acid sequence of the heavy chain variable region of FABP antibody 6H2 is shown as SEQ ID NO. 9, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO. 10.
  9. 9. The method of claim 6, wherein the heavy chain has an amino acid sequence shown in SEQ ID NO.1 and the light chain has an amino acid sequence shown in SEQ ID NO. 2.
  10. 10. A pharmaceutical composition for preventing or treating sepsis-associated brain diseases, the pharmaceutical composition comprising a therapeutically effective amount of an A-FABP antibody 6H2, wherein the amino acid sequence of the variable region complementarity determining region 1 of the A-FABP antibody 6H2 is shown as SEQ ID No. 3, the amino acid sequence of the heavy chain variable region complementarity determining region 2 is shown as SEQ ID No. 4, and the amino acid sequence of the heavy chain variable region complementarity determining region 3 is shown as SEQ ID No. 5, and/or The amino acid sequence of the light chain variable region complementarity determining region 1 is shown in SEQ ID No. 6, the amino acid sequence of the light chain variable region complementarity determining region 2 is shown in SEQ ID No. 7, and the amino acid sequence of the light chain variable region complementarity determining region 3 is shown in SEQ ID No. 8.

Description

Antibody medicine for preventing and treating sepsis related encephalopathy and application thereof Technical Field The invention relates to the field of medicines, in particular to an antibody medicine for preventing and treating sepsis related encephalopathy and application thereof. Background Sepsis (sepsis) is a systemic excessive inflammatory response caused by infection, often leading to multiple organ failure, has become one of the leading causes of death worldwide. Sepsis-associated encephalopathy (SAE) is the most common and serious complication of sepsis, manifested by acute disturbance of consciousness and decline of cognitive function, with a severity positively correlated with mortality. Studies have shown that 30-day mortality rates for severe SAE patients are up to 60%, whereas in severe sepsis patients, the incidence of SAE can be up to 50% -70%. Long-term sequelae of SAE include persistent cognitive impairment, dementia and post-traumatic stress disorder, severely compromising the quality of life of the patient. The current clinical lack of specific treatment schemes for SAE mainly depends on systemic control and supportive treatment of sepsis, and cannot directly block pathological processes of central nervous system injury. The pathogenesis of SAE is not completely understood, but it is widely accepted in the academia that Blood Brain Barrier (BBB) damage and neuroinflammation are key links thereto. In systemic inflammatory conditions, a large number of inflammatory factors (e.g., TNF- α, IL-1β, IL-6, etc.) enter the central nervous system via the damaged BBB, activate immune cells such as microglia, exacerbate the inflammatory response in the brain, and ultimately lead to neuronal damage. At the same time, infection and inflammation directly destroy the integrity of brain microvascular endothelial cells, increase BBB permeability, and form malignant circulation. Therefore, developing a targeted therapeutic strategy capable of protecting the BBB and inhibiting neuroinflammation is an important direction to break through the SAE therapeutic bottleneck. The adipocyte type fatty acid binding protein (A-FABP, also called FABP4 or aP 2) is not only highly expressed in adipocytes, but also secreted by macrophages, and is a key fat factor for connecting metabolic disorders. A-FABP is reported to be a potential diagnosis target of sepsis, but no prior art discloses that the A-FABP can be used as a treatment target and a treatment scheme can treat sepsis-related encephalopathy. Neutralizing antibodies developed in the past (such as CA 33) showed metabolic improvement in a model of type 2 diabetes, but had limited affinity and no significant efficacy report in central nervous system diseases (such as cerebral apoplexy or SAE). It is speculated that it is difficult to effectively regulate BBB function under inflammatory conditions due to insufficient binding activity and function. CA33 has not entered clinical development, suggesting that existing antibody protocols are unable to meet therapeutic needs. Disclosure of Invention In order to solve the technical bottleneck, the invention provides a novel anti-A-FABP monoclonal antibody 6H2 which provides a novel solution for SAE targeted therapy. The invention provides an application of A-FABP antibody 6H2 in preparing a medicament for preventing and/or treating sepsis related encephalopathy (SAE) or improving sepsis related encephalopathy symptoms or symptoms, Wherein the amino acid sequence of the complementarity determining region 1 of the variable region of the A-FABP antibody 6H2 is shown as SEQ ID No. 3, the amino acid sequence of the complementarity determining region 2 of the heavy chain is shown as SEQ ID No. 4, and the amino acid sequence of the complementarity determining region 3 of the heavy chain is shown as SEQ ID No. 5, and/or The amino acid sequence of the light chain variable region complementarity determining region 1 is shown in SEQ ID No. 6, the amino acid sequence of the light chain variable region complementarity determining region 2 is shown in SEQ ID No. 7, and the amino acid sequence of the light chain variable region complementarity determining region 3 is shown in SEQ ID No. 8. Further, the sepsis-related encephalopathy is decreased blood brain barrier integrity and neuronal apoptosis. Further, the sepsis-associated brain disease symptoms are fluctuation of consciousness level, somnolence or agitation, cognitive dysfunction, disorientation, abnormal eye movement, gaze paralysis, retarded pupil light reflex, nystagmus, abnormal respiratory rhythm, central respiratory disorder, autonomic nerve dysfunction, abnormal sweating, flushing of skin, or pale. Further, the sepsis-related brain disease is an acute central nervous system complication caused by sepsis. Further, the AThe amino acid sequence of the heavy chain variable region of FABP antibody 6H2 is shown as SEQ ID NO. 9, and the amino acid sequence of the light chain variab